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XLS - California Institute for Regenerative Medicine

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XLS - California Institute for Regenerative Medicine Powered By Docstoc
					Reference number                     Institution                      Researcher name




TR1-01267          Sanford-Burnham Medical Research Institute   Evan Snyder




DT1-00704-1        Sanford-Burnham Medical Research Institute   Mark Mercola
RS1-00302-1   Scripps Research Institute               Peter Schultz




DT1-00656-1   University of California San Francisco   Jeffrey Lotz
DT1-00652-1   University of California San Francisco   Jeffrey Bluestone
DR2-05410   University of Southern California   Roberta Brinton
TR2-01841   University of California Irvine   Leslie Thompson
RS1-00174-1   The Salk Institute for Biological Studies   Senyon Choe
DR2-05365     Stanford University               Judith Shizuru




RT1-01120-1   University of California Irvine   Orhan Nalcioglu
DR2-05352   OncoMed Pharmaceuticals Inc   Timothy Hoey
DR2-05352     OncoMed Pharmaceuticals Inc       Timothy Hoey




RN1-00566-1   University of California Irvine   Andrew Putnam
RN2-00945-1   University of California San Diego   Shyni Varghese
RT1-01027-1   Gamma Medica-Ideas Inc.              Douglas Wagenaar




CL1-00508-1   University of California Riverside   Prudence Talbot
TR1-01276   BioTime Inc.   Michael West
DR2-05298   University of California Davis   Martin Birchall
RC1-00359-1   University of California Davis               Mark Zern




RS1-00466-1   Sanford-Burnham Medical Research Institute   Alexey Terskikh
RT2-02060   Stanford University   Irving Weissman
RT1-01095-1   University of California Santa Cruz   Joel Kubby
RM1-01710   Palo Alto Institute for Research and Education   Husein Hadeiba
RS1-00199-1   University of California Santa Cruz   David Feldheim
DR1-01461   Cedars-Sinai Medical Center   Eduardo Marban
TR1-01219   Scripps Research Institute   Martin Friedlander
TR2-01856     Buck Institute for Age Research   Xianmin Zeng




RN1-00535-1   Stanford University               Karl Deisseroth
RB3-02266   University of California San Diego   Charles King
TR2-01787   University of California Davis   Roslyn (Rivkah) Isseroff
TB1-01192   Pasadena City College   Pamela Eversole-Cire
RN2-00921-1   University of California Merced   Kara McCloskey
T2-00004   Sanford-Burnham Medical Research Institute   Mark Mercola
TB1-01176   California State Polytechnic University Pomona   Jill Adler-Moore
TB1-01186   California State University San Marcos   Bianca Mothe
TR2-01829   Scripps Research Institute   Peter Schultz
DT1-00698-1   Cedars-Sinai Medical Center   Eduardo Marban
DR1-01423     ViaCyte Inc.                           Emmanuel Baetge




RS1-00245-1   University of California Los Angeles   Siavash Kurdistani
RB2-01628   iPierian Inc.         Berta Strulovici




RT2-02061   Stanford University   Marius Wernig
RB3-05086   University of California Los Angeles   Robb MacLellan
RB3-05086   University of California Los Angeles   Robb MacLellan
RN1-00544-1   The Salk Institute for Biological Studies    Leanne Jones




RC1-00132-1   Sanford-Burnham Medical Research Institute   Mark Mercola
TG2-01168   Children's Hospital of Los Angeles   David Warburton
TC1-05946     Children's Hospital of Oakland Research Institute Vasanthy Narayanaswami




FA1-00600-1   Buck Institute for Age Research
DT1-00697-1   Children's Hospital of Oakland Research Institute Mark Walters




FA1-00614-1   University of California Merced
FA1-00607-1   Sanford Consortium for Regenerative Medicine
FA1-00610-1   University of California Berkeley
FA1-00611-1   University of California Davis
FA1-00612-1   University of California Irvine
FA1-00613-1   University of California Los Angeles
FA1-00617-1   University of California Santa Cruz
FA1-00618-1   University of California San Francisco




FA1-00619-1   University of Southern California
DT1-00709-1   University of California San Diego   Dennis Carson
TG2-01155   Buck Institute for Age Research   David Greenberg
CL1-00505-1   University of California Los Angeles   Scott Waugh




TC1-06302     University of Southern California      Roberta Brinton
T1-00004    University of Southern California   Robert Maxson




TG2-01161   University of Southern California   Robert Maxson
TB1-01182   California State University Long Beach   Lisa Klig
T1-00005   University of California Los Angeles   Owen Witte
TB1-01188   City College Of San Francisco   Carin Zimmerman
TG2-01150   The City Of Hope   Michael Barish
DR2-05368   Wintherix LLC   John Hood
DT1-00653-1   University of Southern California            David Woodley




CL1-00511-1   Sanford-Burnham Medical Research Institute   Mark Mercola
DR2-05426   University of California Los Angeles   Stanley Nelson
RN1-00561-1   University of California Davis       Chong-xian Pan




RS1-00173-1   University of California San Diego   Shu Chien
RC1-00113-1   University of California San Francisco   Susan Fisher
RB3-02209   Stanford University   Renee Reijo Pera




TC1-06227   The City Of Hope      Paul Salvaterra
TR2-01778   The Salk Institute for Biological Studies   Fred Gage




TB1-01183   California State University Northridge      Randy Cohen
TB1-01185   California State University San Bernardino   Nicole Bournias-Vardiabasis
TR1-01273   The Salk Institute for Biological Studies   Inder Verma
TB1-01177   California State University Channel Islands   Ching-Hua Wang
RN2-00952-1   The J. David Gladstone Institutes   Yadong Huang




RB1-01353     University of Southern California   Wange Lu
RL1-00662-1   Stanford University   Michael Longaker
RS1-00228-1   University of California San Diego   Catriona Jamieson
RS1-00455-1   University of California Irvine      Kyoko Yokomori




RN2-00910-1   University of California San Diego   Catriona Jamieson
RL1-00670-1   Stanford University   Renee Reijo Pera
RL1-00630-1   Stanford University                      Julie Baker

RC1-00346-1   University of California San Francisco   Arnold Kriegstein
RL1-00642-1   Scripps Research Institute   Sheng Ding
RL1-00682-1   Sanford-Burnham Medical Research Institute   Zhuohua Zhang
DT1-00688-1   Buck Institute for Age Research   Xiamin Zeng
TR2-01814   University of California San Diego   Alysson Muotri
RT2-01927   University of California San Diego   Lawrence Goldstein
LA1-05735   University of California Berkeley   Zhigang He
TR2-01832   The City Of Hope   Yanhong Shi
TR1-01277   University of California San Diego   Yang Xu
RT2-02052   Fluidigm Corporation   Marc Unger
RT2-01975   University of California San Francisco   Daniel Lim
DT1-00672-1   ViaCyte Inc.   Emmanuel Baetge
RT2-01881     University of California Los Angeles   Stanley Carmichael




RT1-01103-1   Scripps Research Institute             Carlos Barbas
DT1-00669-1   University of California Los Angeles   Stanley Carmichael
TR1-01272     University of California Los Angeles   Gabriel Travis




RT1-01012-1   VistaGen Therapeutics Inc.             Kristina Bonham
RM1-01711     Escape Therapeutics Inc             Basil Hantash




RT1-01028-1   University of Southern California   Pin Wang
LA1-02086   University of California Santa Barbara   Peter Coffey




DR1-01430   University of California San Diego       Dennis Carson
RS1-00247-1   University of California Irvine             Frank LaFerla




RL1-00649-1   The Salk Institute for Biological Studies   Fred Gage
RS1-00171-1   Sanford-Burnham Medical Research Institute   Huei-sheng Chen
TR2-01771   The City Of Hope      David DiGiusto




RT2-02018   Stanford University   Brian Rutt
RT2-01906   Stanford University   Ricardo Dolmetsch
RT1-01057-1   The City Of Hope   Larry Couture
RT2-01889   University of California San Diego   Shu Chien
RT1-01093-1   ViaCyte Inc.   Evert Kroon
DR1-01485   Stanford University   Irving Weissman
RB2-01567   University of California Davis   Eric Kurzrock
RS1-00243-1   Stanford University   Calvin Kuo
RT1-01021-1   University of California Berkeley   David Schaffer
RB1-01417   University of California Davis   Min Zhao
RS1-00169-1   Human BioMolecular Research Institute   John Cashman
RT1-01097-1   University of California Davis   Kit Lam
RB3-05080   University of California Los Angeles   Kathrin Plath
RB3-05080   University of California Los Angeles   Kathrin Plath
RM1-01724     University of California Davis         William Murphy




RS1-00402-1   University of California Los Angeles   Noriyuki Kasahara
DR2-05423   University of California Davis   John Laird
TR2-01816   Children's Hospital of Los Angeles   Markus Muschen
RS1-00183-1   Stanford University         John Cooke




RT2-01965     The Parkinson's Institute   J. William Langston
RB3-05129   Stanford University   Joseph Wu
RC1-00124-1   University of California San Francisco   Randall Lee
RS1-00321-1   Stanford University   Kenneth Weinberg
DR1-01480     Stanford University                      Gary Steinberg




RS1-00308-1   University of California San Francisco   Didier Stainier
RB2-01512   Sanford-Burnham Medical Research Institute   Huei-sheng Chen
RM1-01739   Stanford University   Kenneth Weinberg
RC1-00151-1   Stanford University   Christopher Zarins
RT2-02022   University of California Berkeley   David Schaffer
RM1-01706   Stanford University                    Christopher Contag




RM1-01707   University of California Los Angeles   Gay Crooks
RB3-05100     Stanford University                  Joanna Wysocka




CL1-00522-1   University of California San Diego   Karl Willert
TR1-01249   Stanford University   Michael Longaker
RN1-00554-1   University of California Merced   Jennifer Manilay




TR1-01250     Scripps Research Institute        Jeanne Loring
RC1-00111-1   University of California Los Angeles   Guoping Fan
RN1-00550-1   University of California Los Angeles   Siavash Kurdistani
RN1-00538-1   University of California Riverside   Douglas Ethell
RL1-00650-1   The J. David Gladstone Institutes   Fen-Biao Gao
RB3-02165   University of California Los Angeles   Shuo Lin
CT1-05168   Geron Corporation   Jane Lebkowski
RS1-00449-1   University of California San Francisco   Valerie Weaver
RB3-05217   University of California Los Angeles   Gay Crooks
RB3-05083     University of California San Diego   Kun Zhang




RC1-00100-1   Stanford University                  Julie Baker
RS1-00298-1   Stanford University                         Julien Sage


RS1-00288-1   The Salk Institute for Biological Studies   Samuel Pfaff
RN1-00584-1   Scripps Research Institute   Kristin Baldwin
RB3-02143   University of California San Diego   Binhai Zheng
RL1-00681-1   University of California Los Angeles   Jerome Zack
RT1-01107-1   University of California San Diego   Ying Liu
RS1-00205-1   University of California San Diego   Anirvan Ghosh
RC1-00119-1   Stanford University                  Stefan Heller




RS1-00280-1   University of California San Diego   Cornelius Murre
RL1-00636-1   University of California Los Angeles   Amander Clark
RM1-01729   La Jolla Institute for Allergy and Immunology   Anjana Rao
RN1-00575-1   University of California San Diego   David Traver
RN1-00577-1   The Salk Institute for Biological Studies   Lei Wang




RS1-00203-1   University of California Los Angeles        Zoran Galic
RS1-00333-1   University of California San Diego     Binhai Zheng




RS1-00172-1   University of California Los Angeles   Irvin Chen
DR2-05309   University of California Los Angeles   Antoni Ribas
DR2-05288:   Cedars-Sinai Medical Center   Dan Gazit
DT1-00708-1   The City Of Hope   Michael Barish
RB3-05020   University of California San Francisco   John Murnane




T2-00003    The J. David Gladstone Institutes        Robert Mahley
TG2-01160   The J. David Gladstone Institutes   Robert Mahley
TC1-06252     The J. David Gladstone Institutes   Shannon Noonan




RC1-00133-1   Stanford University                 Roeland Nusse
RS1-00453-1   University of California Davis   Ebenezer Yamoah
TR2-01821     University of California Los Angeles   Bruno Peault




RS1-00249-1   Children's Hospital of Los Angeles     Elizabeth Lawlor
RC1-00345-1   University of California Irvine   Hans Keirstead
DR2-05272     Sanford-Burnham Medical Research Institute   Stuart Lipton




RS1-00464-1   University of California Davis               Hari Reddi
RN2-00919-1   University of California San Francisco   Jeremy Reiter
RT2-02064   University of California San Diego     Karl Willert




DR1-01431   University of California Los Angeles   Irvin Chen
RB1-01354     University of California Los Angeles     Robb MacLellan




RS1-00207-1   University of California San Francisco   Linda Giudice
RC1-00149-1   University of California Los Angeles   Jerome Zack




DR2-05394     Stanford University                    Robert Robbins
RS1-00409-1   University of California Irvine     Thomas Lane




RM1-01732     University of California Berkeley   Ellen Robey
RC1-00137-1   Stanford University   Renee Reijo Pera
TR2-01794     University of California Irvine      Henry Klassen




DT1-00675-1   University of California San Diego   Larry Goldstein
RC1-00135-1   University of California San Francisco   Samuel Pleasure

T1-00007      University of California Berkeley        Randy Schekman
DT1-00700-1   University of California Irvine   Leslie Thompson
RB1-01358   Stanford University   Susan McConnell
RN1-00532-1   University of California Berkeley        Irina Conboy




RS1-00215-1   University of California San Francisco   Su Guo
RB3-02186     Scripps Research Institute   Kristin Baldwin




RC1-00134-1   Stanford University          Theo Palmer
RC1-00110-1   University of California Irvine        Peter Donovan




RS1-00420-1   University of California Los Angeles   Hanna Mikkola




TR1-01269     University of California Davis         Alice Tarantal
RS1-00170-1   University of California Santa Cruz   Bin Chen
RS1-00295-1   University of California Berkeley      Ellen Robey




RN1-00564-1   University of California Los Angeles   Kathrin Plath
RT1-01019-1   University of California Davis   Alice Tarantal




RS1-00322-1   Stanford University              Joseph Wu
RS1-00326-1   Stanford University   Philip Yang
RM1-01730   University of California Berkeley   David Raulet
DR2-05302   University of California Davis   Nancy Lane
RL1-00639-1   The J. David Gladstone Institutes   Bruce Conklin
RB3-05232     University of California Berkeley   Song Li




RN2-00903-1   The J. David Gladstone Institutes   Benoit Bruneau
RM1-01720   University of California San Diego   Martin Marsala
RM1-01743     University of California San Diego       Yang Xu




RS1-00452-1   University of California San Francisco   Holger Willenbring
RL1-00660-1   University of California San Francisco   Long-Cheng Li




TR2-01749     University of California San Francisco   Arturo Alvarez-Buylla
T1-00003   University of California San Diego   Larry Goldstein
TG2-01154   University of California San Diego   Larry Goldstein
TG2-01164   University of California Berkeley   Ellen Robey
TC1-06070   University of California Davis   Gerhard Bauer
RB3-05229   University of California San Diego   Anirvan Ghosh
DR1-01454   Stanford University   Alfred Lane
RB2-01592     Stanford University                      Garry Nolan




RS1-00381-1   University of California San Francisco   Heike Daldrup-Link
RN2-00933-1   University of California San Francisco   Ophir Klein




TR2-01857     University of California Davis           Mark Zern
RT1-01055-1   University of California Berkeley   Steven Conolly
RT2-01893   University of California Berkeley   Steven Conolly
RS1-00292-1   Ludwig Institute for Cancer Research   Bing Ren
            California Polytechnic State University San Luis
TB1-01175   Obispo                                             Daniel Walsh
RM1-01718   University of California San Francisco   Tippi MacKenzie
RB2-01553   Stanford University                 Aaron Hsueh




TR1-01227   The J. David Gladstone Institutes   Warner Greene
RN2-00946-1   Children's Hospital of Los Angeles   Tracy Grikscheit
RN2-00915-1   University of California Irvine   Edwin Monuki
RN2-00905-1   Ludwig Institute for Cancer Research   Bing Ren
RB3-05174     The J. David Gladstone Institutes      Deepak Srivastava




RN1-00557-1   University of California Los Angeles   Hanna Mikkola
RN2-00906-1   University of California San Francisco   Robert Blelloch




RN1-00540-1   University of California Santa Cruz      Camilla Forsberg
RC1-00148-1   University of California San Diego   Yang Xu
RN2-00938-1   University of Southern California   Qilong Ying
RN2-00934-1   University of California San Francisco       Emmanuelle Passegue




RC1-00125-1   Sanford-Burnham Medical Research Institute   Stuart Lipton
TR1-01215   ViaCyte Inc.                             Justine Cunningham




RB2-01602   University of California San Francisco   John Rubenstein
RT1-01022-1   University of California Los Angeles   Hsian-Rong Tseng
RC1-00142-1   The J. David Gladstone Institutes   Deepak Srivastava
RS1-00161-1   University of California San Francisco   Robert Blelloch
RS1-00462-1   The J. David Gladstone Institutes   Fen-Biao Gao




RS1-00239-1   University of California Merced     Michelle Khine
RS1-00432-1   University of California Irvine        Vincent Procaccio




RB1-01397     University of California Los Angeles   Michael Teitell
RS1-00259-1   University of California Los Angeles         William Lowry




RC1-00104-1   University of California San Francisco       Harold Bernstein

RS1-00331-1   Sanford-Burnham Medical Research Institute   Zhuohua Zhang
RC1-00115-1   The Salk Institute for Biological Studies   Fred Gage




RB3-02098     University of California San Diego          David Cheresh
RB1-01328   University of California Los Angeles   Luisa Iruela-Arispe
RB2-01530   The Salk Institute for Biological Studies   Ronald Evans
RB1-01367   University of California Los Angeles   Bennett Novitch
RB3-05207   University of California Los Angeles   William Lowry
RN2-00950-1   University of California San Francisco   Holger Willenbring
RN2-00922-1   University of California Davis   Paul Knoepfler




RN1-00527-1   Stanford University              Anne Brunet
RN1-00530-1   University of California Santa Cruz   Bin Chen
RB1-01292     Stanford University                  Helen Blau




RN2-00931-1   University of California San Diego   Mana Parast
RB3-05103   University of California San Diego   Farah Sheikh
DT1-00659-1   The Salk Institute for Biological Studies   Samuel Pfaff
TR1-01232   The Jackson Laboratory West   Leon Hall
DR2-05415   University of California Davis   Vicki Wheelock
DR2-05415   University of California Davis   Vicki Wheelock
RB3-05009   University of California San Diego   Eugene Yeo
TR2-01767   University of California Irvine   Brian Cummings
DR2-05431   Sanford-Burnham Medical Research Institute   Marcel Daadi
TR1-01245   University of California Irvine   Frank LaFerla
DR2-05416   StemCells Inc.   Alexandra Capela
RL1-00678-1   University of California Irvine   Leslie Thompson
RS1-00225-1   Sanford-Burnham Medical Research Institute   Ziwei Huang
TR2-01844   iPierian Inc.   Michael Venuti
RL1-00667-1   University of Southern California    Martin Pera




RS1-00477-1   University of California Riverside   Frank Sauer
RN1-00529-1   Stanford University               Howard Chang




CL1-00501-1   Buck Institute for Age Research   Xiamin Zeng
RB2-01562   University of California Los Angeles   Yong Kim
RT1-01074-1   University of California Irvine        Lisa Flanagan




RT1-01126-1   University of California Los Angeles   Michael Phelps
RS1-00236-1   Stanford University   Mark Kay
RT1-01143-1   Vala Sciences Inc.   Patrick McDonough
RS1-00271-1   Stanford University   Susan McConnell
RL1-00648-1   University of California San Francisco   Susan Fisher
RN1-00572-1   University of Southern California   Songtao Shi
RS1-00404-1   Stanford University                      Aaron Hsueh




RB3-05041     University of California San Francisco   Harold Bernstein
RT2-01985   University of California Los Angeles   Martin Gabriel Martin
DT1-00671-1   The J. David Gladstone Institutes   Deepak Srivastava
DR2-05434   Geron Corporation   Jane Lebkowski
TR2-01789   University of California San Diego   Catriona Jamieson
RC1-00144-1   University of California Davis   Alice Tarantal




RT2-01938     Stanford University              Sarah Heilshorn
RS1-00416-1   University of California Irvine     Grant MacGregor




RS1-00365-1   University of California Berkeley   Carolyn Bertozzi
RS1-00163-1   Buck Institute for Age Research   Dale Bredesen
RB2-01502   University of California Los Angeles   Douglas Black
RC1-00354-1   Stanford University   Irving Weissman
RL1-00644-1   University of California San Diego   Steven Dowdy
RM1-01733   Stanford University   Judith Shizuru
DR2-05373   Stanford University   Albert Wong
TR2-01768   University of California Los Angeles   Sophie Deng
RC1-00108-1   Children's Hospital of Los Angeles   Gay Crooks
RN2-00908-1   University of California San Diego   Benjamin Yu


RS1-00262-1   University of Southern California    Wange Lu
RS1-00195-1   The Salk Institute for Biological Studies   Beverly Emerson




RT1-01001-1   Stanford University                         Helen Blau
RM1-01725   Stanford University   Robert Negrin
TR2-01785   University of California Los Angeles   Leif Havton
RS1-00319-1   Stanford University   Thomas Wandless
RN1-00536-1   Scripps Research Institute   Sheng Ding
TC1-05787   University of California Santa Barbara   Miriam Fuller
RS1-00193-1   Sanford-Burnham Medical Research Institute   Gregg Duester
RT1-01052-1   University of California Merced   Michael Cleary
RB1-01413   University of California San Diego   Gene Yeo
RT2-01942     GMR Epigenetics       Jifan Hu




RS1-00323-1   Stanford University   Joanna Wysocka
RS1-00200-1   Sanford-Burnham Medical Research Institute   Hudson Freeze




RS1-00317-1   The J. David Gladstone Institutes            Eric Verdin
RM1-01735   Cedars-Sinai Medical Center   Terrence Town
RM1-01709   Scripps Research Institute   Nicholas Gascoigne
RS1-00313-1   University of California Los Angeles   Michael Teitell
RB2-01496     University of California Irvine          Aileen Anderson




RS1-00444-1   University of California San Francisco   Thea Tlsty
RB2-01645   University of California San Diego   Dong-Er Zhang
RL1-00634-1   Stanford University   Michele Calos
TB1-01195   San Jose State University   John Boothby
RT1-01024-1   Fluidigm Corporation                Marc Unger




RS1-00408-1   University of Southern California   Peter Laird
TB1-01193   San Diego State University   Christopher Glembotski
RB2-01497     Stanford University                 Steven Artandi




RS1-00327-1   University of Southern California   Qilong Ying
TB1-01194     San Francisco State University              Carmen Domingo




CL1-00500-1   The Salk Institute for Biological Studies   Inder Verma
TC1-05868   Stanford University   Paul. J. Utz




RT2-01880   Stanford University   Michele Calos
RN1-00525-1   The City Of Hope                    Tiziano Barberi




RN2-00916-1   University of Southern California   Gage Crump
RL1-00669-1   University of California San Francisco   Miguel Ramalho-Santos
RS1-00428-1   The City Of Hope   Timothy O'Connor
TB1-01197     Berkeley City College                Barbara Des Rochers




RS1-00198-1   University of California San Diego   Sylvia Evans
RC1-00131-1   University of California San Diego   Martin Marsala
DT1-00710-1   Stanford University   Robert Robbins
TG2-01159   Stanford University   Michael Longaker
T1-00001   Stanford University   Michael Longaker
FA1-00609-1   Stanford University
DT1-00657-1   University of Southern California   Mark Humayun




DR1-01444     University of Southern California   Mark Humayun
RM1-01702   University of California San Francisco   Mark Anderson
DR2-05327   University of California Davis   Mehrdad Abedi
DR2-05327     University of California Davis       Mehrdad Abedi




DT1-00701-1   Children's Hospital of Los Angeles   Donald Kohn
DR1-01452   University of California Los Angeles   Donald Kohn
T1-00006   University of California Davis   Frederick Meyers
T1-00008    University of California Irvine   Peter Bryant




TC1-05956   Scripps Research Institute        James Williamson
RS1-00289-1   University of California Riverside     Michael Pirrung




DT1-00683-1   University of California Los Angeles   Irvin Chen
TR2-01756     Stanford University   Michele Calos




DT1-00674-1   Stanford University   Thomas Rando
RM1-01703   University of California San Francisco   Jeffrey Bluestone
TB1-01181   California State University Fullerton   Nilay Patel
TR2-01791   University of California Los Angeles   Noriyuki Kasahara




TR1-01216   Scripps Health                         Darryl D'Lima
DR1-01471   University of California San Diego       Larry Goldstein




DR1-01426   University of California San Francisco   Mitchel Berger
DT1-00696-1   Ludwig Institute for Cancer Research   Webster Cavenee
DR1-01421   The City Of Hope   Karen Aboody
RN2-00902-1   University of California Los Angeles   Antoni Ribas




DT1-00690-1   University of California Irvine        Henry Klassen
RN2-00904-1   University of California Los Angeles   Brigitte Gomperts
DR2-05320   Cedars-Sinai Medical Center   Clive Svendsen
TB1-01184   California State University Sacramento   Laurel Heffernan
RB3-02129   University of California Los Angeles   Yi Sun
TR1-01257     University of California Davis           Jan Nolta




RT1-01053-1   University of California Santa Barbara   Dennis Clegg
TR2-01780   Cedars-Sinai Medical Center                      Dan Gazit




RB2-01637   Palo Alto Institute for Research and Education   Tony Wyss-Coray
RT1-01063-1   University of California San Diego   Steven Dowdy




RB2-01629     University of California Irvine      Marian Waterman
RS1-00242-1   Stanford University                 Krishna Shenoy




RS1-00210-1   The J. David Gladstone Institutes   Warner Greene
CL1-00519-1   University of California Berkeley   David Schaffer
CL1-00507-1   Children's Hospital of Los Angeles   Carolyn Lutzko


RC1-00353-1   University of California Irvine      Douglas Wallace
RB2-01571   University of California Los Angeles   Benhur Lee
RB2-01547   University of California San Diego   Kun-Liang Guan
CL1-00514-1   The J. David Gladstone Institutes   Deepak Srivastava




TB1-01190     Humboldt State University           Jacob Varkey
RS1-00377-1   University of California Irvine   Brian Cummings
RN2-00940-1   San Diego State University   Ricardo Zayas




RB1-01385     Stanford University          Julien Sage
LA1-01747   Sanford-Burnham Medical Research Institute   Robert Wechsler-Reya
RN2-00923-1   University of California Berkeley   Lin He




CL1-00518-1   Stanford University                 Renee Reijo Pera
RT1-01108-1   Scripps Research Institute   Jeanne Loring
RB1-01372   University of Southern California   Martin Pera
CL1-00521-1   University of California Santa Barbara   Dennis Clegg




CL1-00523-1   University of California San Francisco   Linda Giudice
CL1-00520-1   University of California Irvine        Peter Donovan




DR1-01477     University of California Los Angeles   Dennis Slamon
RS1-00222-1   University of Southern California   David Hinton




RM1-01717     Scripps Research Institute          Jeanne Loring
T2-00005   Children's Hospital of Los Angeles   Donald Kohn




T2-00001   Scripps Research Institute           Peter Schultz
T1-00002   University of California San Francisco   Susan Fisher




T2-00006   California Institute of Technology       Paul Patterson
TG2-01158   The Salk Institute for Biological Studies   Juan Carlos Belmonte
T3-00007   The Salk Institute for Biological Studies   Juan Carlos Izpisua Belmonte
TG2-01151   University of California Santa Barbara   Dennis Clegg
TG2-01153   University of California San Francisco   Susan Fisher


T3-00006    University of California Santa Cruz      David Haussler
TG2-01165   Scripps Research Institute   Ulrich Mueller
RN1-00562-1   University of Southern California   Mohammad Pashmforoush
RS1-00434-1   University of California San Francisco   Miguel Ramalho-Santos
RT2-02057   Gamma Medica-Ideas Inc.      Douglas Wagenaar




RB3-05022   Scripps Research Institute   Joel Gottesfeld
RN1-00579-1   Stanford University                          Joanna Wysocka




RS1-00283-1   Sanford-Burnham Medical Research Institute   Robert Oshima
CL1-00502-1   Scripps Research Institute   Sheng Ding
TG2-01162   Sanford-Burnham Medical Research Institute   Mark Mercola
RB3-02222   University of California Berkeley   Michael Rape
TG2-01163   University of California Davis   Frederick Meyers
CL1-00504-1   University of California Davis   Alice Tarantal
FA1-00616-1   University of California Santa Barbara




TG2-01152     University of California Irvine          Peter Donovan
TG2-01169   University of California Los Angeles   Owen Witte
T3-00009   University of California Santa Barbara   Dennis Clegg
TG2-01157     University of California Santa Cruz   David Haussler




CL1-00506-1   University of California Santa Cruz   Lindsay Hinck
TC1-05961     University of California San Francisco   Katherine Nielsen




RC1-00347-1   University of California San Francisco   Andrew Leavitt
RB3-02221     The Parkinson's Institute           R. Jeremy Nichols




CL1-00524-1   University of Southern California   Martin Pera
RT2-01920   University of California Los Angeles   Richard Gatti
RB3-02161   The City Of Hope   Jiing-Kuan Yee
RT2-02040     Cedars-Sinai Medical Center       Clive Svendsen




RS1-00413-1   University of California Irvine   Charles Limoli
RC1-00116-1   University of California San Diego   Larry Goldstein
TR1-01246   The Parkinson's Institute   J. William Langston
RB3-05066   Stanford University   Michael Clarke
RN2-00909-1   Stanford University   Ching-Pin Chang
RB3-05219   University of California San Diego   Deborah Spector
RB1-01406   University of California San Diego   Karl Willert
DR1-01490   The City Of Hope   John Zaia
           Grant Type                       Grant Title




                        'Developmental Candidates' for Cell-Based
Early Translational     Therapies for Parkinson's Disease (PD)




Disease Team Planning   'Stem Cell Therapies for Heart Failure'
SEED                    A Chemical Approach to Stem Cell Biology




                        A CIRM Disease Team for the Repair of
Disease Team Planning   Traumatically Injured and Arthritic Cartilage
                        A CIRM Disease Team for the Treatment and Cure
Disease Team Planning   of Diabetes
                           A CIRM Disease Team to Develop
                           Allopregnanolone for Prevention and Treatment
Disease Team Planning II   of Alzheimer's Disease
                         A hESc-based Development Candidate for
Early Translational II   Huntington's Disease
       A method to maintain and propagate pluripotent
SEED   human ES cells
                           A monoclonal antibody that depletes blood stem
Disease Team Planning II   cells and enables chemotherapy free transplants




                           A MULTI-MODALITY MOLECULAR IMAGING
                           SYSTEM (MRSPECT) FOR IN VIVO STEM CELL
Tools & Technology         TRACKING
                           A New Cancer Therapeutic to Reduce CSC
Disease Team Planning II   Frequency
                           A New Cancer Therapeutic to Reduce CSC
Disease Team Planning II   Frequency




                           A Novel Engineered Niche to Explore the
New Faculty I              Vasculogenic Potential of Embryonic Stem Cells
                 A Novel Microenvironment-Mediated Functional
                 Skeletal Muscle from Human Embryonic Stem
New Faculty II   Cells and their In Vivo Engraftment
                     A Novel SPECT Microscopy System for 3D Imaging
Tools & Technology   of Single Stem Cells In Vivo




                     A Stem Cell Core Facility for Studying Human
Shared Labs          Embryonic Stem Cell Differentiation
                      Addressing the Cell Purity and Identity Bottleneck
                      Through Generation and Expansion of Clonal
Early Translational   Human Embryonic Progenitor Cell Lines
Disease Team Planning II   Airways for Children
                An in vitro and in vivo comparison among three
Comprehensive   different human hepatic stem cell populations.




                Analysis of Candidate Neural Crest Cells Derived
SEED            from Human ES Cells
                        Antibody tools to deplete or isolate teratogenic,
Tools & Technology II   cardiac, and blood stem cells from hESCs
Tools & Technology   AO Wide-Field Microscope
                             Application of Tolerogenic Dendritic Cells for
Transplantation Immunology   Hematopoietic Stem Cell Transplantation
       Assessing the role of Eph/ephrin signaling in hESC
SEED   growth and differentiation
               Autologous cardiac-derived cells for advanced
Disease Team   ischemic cardiomyopathy
                      Autologous Retinal Pigmented Epithelial Cells
                      Derived from Induced Pluripotent Stem Cells for
                      the Treatment of Atrophic Age Related Macular
Early Translational   Degeneration
                         Banking transplant ready dopaminergic neurons
Early Translational II   using a scalable process




                         Bioengineering technology for fast optical control
                         of differentiation and function in stem cells and
New Faculty I            stem cell progeny
                    Biological relevance of microRNAs in hESC
Basic Biology III   differentiation to endocrine pancreas
                         Bone Marrow Mesenchymal Stem Cells to Heal
Early Translational II   Chronic Diabetic Wounds
          Bridges to Stem Cell Research at Pasadena City
Bridges   College
                 Building Cardiac Tissue from Stem Cells and
New Faculty II   Natural Matrices
             Burnham Institute CIRM Stem Cell Training Grant
Training I   (Type II)
          Cal Poly Pomona and Cal State LA Collaborative
          CIRM Bridges Program to Enhance Stem Cell
Bridges   Research Training and Education
          California State University-San Marcos CIRM
Bridges   Bridges to the Stem Cell Research Training Grant
                         Cartilage Regeneration by the Chondrogenic
Early Translational II   Small Molecule PRO1 during Osteoarthritis
                        Cedars-Sinai Heart Disease Regenerative
Disease Team Planning   Medicine Team Planning Award
Disease Team   Cell Therapy for Diabetes




               Cellular epigenetic diversity as a blueprint for
               defining the identity and functional potential of
SEED           human embryonic stem cells
                        Cellular Reprogramming: Dissecting the
Basic Biology II        Molecular Mechanism and Enhancing Efficiency




                        Cellular tools to study brain diseases affecting
Tools & Technology II   synaptic transmission
                    Characterization and Engineering of the Cardiac
Basic Biology III   Stem Cell Niche
                    Characterization and Engineering of the Cardiac
Basic Biology III   Stem Cell Niche
                Characterization of mechanisms regulating de-
                differentiation and the re-acquisition of stem cell
New Faculty I   identity




                Chemical Genetic Approach to Production of
Comprehensive   hESC-derived Cardiomyocytes
Training II   CHLA Stem Cell Training Grant
                    CHORI/UC Berkeley Summer Stem Cell Research
Creativity Awards   Internship Program for High School Students




                    CIRM Center of Excellence at Buck Institute for
Major Facilities    Age Research
Disease Team Planning   CIRM Disease Team Planning Award




Major Facilities        CIRM Major Facilities
Major Facilities   CIRM Major Facilities
Major Facilities   CIRM Major Facilities
Major Facilities   CIRM Major Facilities
Major Facilities   CIRM Major Facilities
Major Facilities   CIRM Major Facilities
Major Facilities   CIRM Major Facilities
Major Facilities   CIRM Major Facilities




Major Facilities   CIRM Major Facilities
Disease Team Planning   CIRM Planning Grant in Leukemia
              CIRM Research Training Program in Stem Cells
Training II   and Aging
Shared Labs         CIRM Shared Research Laboratories




                    CIRM STAR High School Summer Research and
Creativity Awards   Creativity Program
Training I    CIRM Stem Cell Biology Training Grant




Training II   CIRM Stem Cell Biology Training Program
          CIRM Stem Cell Research Biotechnology Training
Bridges   Program at CSULB
Training I   CIRM Type I Comprehensive Training Program
          City College of San Francisco Stem Cell Training
Bridges   Enhancement Program
              City of Hope Research Training Program in Stem
Training II   Cell Biology
                           Clinical Development of an osteoinductive
Disease Team Planning II   therapy to prevent osteoporosis-related fractures
                        Clinical Regenerative Wound Healing With Stem
Disease Team Planning   Cells



                        Collaborative Laboratory and Training Course for
                        Human Embryonic Stem Cell Research at
Shared Labs             Burnham Institute for Medical Research
                           Combination therapy to Enhance Antisense
                           Mediated Exon Skipping for Duchenne Muscular
Disease Team Planning II   Dystrophy
                Combinatorial Chemistry Approaches to Develop
New Faculty I   LIgands against Leukemia Stem Cells




                Combinatorial Platform for Optimizing
SEED            Microenvironments to Control hESC Fate
Comprehensive   Constructing a fate map of the human embryo
                    Correlated time-lapse imaging and single cell
                    molecular analysis of human embryo
Basic Biology III   development




                    Creativity Award Program in Stem Cell Biology for
Creativity Awards   California High School Students
                         Crosstalk: Inflammation in Parkinson's disease
Early Translational II   (PD) in a humanized in vitro model




Bridges                  CSUN-UCLA Bridges to Stem Cell Research
Bridges   CSUSB Bridges to Stem Cell Research
Early Translational   Curing Hematological Diseases
          Curriculum Development and Implementation of
          Stem Cell Technology and Laboratory
          Management Emphasis in an Established MS
          Biotechnology and Bioinformatics Program at
          California State University Channel Islands and Co-
Bridges   development of a GE Course on Stem Cel
                  Defining the Isoform-Specific Effects of
                  Apolipoprotein E on the Development of iPS Cells
New Faculty II    into Functional Neurons in Vitro and in Vivo




                  Defining the molecular mechanisms of somatic
Basic Biology I   cell reprogramming
                 Derivation and analysis of pluripotent stem cell
                 lines with inherited TGF-b mediated disorders
                 from donated IVF embryos and reprogrammed
New Cell Lines   adult Skin Disease fibroblasts
       Derivation and Characterization of Cancer Stem
SEED   Cells from Human ES Cells
                 Derivation and characterization of human ES cells
SEED             from FSHD embryos




                 Derivation and Characterization of
                 Myeloproliferative Disorder Stem Cells from
New Faculty II   Human ES Cells
                 Derivation and comparative analysis of human
                 pluripotent ESCs, iPSCs and SSCs: Convergence to
New Cell Lines   an embryonic phenotype
New Cell Lines   Derivation of hESC Lines with Disease Lesions
                 Derivation of Inhibitory Nerve Cells from Human
Comprehensive    Embryonic Stem Cells
New Cell Lines   Derivation of New ICM-stage hESCs
                 Derivation of Parkinson's Disease Coded-Stem
New Cell Lines   Cells (PD-SCs)
                        Develop a cell replacement therapy for
                        Parkinson's disease using human embryonic stem
Disease Team Planning   cells
                         Developing a drug-screening system for Autism
Early Translational II   Spectrum Disorders using human neurons
                        Developing a method for rapid identification of
Tools & Technology II   high-quality disease specific hIPSC lines
                      Developing a regeneration-based functional
Research Leadership   restoration treatment for spinal cord injury
                         Developing a therapeutic candidate for Canavan
Early Translational II   disease using induced pluripotent stem cell
                      Developing induced pluripotent stem cells into
Early Translational   human therapeutics and disease models
                        Development and Application of Versatile,
Tools & Technology II   Automated, Microfluidic Cell Culture System
                        Development and preclinical testing of new
Tools & Technology II   devices for cell transplantation to the brain
                        Development of a Cell Replacement Therapy
Disease Team Planning   Product for Insulin Dependent Diabetes
                        Development of a Hydrogel Matrix for Stem Cell
Tools & Technology II   Growth and Neural Repair after Stroke




                        Development of a novel technology for precise,
                        efficient, and safe genetic modification of stem
Tools & Technology      cells
                        Development of a Stem Cell Therapy to Promote
Disease Team Planning   Functional Recovery in Stroke
                      Development of a Stem Cell-based
                      Transplantation Strategy for Treating Age-related
Early Translational   Macular Degeneration




                      Development of an hES Cell-Based Assay System
                      for Hepatocyte Differentiation Studies and
Tools & Technology    Predictive Toxicology Drug Screening
                             Development of an immune tolerant hESC source
Transplantation Immunology   for allogeneic cell therapy applications




                             Development of Baculoviral Vectors for Gene
Tools & Technology           Editing of Human Stem Cells
                      Development of Cellular Therapies for Retinal
Research Leadership   Disease




                      Development of Highly Active Anti-Leukemia
Disease Team          Stem Cell Therapy (HALT)
                 Development of human ES cell lines as a model
SEED             system for Alzheimer disease drug discovery




                 Development of Induced Pluripotent Stem Cells
New Cell Lines   for Modeling Human Disease
       Development of Neuro-Coupled Human
       Embryonic Stem Cell-Derived Cardiac Pacemaker
SEED   Cells.
                         Development of RNA-based approaches to stem
Early Translational II   cell gene therapy for HIV




                         Development of Single Cell MRI Technology using
Tools & Technology II    Genetically-Encoded Iron-Based Reporters
                        Development of small molecule screens for
Tools & Technology II   autism using patient-derived iPS cells
                     Development of Suspension Adaptation, Scale-up
                     cGMP Banking and Cell Characterization
Tools & Technology   Technologies for hESC Lines
                        Development of Synthetic Microenvironments for
Tools & Technology II   Stem Cell Growth and Differentiation
                     Development of the [REDACTED] Cellular
                     Encapsulation System for Delivery of human ES
Tools & Technology   Cell-derived Pancreatic Islets and Progenitors.
               Development of Therapeutic Antibodies Targeting
Disease Team   Human Acute Myeloid Leukemia Stem Cells
                   Differentiation of Human Embryonic Stem Cells
Basic Biology II   into Urothelium
       Differentiation of Human Embryonic Stem Cells to
SEED   Intestinal Fates
                     Directed Evolution of Novel AAV Variants for
                     Enhanced Gene Targeting in Pluripotent Human
                     Stem Cells and Investigation of Dopaminergic
Tools & Technology   Neuron Differentiation
                  Directing migration of human stem cells with
Basic Biology I   electric fields
       Discovering Potent Molecules with Human ESCs
SEED   to Treat Heart Disease
                     Discovery of adhesion ligands for pluripotent
Tools & Technology   human stem cells
                    Discovery of mechanisms that control epigenetic
                    states in human reprogramming and pluripotent
Basic Biology III   cells
                    Discovery of mechanisms that control epigenetic
                    states in human reprogramming and pluripotent
Basic Biology III   cells
                             Donor natural killer (NK) cells as veto cells to
Transplantation Immunology   promote donor-specific tolerance




                             Down-Regulation of Alloreactive Immune
SEED                         Responses to hES Cell-Derived Graft Tissues
                           DR2-05423: Phase I study of IM Injection of VEGF
                           Producing MSC for the Treatment of Critical Limb
Disease Team Planning II   Ischemia
                         Dual targeting of tyrosine kinase and BCL6
Early Translational II   signaling for leukemia stem cell eradication
                        EC regeneration in cerebrovascular ischemia: role
SEED                    of NO




                        Editing of Parkinson's disease mutation in patient-
Tools & Technology II   derived iPSCs by zinc-finger nucleases
                    Elucidating Molecular Basis of Hypertrophic
                    Cardiomyopathy with Human Induced Pluripotent
Basic Biology III   Stem Cells
                Embryonic Stem Cell-Derived Therapies Targeting
Comprehensive   Cardiac Ischemic Disease
       Embryonic stem cell-derived thymic epithelial
SEED   cells
               Embryonic-Derived Neural Stem Cells for
               Treatment of Motor Sequelae following Sub-
Disease Team   cortical Stroke




SEED           Endodermal differentiation of human ES cells
                   Endothelial cells and ion channel maturation of
Basic Biology II   human stem cell-derived cardiomyocytes
                             Engineered immune tolerance by Stem Cell-
Transplantation Immunology   derived thymic regeneration
                Engineering a Cardiovascular Tissue Graft from
Comprehensive   Human Embryonic Stem Cells
                        Engineering Defined and Scaleable Systems for
Tools & Technology II   Dopaminergic Neuron Differentiation of hPSCs
                             Engineering Embryonic Stem Cell Allografts for
Transplantation Immunology   Operational Tolerance




                             Engineering Thymic Regeneration to Induce
Transplantation Immunology   Tolerance
                    Enhancer-mediated gene regulation during early
Basic Biology III   human embryonic development




                    Enhancing Facilities for Genetic Manipulation and
                    Engineering of Human Embryonic Stem Cells at
Shared Labs         UCSD
                      Enhancing healing via Wnt-protein mediated
Early Translational   activation of endogenous stem cells
                      Enhancing Survival of Embryonic Stem Cell-
                      Derived Grafts by Induction of Immunological
New Faculty I         Tolerance




                      Ensuring the safety of cell therapy: a quality
                      control pipeline for cell purification and
Early Translational   validation
                Epigenetic gene regulation during the
                differentiation of human embryonic stem cells:
Comprehensive   Impact on neural repair
                Epigenetics in cancer stem cell initiation and
New Faculty I   clinical outcome prediction
                ES-Derived Cells for the Treatment of Alzheimer's
New Faculty I   Disease
                 Establishment of Frontotemporal Dementia
                 Patient-Specific Induced Pluripotent Stem (iPS)
New Cell Lines   Cell Lines with Defined Genetic Mutations
                    Etsrp/ER71 mediated stem cell differentiation
Basic Biology III   into vascular lineage
                                Evaluation of Safety and Preliminary Efficacy of
                                Escalating Doses of GRNOPC1 in Subacute Spinal
Targeted Clinical Development   Cord Injury
SEED   Force, Dimensionality and Stem Cell Fate
                    Forming the Hematopoietic Niche from Human
Basic Biology III   Pluripotent Stem Cells
                    Functional characterization of mutational load in
Basic Biology III   nuclear reprogramming and differentiation




                    Functional Genomic Analysis of Chemically
Comprehensive       Defined Human Embryonic Stem Cells
       Functions of RB family proteins in human
SEED   embryonic stem cells

       Gene regulatory mechanisms that control spinal
SEED   neuron differentiation from hES cells.
New Faculty I   Generating pluripotent cell lines from neurons.
                    Generation and characterization of corticospinal
Basic Biology III   neurons from human embryonic stem cells
New Cell Lines   Generation of clinical grade human iPS cells
                     Generation of disease models for
                     neurodegenerative disorders in hESCs by gene
Tools & Technology   targeting
       Generation of forebrain neurons from human
SEED   embryonic stem cells
                Generation of inner ear sensory cells from human
Comprehensive   ES cells toward a cure for deafness




                Generation of long-term cultures of human
                hematopoietic multipotent progenitors from
SEED            embryonic stem cells
                 Generation of Pluripotent Cell Lines from Human
New Cell Lines   Embryos
                             Generation of regulatory T cells by
Transplantation Immunology   reprogramming
                Genetic dissection of mesodermal commitment
New Faculty I   to the hematopoietic fates.
                Genetic Encoding Novel Amino Acids in
                Embryonic Stem Cells for Molecular
                Understanding of Differentiation to Dopamine
New Faculty I   Neurons




                Genetic Enhancement of the Immune Response
SEED            to Melanoma via hESC-derived T cells
       Genetic manipulation of human embryonic stem
       cells and its application in studying CNS
SEED   development and repair




       Genetic modification of the human genome to
SEED   resist HIV-1 infection and/or disease progression
                           Genetic Re-programming of Stem Cells to Fight
Disease Team Planning II   Cancer
                           Genetically Engineered Mesenchymal Stem Cells
                           for the Treatment of Vertebral Compression
Disease Team Planning II   Fractures
                        Genetically-modified neural stem cells for
Disease Team Planning   treatment of high-grade glioma
                    Genomic instability during culturing of human
Basic Biology III   embryonic stem cells




Training I          Gladstone CIRM Scholar Program
Training II   Gladstone CIRM Scholars Program
                    Gladstone Summer Scholars (GSS) Research
Creativity Awards   Program




                    Guiding the developmental program of human
Comprehensive       embryonic stem cells by isolated Wnt factors
       Hair Cells and Spiral Ganglion Neuron
SEED   Differentiation from Human Embryonic Stem Cells
                         Harnessing native fat-residing stem cells for bone
Early Translational II   regeneration




                         hESC as tools to investigate the neural crest origin
SEED                     of Ewing's sarcoma
                hESC-Derived Motor Neurons For the Treatment
Comprehensive   of Cervical Spinal Cord Injury
                           hESC-derived NPCs Programmed with MEF2C for
Disease Team Planning II   Cell Transplantation in Parkinson's Disease




SEED                       hESCs for Articular Cartilage Regeneration
                 High throughput modeling of human
                 neurodegenerative diseases in embryonic stem
New Faculty II   cells
                        Homologous recombination in human pluripotent
Tools & Technology II   stem cells using adeno-associated virus




                        HPSC based therapy for HIV disease using RNAi to
Disease Team            CCR5.
                  Human Cardiovascular Progenitors, their Niches
Basic Biology I   and Control of Self-renewal and Cell Fate




                  Human Embryonic Stem Cell Differentiation to
                  Trophoblast: Basic Biology and Clinical Translation
SEED              to Improve Human Fertility
                           Human Embryonic Stem Cell Therapeutic
Comprehensive              Strategies to Target HIV Disease




                           Human Embryonic Stem Cell-Derived
                           Cardiomyocytes for Patients with End Stage Heart
Disease Team Planning II   Failure
                             Human Embryonic Stem Cells and Remyelination
SEED                         in a Viral Model of Demyelination




                             Human Immune System Mouse models as
Transplantation Immunology   preclinical platforms for stem cell derived grafts
                Human oocyte development for genetic,
Comprehensive   pharmacological and reprogramming applications
                         Human retinal progenitor cells as candidate
Early Translational II   therapy for retinitis pigmentosa




                         HUMAN STEM CELL APPROACHES TO
Disease Team Planning    ALZHEIMERS DISEASE THERAPIES
                Human stem cell derived oligodendrocytes for
Comprehensive   treatment of stroke and MS
                Human Stem Cell Training at UC Berkeley and
Training I      Children's Hospital of Oakland
Disease Team Planning   Huntington's Disease Team
                  Identification and characterization of human ES-
Basic Biology I   derived DA neuronal subtypes
                Identification of hESC-mediated molecular
                mechanism that positively regulates the
New Faculty I   regenerative capacity of post-natal tissues




                Identifying small molecules that stimulate the
                differentiation of hESCs into dopamine-producing
SEED            neurons
                    Identifying sources of mutation in human induced
                    pluripotent stem cells by whole genome
Basic Biology III   sequencing




Comprehensive       Immunology of neural stem cell fate and function
Comprehensive         Improved hES Cell Growth and Differentiation




                      Improving microenvironments to promote
                      hematopoietic stem cell development from
SEED                  human embryonic stem cells




                      In Utero Model to Assess the Fate of
                      Transplanted Human Cells for Translational
Early Translational   Research and Pediatric Therapies
       In vitro differentiation of hESCs into corticospinal
SEED   motor neurons
                In Vitro Differentiation of T cells from Human
SEED            Embryonic Stem Cells.




                In vitro reprogramming of mouse and human
New Faculty I   somatic cells to an embryonic state
                     In Vivo Imaging for the Detection and
                     Quantitation of Transplanted Stem/Progenitor
Tools & Technology   Cells in Nonhuman Primates




                     In Vivo Imaging of Human Embryonic Stem Cell
SEED                 Derivatives and Tumorigenicity
       In Vivo Molecular Magnetic Resonance Imaging of
       Human Embryonic Stem Cells in Murine Model of
SEED   Myocardial Infarction
                             Inactivating NK cell reactivity to facilitate
Transplantation Immunology   transplantation of stem cell derived tissue
                           Increasing the endogenous mesenchymal stem
Disease Team Planning II   cells to the bone surface to treat osteoporosis
                 Induced Pluripotent Stem Cells for Cardiovascular
New Cell Lines   Diagnostics
                    Induced Pluripotent Stem Cells for Tissue
Basic Biology III   Regeneration




                    Induction of cardiogenesis in pluripotent cells via
New Faculty II      chromatin remodeling factors
                             Induction of immune tolerance after spinal
Transplantation Immunology   grafting of human ES-derived neural precursors
                             Induction of immune tolerance to human
Transplantation Immunology   embryonic stem cell-derived allografts




                             Induction of pluripotency in fibroblasts by fusion
                             with enucleated human embryonic stem cell
SEED                         syncytia
                         Induction of pluripotent stem cells by small RNA-
New Cell Lines           guided transcriptional activation




                         Inhibitory Nerve Cell Precursors: Dosing, Safety
Early Translational II   and Efficacy
             Interdisciplinary Stem Cell Training Program at
Training I   UCSD
              Interdisciplinary Stem Cell Training Program at
Training II   UCSD II
              Interdisciplinary Training in Stem Cell Biology,
Training II   Engineering and Medicine
                    Internship at a Cutting Edge CIRM-funded Stem
Creativity Awards   Cell Research Facility
                    Investigation of synaptic defects in autism using
Basic Biology III   patient-derived induced pluripotent stem cells
               iPS Cell-Based Treatment of Dystrophic
Disease Team   Epidermolysis Bullosa
                   Kinase signaling analysis of iPS cell
Basic Biology II   reprogramming and differentiation




                   Labeling of human embryonic stem cells with iron
                   oxide nanoparticles and fluorescent dyes for a
                   non-invasive cell depiction with MR imaging and
SEED               optical imaging
                         Laying the groundwork for building a tooth:
New Faculty II           analysis of dental epithelial stem cells




Early Translational II   Liver Cell Transplantation
                     Magnetic Particle Imaging: A Novel Ultra-sensitive
Tools & Technology   Imaging Scanner for Tracking Stem Cells In Vivo
                        Magnetic Particle Imaging: A Novel Ultra-sensitive
Tools & Technology II   Imaging Scanner for Tracking Stem Cells In Vivo
       Mapping the transcriptional regulatory elements
SEED   in the genome of hESC
          Master's of Science Specialization in Stem Cell
Bridges   Technology
                             Maternal and Fetal Immune Responses to In
Transplantation Immunology   Utero Hematopoietic Stem Cell Transplantation
                      Maturation of Human Oocytes for SCNT and
Basic Biology II      Embryonic Stem Cell Derivation

                      Maximizing the Safety of Induced Pluripotent
                      Stem Cells as an Infusion Therapy: Limiting the
                      Mutagenic Threat of Retroelement
                      Retrotransposition during iPSC Generation,
Early Translational   Expansion and Differentiation
                 Mechanism of Tissue Engineered Small Intestine
New Faculty II   Formation
                 Mechanisms in Choroid Plexus Epithelial
New Faculty II   Development
                 Mechanisms of chromatin dynamics at enhancers
New Faculty II   during ES cell differentiation
Basic Biology III   Mechanisms of Direct Cardiac Reprogramming




                    Mechanisms of Hematopoietic stem cell
New Faculty I       Specification and Self-Renewal
                 Mechanisms of small RNA regulation in early
New Faculty II   embryonic development




New Faculty I    Mechanisms of Stem Cell Fate Decisions
                Mechanisms to maintain the self-renewal and
Comprehensive   genetic stability of human embryonic stem cells
                 Mechanisms Underlying the Diverse Functions of
New Faculty II   STAT3 in Embryonic Stem Cell Fate Regulation
                 Mechanisms Underlying the Responses of Normal
                 and Cancer Stem Cells to Environmental and
New Faculty II   Therapeutic Insults



                 MEF2C-Directed Neurogenesis From Human
Comprehensive    Embryonic Stem Cells
                      Methods for detection and elimination of residual
                      human embryonic stem cells in a differentiated
Early Translational   cell product




                      MGE Enhancers to Select for Interneuron
Basic Biology II      Precursors Produced from Human ES Cells
                     Microfluidic Platform for Screening Chemically
                     Defined Conditions that Facilitate Clonal
Tools & Technology   Expansion of Human Pluripotent Stem Cells
                microRNA Regulation of Cardiomyocyte
Comprehensive   Differentiation from Human Embryonic Stem Cells
       MicroRNA Regulation of Human Embryonic Stem
SEED   Cell Self-Renewal and Differentiation
       MicroRNAs in Human Stem Cell Differentiation
SEED   and Mental Disorders




       Microsystem for Controlled Cardiomyocyte
SEED   Differentiation
                  Mitochondrial Dysfunction in Embryonic Stem
SEED              Cells




                  Mitochondrial Metabolism in hESC and hiPSC
Basic Biology I   Differentiation, Reprogramming, and Cancer
                Modeling Human Embryonic Development with
SEED            Human Embryonic Stem Cells




                Modeling Myocardial Therapy with Human
Comprehensive   Embryonic Stem Cells
                Modeling Parkinson's Disease Using Human
SEED            Embryonic Stem Cells
                    Molecular and Cellular Transitions from ES Cells
Comprehensive       to Mature Functioning Human Neurons




                    Molecular basis of human ES cell neurovascular
Basic Biology III   differentiation and co-patterning
                  Molecular Characterization and Functional
Basic Biology I   Exploration of Hemogenic Endothelium
                   Molecular Characterization and Functional
Basic Biology II   Exploration of Nuclear Receptors in hiPSCs
                  Molecular Characterization of hESC and hIPSC-
Basic Biology I   Derived Spinal Motor Neurons
                    Molecular determinants of accurate
Basic Biology III   differentiation from human pluripotent stem cells
                 Molecular dissection of adult liver regeneration
                 to guide the generation of hepatocytes from
New Faculty II   pluripotent stem cells
                 Molecular mechanisms governing hESC and iPS
New Faculty II   cell self-renewal and pluripotency




                 Molecular mechanisms involved in adult neural
New Faculty I    stem cell maintenance
                Molecular mechanisms of neural stem cell
New Faculty I   differentiation in the developing brain
                  Molecular Mechanisms of Reprogramming
Basic Biology I   towards Pluripotency




                  Molecular Mechanisms of Trophoblast Stem Cell
New Faculty II    Specification and Self-Renewal
                    Molecular Mechanisms Underlying Human
                    Cardiac Cell Junction Maturation and Disease
Basic Biology III   Using Human iPSC
                        Motor neuron diseases: Finding cures through
Disease Team Planning   basic, translational, and clinical collaboration
                      Mouse Models for Stem Cell Therapeutic
Early Translational   Development
                           MSC engineered to produce BDNF for the
Disease Team Planning II   treatment of Huntington's disease
                           MSC engineered to produce BDNF for the
Disease Team Planning II   treatment of Huntington's disease
                    Neural and general splicing factors control self-
Basic Biology III   renewal, neural survival and differentiation
                         Neural restricted, FAC-sorted, human neural stem
Early Translational II   cells to treat traumatic brain injury
                           Neural Stem Cell-Based Therapy For Parkinson's
Disease Team Planning II   Disease
                      Neural Stem Cells as a Developmental Candidate
Early Translational   to Treat Alzheimer Disease
                           Neuroprotection to treat Alzheimer's: a new
                           paradigm using human central nervous system
Disease Team Planning II   cells
New Cell Lines   New Cell Lines for Huntington's Disease
       New Chemokine-Derived Therapeutics Targeting
SEED   Stem Cell Migration
                         New Drug Discovery for SMA using Patient-
Early Translational II   derived Induced Pluripotent Stem Cells
                 New Technology for the Derivation of Human
New Cell Lines   Pluripotent Stem Cell Lines for Clinical Use




                 Non-coding RNA as tool for the active control of
SEED             stem cell differentiation
New Faculty I   Noncoding RNAs in Cell Fate Determination


                North Bay CIRM Shared Research Laboratory for
Shared Labs     Stem Cells and Aging
                   Novel Mechanism in Self-Renewal/Differentiation
Basic Biology II   of Human Embryonic Stem Cells
Tools & Technology   Novel Separation of Stem Cell Subpopulations




                     Novel Tools and Technologies for Translational
Tools & Technology   PET Imaging of Cell-based Therapies
       Novel vectors for gene transfer into human ES
SEED   cells
                     Optimization in the Identification, Selection and
                     Induction of Maturation of Subtypes of
                     Cardiomyocytes derived from Human Embryonic
Tools & Technology   Stem Cells
       Optimization of guidance response in human
       embryonic stem cell derived midbrain
       dopaminergic neurons in development and
SEED   disease
                 Optimization of Human Embryonic Stem Cell
                 Derivation Techniques and
New Cell Lines   Production/Distribution of GMP-Grade Lines
                Oral and Craniofacial Reconstruction Using
New Faculty I   Mesenchymal Stem Cells
SEED                Patient-specific cells with nuclear transfer




                    Phenotypic Analysis of Human ES Cell-Derived
Basic Biology III   Muscle Stem Cells
                        Pluripotent and Somatic Stem Cell Models to
Tools & Technology II   Study Inherited Diarrheal Disorders
                        Pluripotent Stem Cell–Based Therapy for Heart
Disease Team Planning   Disease
                           Preclinical Development and First-In-Human
Disease Team Planning II   Testing of [REDACTED] in Advanced Heart Failure
                         Preclinical development of a pan Bcl2 inhibitor for
Early Translational II   cancer stem cell directed therapy
                        Preclinical Model for Labeling, Transplant, and In
                        Vivo Imaging of Differentiated Human Embryonic
Comprehensive           Stem Cells




                        Preparation and Delivery of Clinically Relevant
Tools & Technology II   Numbers of Stem Cells Using 3D Hydrogels
SEED   Production of Oocytes from Human ES Cells




       Profiling surface glycans and glycoprotein
SEED   expression of human embryonic stem cells
       Programmed Cell Death Pathways Activated in
SEED   Embryonic Stem Cells
                   Programs of alternative splicing regulation by
Basic Biology II   polypyrimidine tract binding protein
                Prospective isolation of hESC-derived
Comprehensive   hematopoietic and cardiomyocyte stem cells
                 Protein transduction of transcription factors: a
                 non-genetic approach to generate new
New Cell Lines   pluripotent cell lines from human Skin Disease.
                             Purified allogeneic hematopoietic stem cells as a
Transplantation Immunology   platform for tolerance induction
                           Recombinant Bispecific Antibody Targeting
                           Cancer Stem Cells for the Therapy of
Disease Team Planning II   Glioblastoma
                         Regeneration of Functional Human Corneal
Early Translational II   Epithelial Progenitor Cells
                Regulated Expansion of Lympho-hematopoietic
                Stem and Progenitor Cells from Human
Comprehensive   Embryonic Stem Cells (hESC)
                 Regulation of Adult Stem Cell Proliferation by RAS
New Faculty II   and Cell-Permeable Proteins

                 Regulation of human neural progenitor cell
SEED             proliferation by Ryk-mediated Wnt signaling
                     Regulation of Specific Chromosomal Boundary
                     Elements by CTCF Protein Complexes in Human
SEED                 Embryonic Stem Cells




                     Regulation of Stem Cell Fate in Bioengineered
Tools & Technology   Arrays of Hydrogel Microwells
                             Regulatory T cell induced tolerance to ESC
Transplantation Immunology   transplantation
                         Repair of Conus Medullaris/Cauda Equina Injury
Early Translational II   using Human ES Cell-Derived Motor Neurons
       Reprogramming Differentiated Human Cells to a
SEED   Pluripotent State
                Reprogramming of human somatic cells back to
New Faculty I   pluripotent embryonic stem cells
                    Research Mentorship Program-Immersing High
Creativity Awards   School Students in College Research
       Retinoic Acid-FGF Antagonism during Motor
SEED   Neuron Differentiation of Human ES Cells
                     RNA Analysis by Biosynthetic Tagging (RABT): a
                     tool for the identification of cell type-specific
Tools & Technology   RNAs
                  RNA Binding Protein-mediated Post-
                  transcriptional Networks Regulating HPSC
Basic Biology I   Pluripotency
                        Robust generation of induced pluripotent stem
Tools & Technology II   cells by a potent set of engineered factors




                        Role of Chromatin Modifiers in Regulating Human
SEED                    Embryonic Stem Cell Pluripotency
       Role of Glycans in Human Embryonic Stem Cell
SEED   Conversion to Neural Precursor Cells




       Role of HDAC in human stem cells
SEED   pluripotentiality and differentiation
                             Role of HLA in neural stem cell rejection using
Transplantation Immunology   humanized mice
                             Role of Innate Immunity in hematopoeitic stem
Transplantation Immunology   cell-mediated allograft tolerance
       Role of Mitochondria in Self-Renewal Versus
SEED   Differentiation of Human Embryonic Stem Cells
                   Role of the microenvironment in human iPS and
Basic Biology II   fetal-derived NSC fate and tumorigenesis




                   Role of the tumor suppressor gene, p16INK4a, in
                   regulating stem cell phenotypes in embryonic
SEED               stem cells and human epithelial cells.
                   RUNX1 in maintenance, expansion, and
                   differentiation of therapeutic pluripotent stem
Basic Biology II   cells
                 Safe, efficient creation of human induced
                 pluripotent stem cells without the use of
New Cell Lines   retroviruses
          San Jose State University Stem Cell Internships for
Bridges   Laboratory-based Learning (SJSU SCILL)
                     Scaleup of Versatile, Fully Automated,
Tools & Technology   Microfluidic Cell Culture System




                     Screening for Oncogenic Epigenetic Alterations in
SEED                 Human ES Cells
Bridges   SDSU/CIRM Stem Cell Internship Program
                   Self-renewal and senescence in iPS cells derived
Basic Biology II   from patients with a stem cell disease




SEED               Self-renewal of human embryonic stem cells
Bridges       SFSU Bridges to Stem Cell Research



              Shared viral vector facility for genetic
Shared Labs   manipulation of huamn ES cell
                        SIRM Program: Stem Cell & Developmental
Creativity Awards       Biology Research Internships




                        Site-specific integration of Lmx1a, FoxA2, & Otx2
Tools & Technology II   to optimize dopaminergic differentiation
                 Skeletal muscle development from hESC and its in
                 vivo applications in animal models of muscular
New Faculty I    dystrophy




                 Skeletogenic Neural Crest Cells in Embryonic
New Faculty II   Development and Adult Regeneration of the Jaw
                 Somatic cell age and memory in the generation of
New Cell Lines   iPS cells
       Sources of Genetic Instability in Human
SEED   Embryonic Stem Cells.
Bridges   Specialty in Stem Cell Biology




          Specification of Ventricular Myocyte and
          Pacemaker Lineages Utilizing Human Embryonic
SEED      Stem Cells
                Spinal ischemic paraplegia: modulation by human
Comprehensive   embryonic stem cell implant.
Disease Team Planning   Stanford Cardiovascular Regenerative Team
Training II   Stanford CIRM Training Program
Training I   Stanford CIRM Training Program
Major Facilities   Stanford SIM1 Building
                        Stem cell based treatment strategy for Age-
Disease Team Planning   related Macular Degeneration (AMD)




                        Stem cell based treatment strategy for Age-
Disease Team            related Macular Degeneration (AMD)
                             Stem cell differentiation to thymic epithelium for
Transplantation Immunology   inducing tolerance to stem cells
                           Stem Cell Gene Therapy for HIV in AIDS
Disease Team Planning II   Lymphoma Patients
                           Stem Cell Gene Therapy for HIV in AIDS
Disease Team Planning II   Lymphoma Patients




                           STEM CELL GENE THERAPY FOR SICKLE CELL
Disease Team Planning      DISEASE
Disease Team   Stem Cell Gene Therapy for Sickle Cell Disease
Training I   Stem Cell Research Training Grant
Training I          Stem Cell Research Training Grant




                    Stem Cell Summer Academy: Creating the Next
Creativity Awards   Generation of Scientists
                        Stem Cell Survival and Differentiation Through
SEED                    Chemical Genetics




                        Stem Cell Therapy for AIDS- Disease Team
Disease Team Planning   Planning
                         Stem Cell Therapy for Duchenne Muscular
Early Translational II   Dystrophy




Disease Team Planning    Stem Cell Therapy for Muscular Dystrophy
                             Stem cell tolerance through the use of
Transplantation Immunology   engineered antigen-specific regulatory T cells
          Stem Cell Training Program at CSU Fullerton - A
Bridges   Bridge to Stem Cell Research
                         Stem cell-based carriers for RCR vector delivery to
Early Translational II   glioblastoma




                         Stem Cell-Based Therapy for Cartilage
Early Translational      Regeneration and Osteoarthritis
               Stem Cell-Derived Astrocyte Precursor
Disease Team   Transplants in Amyotrophic Lateral Sclerosis




               Stem Cell-Mediated Oncocidal Gene Therapy of
Disease Team   Glioblastoma (GBM)
                        Stem Cell-Mediated Oncocidal Therapy of Primary
Disease Team Planning   & Metastatic Brain Tumors
               Stem Cell-mediated Therapy for High-grade
Disease Team   Glioma: Toward Phase I-II Clinical Trials
                        Stem Cells for Immune System Regeneration to
New Faculty II          Fight Cancer




                        Stem cells for neuroprotection of photoreceptors
Disease Team Planning   in retinitis pigmentosa
New Faculty II   Stem Cells in Lung Cancer
                           Stem Cells Secreting GDNF for the Treatment of
Disease Team Planning II   ALS
          Strengthening the Pipeline of Master's-level
          Scientific and Laboratory Personnel in Stem Cell
Bridges   Research
                    Studying neurotransmission of normal and
Basic Biology III   diseased human ES cell-derived neurons in vivo
                      Sustained siRNA production from human MSC to
                      treat Huntingtons Disease and other
Early Translational   neurodegenerative disorders




                      Synthetic Matrices for Stem Cell Growth and
Tools & Technology    Differentiation
                         Systemic Adult Stem Cell Therapy for
                         Osteoporosis-Related Vertebral Compression
Early Translational II   Fractures




                         Systemic Protein Factors as Modulators of the
Basic Biology II         Aging Neurogenic Niche
                     TAT Cell-Permeable Protein Delivery of siRNAs for
                     Epigenetic Programming of Human Pluripotent
Tools & Technology   and Adult Stem Cells




                     TCF-3: A Wnt Pathway Effector and Nanog
Basic Biology II     Regulator in Pluripotent Stem Cell Self-Renewal
       Technology for hESC-Derived Cardiomyocyte
       Differentiation and Optimization of Graft-Host
SEED   Integration in Adult Myocardium




       The APOBEC3 Gene Family as Guardians of
SEED   Genome Stability in Human Embryonic Stem Cells
              The Berkeley Human Embryonic Stem Cell Shared
Shared Labs   Research Laboratory
                The Childrens Hospital of Los Angeles hESC
Shared Labs     Facility

                The Dangers of Mitochondrial DNA Heteroplasmy
Comprehensive   in Stem Cells Created by Therapeutic Cloning
                   The EphrinB2/EphB4 axis in regulating hESC
Basic Biology II   pluripotency and differentiation
                   The function of YAP in human embryonic stem
Basic Biology II   cells
              The Gladstone CIRM Shared Human Embryonic
Shared Labs   Stem Cell Core Laboratory




              The HSU CIRM Bridges to Stem Cell Research
Bridges       Certificate Program
       The Immunological Niche: Effect of
       immunosuppressant drugs on stem cell
       proliferation, gene expression, and differentiation
SEED   in a model of spinal cord injury.
                  The molecular basis underlying adult
                  neurogenesis during regeneration and tissue
New Faculty II    renewal




                  The retinoblastoma (RB) gene family in cellular
Basic Biology I   reprogramming
                      The role of neural stem cells in cerebellar
Research Leadership   development, regeneration and tumorigenesis
                 The roles of non-coding RNAs in the self-renewal
New Faculty II   and differentiation of pluripotent stem cells




                 The Stanford University Center for Human
Shared Labs      Embryonic Stem Cell Research and Education
                     The Stem Cell Matrix: a map of the molecular
Tools & Technology   pathways that define pluripotent cells
                  The stem cell microenvironment in the
Basic Biology I   maintenance of pluripotency and reprogramming
              The UCSB Laboratory for Stem Cell Biology and
Shared Labs   Engineering




              The University of California San Francisco Shared
              Research and Teaching Laboratory: a Non-Federal
              Human Embryonic Stem Cell Resource for the Bay
Shared Labs   Area Community
               The University of California: irvine Regional
               Human Embryonic Stem Cell Shared Research
Shared Labs    Laboratory and Stem Cell Techniques Course




               Therapeutic Opportunities To Target Tumor
Disease Team   initiating Cells In Solid Tumors
                             Therapeutic potential of Retinal Pigment
                             Epithelial cell lines derived from hES cells for
SEED                         retinal degeneration.




Transplantation Immunology   Thymus based tolerance to stem cell therapies
Training I   Training Grant 1




Training I   Training Grant I
Training I   Training Grant I




Training I   Training in Stem Cell Biology at CIT
              Training in the Biology of Human Embryonic Stem
Training II   Cells and Emerging Technologies II
             Training in the Biology of Human Enbryonic Stem
Training I   Cells and Emerging Technologies
              Training Program in Stem Cell Biology and
Training II   Engineering
Training II   Training Program in Stem Cell Research at UCSF


Training I    Training Program in Systems Biology of Stem Cells
              Training Stem Cell Researchers at the Chemistry-
Training II   Biology Interface
                Transcriptional Regulation of Cardiac Pacemaker
New Faculty I   Cell Progenitors
       Transcriptional Regulation of Human Embryonic
SEED   Stem Cells
                        Tri-resolution Visualization System for Stem Cells
Tools & Technology II   and Tissue Regeneration Monitoring




Basic Biology III       Triplet Repeat Instability in Human iPSCs
                Trithorax and Polycomb methyltransferase
New Faculty I   complexes in cell fate determination.




SEED            Trophoblast differentiation of human ES cells.
Shared Labs   TSRI Center for hESC Research
              Type III CIRM Stem Cell Research Training
Training II   Program
                    Ubiquitin-dependent control of hESC self-renewal
Basic Biology III   and expansion
Training II   UC Davis Stem Cell Training Program
              UC Davis Translational Human Embryonic Stem
Shared Labs   Cell Shared Research Facility
Major Facilities   UC Santa Barbara Bio Sciences II




Training II        UCI-CIRM Research Training Program II
Training II   UCLA CIRM Research Training Program II
Training I   UCSB Stem Cell Biology Training Program
              UCSC CIRM Training Program in Systems Biology
Training II   of Stem cells




Shared Labs   UCSC Shared Stem Cell Facility
Creativity Awards   UCSF SEP High School Intern Program




                    Understanding hESC-based Hematopoiesis for
Comprehensive       Therapeutic Benefit
                    Understanding the role of LRRK2 in iPSC cell
Basic Biology III   models of Parkinson's Disease




                    USC Center for Stem Cell and Regenerative
                    Medicine: Shared Research Laboratory and
                    Course in Current Protocols in Human Embryonic
Shared Labs         Stem Cell Research
                        Use of hiPSCs to develop lead compounds for the
Tools & Technology II   treatment of genetic diseases
                    Use of human iPS cells to study spinal muscular
Basic Biology III   atrophy
                        Use of iPS cells (iPSCs) to develop novels tools for
Tools & Technology II   the treatment of spinal muscular atrophy




                        Using human embryonic stem cells to treat
                        radiation-induced stem cell loss: Benefits vs
SEED                    cancer risk
                Using Human Embryonic Stem Cells to
                Understand and to Develop New Therapies for
Comprehensive   Alzheimer's Disease
                      Using patient-specific iPSC derived dopaminergic
                      neurons to overcome a major bottleneck in
Early Translational   Parkinson's disease research and drug discovery
                    USP16 controls stem cell number: implications for
Basic Biology III   Down Syndrome
                 VEGF signaling in adventitial stem cells in vascular
New Faculty II   physiology and disease
                    Viral-host interactions affecting neural
Basic Biology III   differentiation of human progenitors
                  WNT signaling and the control of cell fate
Basic Biology I   decisions in human pluripotent stem cells.
               ZINC FINGER NUCLEASE-BASED STEM CELL
Disease Team   THERAPY FOR AIDS
                    Public abstract                   Total Funds                   Disease focus
Parkinson's Disease (PD) is a devastating disorder,
stealing vitality from vibrant, productive adults &
draining our health care dollars.It is also an
excellent model for studying other
neurodegenerative conditions. We have
discovered that human neural stem cells (hNSCs)
may exert a significant beneficial impact in the
most authentic, representative, & predictive
animal model of actual human PD (the adult
African/St. Kitts Green Monkeys exposed
systemically to the neurotoxin MPTP).
Interestingly, we have learned that, while some
of the hNSCs differentiate into replacment
dopamine (DA) neurons, much of the therapeutic
benefit derived from a stem cell action we
diseovered a called the                                 $3,562,824 Parkinson's disease
Our multi-institutional program is dedicated to
the treatment of heart failure, which has become
a leading cause of death in California and the U.
S. The high death toll continues to climb despite
many significant recent advances in the medical
treatment of heart failure. The disease is due to a
debilitating loss and/or dysfunction of heart
muscle cells (cardiomyocytes) in the injured
heart. Most current therapies and clinical trials
are not designed to regenerate these cells.
Rather, they focus on boosting output of the
failing heart and/or forestalling further decline.
Our intention is to regenerate or replace the
damaged cardiomyocytes and their supporting
cells. Our consortium unites over 20 highly
successful laboratories with expertise in
cardiomyocyte stem cell biology, high throughput
chemical library screening and drug discovery,
biomaterials and bioengineering, cardiac imaging,
heart failure therapeutics, and advanced clinical
interventional cardiology. These groups will be
organized into Basic Discovery, Translational, and
Applied and Clinical research teams to bring two
types of therapies from the research lab to the
clinic. The first will be to replace damaged              $53,150
The aim of this project is to screen large
collections of small molecules to identify
molecules that allow one to propagate human
embryonic stem cells (hESCs) in cell culture under
defined conditions in an undifferentiated,
pluripotent state. The chemical structures of any
biologically active small molecules will be
optimized with respect to potency, selectivity and
biological stability. The ability of hESCs
proliferated in the presence of such small
molecules to be differentiated into specific cell
lineages both in cell culture and in vivo will also
be assessed. And finally, we will determine the
mechanism of action of active small molecules by
a variety of biochemical and genomic methods.
The demonstration that one can identify
synthetic drug-like molecules that allow one to
control the self-renewal and/or differentiation of
hESCs will represent an important step in the
ultimate therapeutic application of hESCs to
human disease. In addition, biological studies of
such molecules should provide new insights into
the processes that control stem cell biology.           $784,900
Arthritis is a disabling condition that afflicts 6
million Californians, costing our state nearly $32
billion annually for health care and lost wages.
Given the growth of an aging population
encouraged to maintain an active lifestyle due to
the overall health benefits, the impact of arthritis
is expected to increase significantly. For example,
the Center for Disease Control projects that 60
million people nationwide will have arthritis by
2020. The goal of this Disease Team Proposal is to
plan an accelerated translation of stem cell
therapies for cartilage repair that will provide an
early intervention to prevent and treat arthritis.
The proposed cartilage regeneration program
builds upon the institutional applicant’s world-
recognized leadership in stem cell and skeletal
biology, and the clinical expertise of the
orthopaedic surgery. In addition, strong
partnerships with California industry will facilitate
successful implementation of clinically beneficial
strategies. The team leader is the director of both
an industry-collaborative center and an
orthopaedic biomechanics laboratory, and a
pioneer of new protocols that direct stem cells to
make cartilage. Our multidisciplinary team               $55,000
This proposal is for the establishment of a group
of faculty, staff and industrial partners to develop
a proposal for a Diabetes Disease Team. Diabetes
is one of the most devastating diseases.
Inadequate blood glucose control results on
many long term complications including: kidney
disease, blindness, amputation and nerve
damage. The diabetes epidemic affects almost
10% of California’s population (an estimated
2,500,000+ cases). In fact, diabetes is now the 4th
leading cause of death. However, form many
individuals, the cure for this disease is at hand.
The combination of an insulin-producing islet
transplant and effective immunotherapies has
resulted in a long-term insulin injection-free
existence for some. However, two critical
elements had prevented this "cure" from
generalized applicability. First, there is a shortage
of cadaveric pancreases from which to derive the
islet cells. Second, the long term use of
immunosuppressive drugs to treat islet rejection
has its own health consequences. Therefore, a
remarkable opportunity lies ahead for the use of
stem cell-derived islets and novel immune
therapies as a cure for this disease. The planning      $55,000
Alzheimer's disease (AD) is now a nation-wide
epidemic and California is at the epicenter of the
epidemic. One-tenth of all people in the United
States diagnosed with AD live in California. In the
US, 5.4 million people have AD and another
American develops AD every 69 seconds. No
therapeutic strategies exist to prevent or treat
AD. And the situation is worse than expected.
Results of a recent two year clinical study show
that the currently available medications for
managing AD symptoms are ineffective in
patients with mild cognitive impairment or mild
AD.
We seek to develop a small molecule therapeutic,
allopregnanolone (AP) to prevent and treat AD.
AP promotes the ability of brain to regenerate
itself by increasing the number and survival of
newly generated neurons. The AP-induced
increase in newly generated neurons was
associated with a reversal of cognitive deficits
and restored learning and memory function to
normal in a preclinical mouse model of AD.
Further, AP reduced the amount of AD pathology
in the brain. Importantly, when given peripherally
either by injection under the skin or applied
topically to the skin, AP was able to enter the
brain to increase the generation of new neurons.
The unique mechanism of AP action reduces the
risk that AP would cause proliferation of other
cells in the body. Because AP was efficacious in
both pre-pathology and post-pathology stages of
AD progression, AP has the potential to be
effective for both the prevention of and early
stage treatment of Alzheimer's disease. Further,
AP induced neurogenesis and restoration of
cognitive function in normal aged mice suggesting
that AP could be efficacious to sustain cognitive
function and prevent development of AD in a
normal aged population. In other clinical studies,




To plan for a Phase I-IIa clinical trial to determine
safety, dosing and clinical efficacy, we have
assembled an interdisciplinary team of clinicians,
scientists, therapeutic development, regulatory,
data management and statistical analysis experts.
The objectives of this proposal are to: a) develop
allopregnanolone as a therapeutic for Alzheimer's
disease; to plan an early clinical development
program for its use as a neurogenesis agent; b)
file a complete and well-supported IND with the
Food and Drug Administration (FDA); c) complete
phase I/IIa clinical studies to evaluate safety,
biological activity, and early efficacy in humans;
and (d) complete a phase II clinical trial that will
evaluate efficacy and lead to larger multisite
clinical studies of efficacy.                           $107,989 Alzheimer's disease
Huntington's disease (HD) is a devastating
degenerative brain disease with a 1 in 10,000
prevalence that inevitably leads to death. These
numbers do not fully reflect the large societal and
familial cost of HD, which requires extensive
caregiving. HD has no effective treatment or cure
and symptoms unstoppably progress for 15-20
years, with onset typically striking in midlife.
Because HD is genetically dominant, the disease
has a 50% chance of being inherited by the
children of patients. Symptoms of the disease
include uncontrolled movements, difficulties in
carrying out daily tasks or continuing
employment, and severe psychiatric
manifestations including depression. Current
treatments only address some symptoms and do
not change the course of the disease, therefore a
completely unmet medical need exists. Human
embryonic stem cells (hESCs) offer a possible long-
term treatment approach that could relieve the
tremendous suffering experienced by patients
and their families. HD is the 3rd most prevalent
neurodegenerative disease, but because it is
entirely genetic and the mutation known, a
diagnosis can be made with certainty and clinical
applications of hESCs may provide insights into       $3,799,817 Huntington's Disease
Human embryonic stem (hES) cells are
pluripotent such that they can differentiate into
all three germ layers, thus potentially all different
types of tissues of the body. Pluripotency is
characteristic of only embryonic cells, but it can
also be achieved by reprogramming
differentiated cells by transferring nuclear
contents into unfertilized, enucleated oocytes or
by fusing with ES cells. To achieve the initial
embryo-like state, it is a pre-requisite to be able
to maintain and propagate these ES cells in
culture conditions in vitro. Currently, such recipe
exists for mouse ES cells. Surprisingly, similar
media components for hES cells do not work. This
very first technical barrier needs to be overcome
in order to realize full clinical potential of stem
cell therapy. We propose to develop a novel
recipe of chemically defined culture media and
culture conditions to grow and maintain
pluripotency of hES cells. The media we will
evaluate are combinatorial mixtures containing
only recombinant proteins, chemically
synthesizable reagents, or human source factors.
To achieve new sets of recombinant protein
reagents known to be involved in controlling            $796,348
Successful stem cell therapy requires
replacement of diseased or dysfunctional stem
cells with healthy ones. These healthy stem cells
can come from either a donor or can be stem
cells that are modified by gene therapy
techniques. One important step in this process of
repair and replacement is to eliminate the
existing diseased cells so that physical space is
created for the healthy ones, and competition for
environmental factors that nurture and support
the stem cells are removed.
The oldest and most common form of stem cell-
based therapy is bone marrow transplantation
(BMT). Thousands of patients undergo BMT
yearly to treat cancers or disorders of blood
formation. Bone marrow contains mixtures of
cells, but only a minority are the blood forming
stem cells, which are critically important as only
stem cells can permanently generate new blood
cells. In a BMT, stem cells from a donor replace
the recipient's diseased stem cells. Currently, the
only known way to eliminate the patient's own
blood forming stem cells is to treat the recipient
to accept donor cells with toxic agents such as
radiation and chemotherapy.



Our team will focus on the treatment of a
disorder in children called severe combined
immune deficiency (SCID). SCID children are born
without a functional immune system and are
therefore highly susceptible to serious infections.
If children with SCID are not treated, most die by
the age of two. BMT is the only established cure
for this disease. Unfortunately, the likelihood of
successful cure is reduced by the way transplants
are currently performed, using toxic treatments
to prepare the children to accept the donor cells.



We will test an antibody that recognizes a
molecule called CD117 present on blood forming
stem cells. This antibody can safely target and
eliminate these cells. When used in mice, such an
antibody enabled excellent donor stem cell
engraftment and cured mice that had a condition
equivalent to human SCID. Our objective is to test
the antibody that targets human CD117 to safely
prepare children with SCID to accept blood
forming stem cells from a donor. Based on the
animal studies we expect that this antibody will
allow engraftment of stem cells at high levels,
rapidly replacing diseased blood cells with
healthy blood cells. Such a result would mean
safer and better outcomes for these patients.
Success in this study would have impact that
extends far beyond a superior treatment for SCID.
If the antibody treatment results in a stronger
blood system originating from a donor in SCID
patients, this result would prove that the
antibody could be used to optimize engraftment
of gene-therapy modified cells and could be
applied to the treatment the many other diseases
that need a BMT. These diseases include, but are
not limited to sickle cell anemia, thalassemia, and
Fanconi's anemia; autoimmune diseases like
diabetes and multiple sclerosis; and cancers that
originate from the blood system such as
leukemias and lymphomas.                              $109,676 Immune Disease
The stem cell research has started making many
promising discoveries already. Future clinical
trials will require that the location and number of
such cells be tracked in live subjects, over long
periods of time. Tracking of stem cells after
administration is essential for a better
understanding of their migrational dynamics that
could be used to understand treatment
effectiveness. Biomedical imaging offers the
potential for tracking the cells in vivo after
labeling of the cells is achieved by using imaging
agents that enables one to visualize the cells
inside a living organism without performing any
invasive procedures such as surgery. In fact the
problem of imaging small numbers of cells in the
living subject is not limited to stem cell–based
treatments but also has broad applicability in
oncology, immunology, and transplantation. To
overcome the shortcomings of existing
technologies we propose to build the world’s first
combined high field MRI and SPECT molecular
imaging system. This system can be used for stem
cell tracking in living small animals. This device
will combine the advantages of MRI with SPECT
since images from both techniques will be             $719,798

A important benefit of the tremendous progress
in stem cell research has been the recognition
that stem cell pathways are frequently re-
activated in cancer cells conferring stem cell-like
properties on a subset of tumor cells. This
understanding is the basis for the emerging field
of cancer stem cell (CSC) research.
The cancer stem cell paradigm is a new approach
in cancer research that has profound implications
for new anti-cancer drug development. It is now
widely understood that tumors are comprised of
different cell types. Experimental evidence has
accumulated from many laboratories indicating
that different tumor cells vary dramatically in
their ability to grow a new tumor. The tumor cells
capable of re-growing a new tumor are the CSCs,
whereas the bulk of the tumor cells lack this
capacity. This property of seeding new tumor
growth is analogous to the growth of distant
metastases that is a major cause of mortality in
cancer patients. The highly tumorigenic cells CSCs
share certain properties with normal stem cells,
but have accumulated cancer causing mutations
clearly making them abnormal. It is now widely
appreciated that may current therapies fail to
effectively target the CSC population, and thus
the CSCs mediate recurrence of disease after
treatment. New drugs that target CSCs to kill
them or cause them to differentiate into less
dangerous, non-tumorigenic cells have the
potential to provide significant benefit to patients
and to dramatically improve cancer treatment.




                                                       $65,120 Cancer
This project is focused on developing a new anti-
cancer drug that has been shown to effectively
block CSC self renewal in a variety of common
types of cancer. New therapeutic agents that are
effective in targeting cancer stem cells may
reduce metastases and relapse after treatment
thus providing a chance for improved long term
survival of cancer patients. In the first phase of
the project, we will complete the manufacturing
of the drug for subsequent use in clinical trial and
also execute safety studies that are necessary
before initiating clinical trials. Next, we will test
the safety of the drug in patients in Phase 1
clinical trials. Lastly, we will determine the
efficacy in breast cancer patients in Phase 2 trials.
This project will utilize innovative clinical trial
designs to identify the patient populations most
likely to benefit from treatment with this new
treatment. We intend to focus our clinical testing
on an important subset of women with breast
cancer for whom effective therapies are currently
lacking. Our project is a unique partnership of
industry and academic researchers and clinicians
dedicated to bringing new medicines to patients
most in need of effective therapy.                        $65,120 Cancer
Cardiovascular diseases account for an estimated
$330 billion in health care costs each year, afflict
61.8 million Americans, and will account for more
than 1.5 million deaths in the U.S. this year alone.
A number of these diseases are characterized by
either insufficient blood vessel growth or damage
to the existing vessels, resulting in inadequate
nutrient and oxygen delivery to the tissues. The
most common clinical example of this is a heart
attack, or myocardial infarction, typically caused
by blockage of a coronary artery. The resulting
ischemia (reduced blood flow) induces
irreversible damage to the heart, leaving behind a
non-functional scar tissue. Efforts to restore
blood flow to ischemic tissues have largely
focused on the delivery of protein growth factors
(called pro-angiogenic molecules) that stimulate
new capillary growth. An alternative approach is
to deliver an appropriate cell type that can either
accelerate the recruitment of host vessels or can
differentiate into a functional vasculature
directly. While adult stem cells have shown
promising potential with respect to the former,
the potential of embryonic stem cells (ESCs) with
respect to either of these two possibilities            $2,108,683 Heart Disease
Muscle wasting is a serious clinical problem
associated with a number of diseases and health
conditions, affecting individuals of all ages.
Muscular dystrophy (MD) is a form of muscle
wasting disease resulting from genetic mutations.
Duchenne muscular dystrophy (DMD) is the most
common form of MD that limits motility and life
expectancy of children. It is characterized by
progressive skeletal muscle degeneration, and
occurs in 1 out of every 3,500 male births.
Currently, there is no effective treatment to stop
or reverse DMD. One of the potential clinical
solutions for treating DMD is cell transplantation
where the implanted cells contribute to the
functional muscle regeneration. Adult stem cells
such as mesoangioblasts and AC133 cells have
already been shown to ameliorate dystrophic
muscle pathology in animals. Although embryonic
stem cells (ESCs) can provide unlimited numbers
of progenitor cells with the ability to contribute
to the formations of functional skeletal muscle,
their ability to reverse/repair wasting muscle has
not been explored in detail. To this end, we seek
to develop an ESC-based cell transplantation
therapy for treating muscle-wasting pathology,
focusing on DMD. Three specific aims are             $2,300,569 Muscular Dystrophy
There are two main avenues of discovery open to
medical scientists to find cures or alleviate
suffering in people: 1) pharmaceuticals and 2)
stem cells. Both of these branches of research use
the emerging technological tools of imaging,
genetic engineering and nanotechnology to
explore new ways to manipulate molecular and
cellular processes. In this project, called "Nicola",
we boldly propose to do what has yet to be done,
that is to make images of individual stem cells
within a living animal (i.e., a lab mouse). In order
to determine the location of the cells relative to
recognizable structures, we will create a "dual-
modality" imager that will use MRI images for
scientists to see where the single cells are located
within the mouse. It should be noted that other
methods such as optical (visible light), PET, MRI,
etc. have shown signals from multiple (usually
thousands) cells but only optical microscopy of
thin slices of tissue on a glass sample slide have
demonstrated single cell identification. Optical
methods involving very thin fibre optics threads
can "see" individual cells within a living mouse,
but only to a depth of 0.3 millimeters from the
end of the fibre. Users of the optical microscopy        $949,748
This application proposes to develop a Stem Cell
Core Facility of ~1700 square feet to support the
use of human embryonic stem cells (hESC) for a
growing consortium of stem cell scientists at the
home institution as well as neighboring
institutions. The facility will be built and managed
so as to allow use of non-NIH-approved hESC cell
lines as well as research funded by non-federal
agencies including the California Institute for
Regenerative Medicine (CIRM). The Facility will be
centrally located adjacent to other existing,
successful core facilities and within short walking
distance of all the users at the home institution.
The Facility will be managed by an Oversight
Committee consisting of faculty experienced in
hESC and associated technologies, as well as
those with experience in managing shared core
facilities. The Committee will have close contact
with an established Biotechnology Impacts Center
to address any ethical issues that may arise. The
users at the home institution consist of an
energetic, interdisciplinary group of both young
and established investigators who have made a
substantial commitment to stem cell biology.
Within the past several years, they have held           $3,658,353
Human embryonic stem (hES) cells and induced
pluripotent (iPS) cells, such as reprogrammed skin
cells, offer the potential to revolutionize medicine
because they can replicate indefinitely and
become virtually any cell in the body. They
therefore have the potential to provide a limitless
source of cells to replace cells lost to injury (spinal
cord, skin wounds, etc.) or degenerative diseases
like diabetes, Alzheimer                                  $4,721,706
The primary goal is to bring a safe and effective
therapy to children with severe large airway
disease. Our intent is to implement all of the
necessary steps for a successful new
stem/progenitor cell-derived airway transplant
for clinical trials in children within 4 years. Our
team builds on first-in-human surgical success
with a stem cell-based tissue engineered airway
implant in a compassionate care case in a young
adult and in a child. To this end, we will perform
the necessary preclinical studies to support a
successful FDA application within 4 years. We
propose to use stem/progenitor cells from the
patient to treat an extraordinarily difficult-to-
manage health problem in children, namely large
airway disease. In children this leads to collapse
of tracheal cartilage causing severe airway
obstruction that is life-threatening. It occurs in
approximately 200 California children each year
and the morbidity and mortality associated with
this disease is very high. Approximately 25% of
these young patients die before their first
birthday. Treatment costs for these children are
very high, and the familial and societal
investments are substantially higher, although
In 2008 and 2010, a stem cell based, tissue
engineered tracheal implant was successfully
used by our team to save a young woman's and a
child's life, respectively. These first-in-human
studies emphasize that our goal is realistic and
paves the way for clinical trials in children after
carefully designed safety studies are completed
for preclinical testing. Stem/progenitor cell-
derived airway transplants that use the patient's
cells have the clinical advantage of not requiring
anti-rejection medications long-term. Our
experience, to date, indicates such medication is
not needed and this finding represents a scientific
and clinical breakthrough in organ
transplantation. While clear medical benefit was
demonstrated in these proof-of-principle,
compassionate care human cases, there is
substantial work that must be done before
considering such transplants for pediatric
patients, and on a large scale, for adults. We
address this challenge with our team approach
and emphasize the synergism resulting from
linking team members with expertise in a variety
of scientific and medical disciplines to address
this critical need. This new therapeutic approach
could offer a tremendous benefit to children and      $71,218 Respiratory Disorders
Because there is still considerable morbidity and
mortality associated with the process of
transplantation, and because more than a
thousand people die each year while on the liver
transplantation list, it is evident that improved
and safer liver transplantation would be valuable,
as would approaches that provide for an
increased number of transplantations in a timely
manner. A technology that might address these
issues is the development of a human liver cell
line that can be employed in liver cell
transplantation or in a bioartificial assist device.
Developing such a cell line from human
embryonic stem cells (hESC) or from other human
stem cell sources would provide a valuable tool
for pharmacology studies, as well as for use in cell-
based therapeutics. In the proposed studies, we
will differentiate human embryonic stem cells or
fetal liver cells or bone-marrow derived cells so
that they act like liver cells in culture. Once it has
been established that the cells are acting like liver
cells by producing normal human liver proteins,
and that they do not act like cancer cells, the cells
will be injected into the livers of
immunoincompetent mice that do not rejects               $2,504,614 Liver Disease

Little is known about human Neurla Crest (NC)
cells, a transient population of cells briefly
present during very early human development;
the reason why these cells are extremely difficult
to obtain and study. In the model organism NC
cells generate an amazing array of tissues,
including peripheral and enteric nervous systems,
cranial bones and cartilage, some cardiac muscle
and virtually all pigmented cells in the body.
Abnormalities in NC cells involved in numerous
human pathologies including various skeletal
syndromes (e.g. Apert syndrome), diseases of
nervous system (e.g. Hirschsprung                         $759,000
Purity is as important for cell-based therapies as
it is for treatments based on small-molecule
drugs or biologics. Pluripotent stem cells possess
two properties: they are capable of self
regeneration and they can differentiate to all
different tissue types (i.e. muscle, brain, heart,
etc.). Despite the promise of pluripotent stem
cells as a tool for regenerative medicine, these
cells cannot be directly transplanted into
patients. In their undifferentiated state they
harbor the potential to develop into tumors.
Thus, tissue-specific stem cells as they exist in the
body or as derived from pluripotent cells are the
true targets of stem cell-based therapeutic
research, and the cell types most likely to be used
clinically. Existing protocols for the generation of
these target cells involve large scale
differentiation cultures of pluripotent cells that
often produce a mixture of different cell types,
only a small fraction of which may possess
therapeutic potential. Furthermore, there
remains the real danger that a small number of
these cells remains undifferentiated and retains
tumor-forming potential. The ideal pluripotent
stem cell-based therapeutic would be a pure             $1,869,487
A deeper understanding of the biological
mechanisms that govern stem cells requires
detailed, real-time image analysis of living cells.
Currently, conventional live microscopy
techniques are ineffective at imaging features like
the nucleus in the center of a cell, principally due
to aberrations caused by imaging through
cytoplasm, organelles and other molecules inside
the cell. Similar image distortions occur when
looking at an object at the bottom of a pool,
where motion of the water causes the image to
“shimmer.” We therefore propose to develop an
improved wide-field microscope with dynamically
adjustable optics for live imaging deep within
tissues containing stem cells. Application of
technical innovations recently developed by
astronomers that provide clearer images of stars
is central to our approach. In astronomy, lasers
are used to create reference beacons which can
be used to adjust the optics in the telescope to
correct for image distortions caused by changes
in the atmosphere, such as winds and dynamic
temperature changes that cause the stars to
“twinkle.” Such distortions can then be corrected
by using a dynamically deformable mirror, similar
to the curved mirrors in fun houses, which make        $552,985
The immune system protects us from invading
pathogens, but has to be kept in check to prevent
harmful responses to our own tissues. Unique
immune "suppressor" cells have been recently
characterized that prevent harmful responses to
our own cells and proteins. We have recently
identified unique populations of white blood
cells, called dendritic cells that can induce the
development of such "suppressor" cells. More
importantly these immunosuppressive dendritic
cells are unique in that they have special
molecules on their cell surface that target them
to tissues in the body where autoaggressive
immune cells are either killed off or shut down
during the development of the immune system.
We wish to (i) expand and isolate populations of
dendritic cells based on their cell surface
expression of these special trafficking molecules
and then (ii) use them as facilitator cells in
transplants of stem cells from a foreign donor.
The idea behind our approach in stem cell
transplantation therapy is that
immunosuppressive dendritic cells from donor A
will educate the immune system in recipient B to
recognize cells and proteins from the donor as
self and not to mount destructive rejection         $885,475
An important aspect of understanding stem cell
biology is to have a basic understanding of the
processes that balance stem cell self-renewal and
differentiation. Stem cell proliferation and
differentiation signals are at least partially
regulated by direct contact between cells. For
example, stem cells normally reside in a specific
microenvironment, or "niche", that integrates
specific cell-cell contacts in order to translate
information from the environment into
proliferation patterns. In this SEED proposal we
plan to investigate the role of Eph/ephrin
signaling in hESC growth and differentiation. Eph
receptor tyrosine kinases and their ligands,
ephrins, are large gene families that initiate signal
transduction pathways which lead to changes in
cellular adhesion, proliferation, and migration.
Both Ephs and ephrins are expressed on the
surfaces of cells, thus restricting their interactions
to sites of direct cell-cell contact. It is known that
Ephs and ephrins are expressed in hESCs and are
therefore in the right place to be involved in
regulating hESC proliferation and differentiation
decisions. To better understand how Ephs and
ephrins might be involved in hESC growth                 $499,999
The adult human heart contains small numbers of
cardiac stem cells that are able to partially repair
the heart following a heart attack or throughout
the course of progressive heart failure. We have
developed a method to isolate these cells and
grow them to large numbers in the lab. Isolation
begins with a minimally-invasive biopsy taken
from a patient's heart. Our method can be used
to then generate clusters of cells (termed
"cardiospheres [CSps]") or individual cells (termed
"cardiosphere-derived cells [CDCs]"), each with
their own advantages and disadvantages. When
delivered to animals after a heart attack or in the
midst of heart failure, these cells can better
repair the heart, form new heart muscle and new
blood vessels. CDCs are currently being given to
patients after a recent heart attack, using a
catheter to deliver the single cells into a blood
vessel supplying the heart, as part of an ongoing
clinical trial. The proposed research aims to test
both CSps and CDCs in large animals in the midst
of heart failure, using a catheter to deliver the
cells directly into the heart muscle, in preparation
for another clinical trial. Preliminary data shows
that CSps may be a more potent cell therapeutic
when compared to their single cell counterparts.       $5,560,232 Heart Disease
The leading cause of visual loss in Americans over
the age of 65 is age related macular degeneration
(AMD) which occurs in both a "wet" and a "dry"
form. Both forms of the disease are associated
with loss of cells called retinal pigmented
epithelium (RPE) which can lead to profound loss
of central vision. Currently, there is no treatment
that will reverse or prevent the loss of these cells
and associated blindness. Nutritional
supplementation with antioxidants, macular
pigments and long chain PUFAs was shown to
slightly reduce disease progression but the clinical
reality is that 6-8% of people over the age of 75
are legally blind from this disease. Others have
observed that RPE cells can be obtained from
human embryonic stem cells and that these cells
may be transplanted into eyes of animals with
diseases that resemble human macular
degeneration with RPE dysfunction. Potential
problems with this approach to treating humans
with this disease include the possibility that the
embryonic stem cells from which the RPE are
derived may be carried over into the eye and
form tumors or elicit an immune response in the
recipient eye since the cells are not from the         $5,945,738 Aging, Vision Loss
Parkinson's disease (PD) is a devastating
movement disorder caused by the death of
dopaminergic neurons (a type of nerve cells in
the central nervous system) present in the
midbrain. These neurons secrete dopamine (a
signaling molecule) and are a critical component
of the motor circuit that ensures movements are
smooth and coordinated. All current treatments
attempt to overcome the loss of these neurons by
either replacing the lost dopamine, or modulating
other parts of the circuit to balance this loss or
attempting to halt or delay the loss of
dopaminergic neurons. Cell replacement therapy
(that is, transplantation of dopaminergic neurons
into the brain to replace lost cells and restore
function) as proposed in this application attempts
to use cells as small pumps of dopamine that will
be secreted locally and in a regulated way, and
will therefore avoid the complications of other
modes of treatment. Indeed, cell therapy using
fetal tissue-derived cells have been shown to be
successful in multiple transplant studies. Work in
the field has been limited however, partially due
to the limited availability of cells for
transplantation.
We believe that human embryonic stem cells
(hESCs) may offer a potentially unlimited source
of the right kind of cell required for cell
replacement therapy. Work in our laboratories
and in others has allowed us to develop a process
of directing hESC differentiation into
dopaminergic neurons. To move forward stem
cell-based therapy development it is important to
develop scale-up GMP-compatible process of
generating therapeutically relevant cells
(dopaminergic neurons in this case). The overall
goal of this proposal is to develop a hESC-based
therapeutic candidate (dopaminergic neurons) by
developing enabling reagents/tools/processes
that will allow us to translate our efforts into
clinical use. We have used PD as a model but
throughout the application have focused on
generalized enabling tools. The tools, reagents
and processes we will develop in this project will
allow us to move towards translational therapy
and establish processes that could be applied to
future IND-enabling projects. In addition, the
processes we will develop would be of benefit to
the CIRM community.                                      $6,016,624 Parkinson's disease


Embryonic stem (ES) cells potentially could
provide clinically important replacement tissue
for central nervous system (CNS) disease
treatment, and regenerative medicine
approaches involving ES cells have been
suggested for common CNS disorders. But it has
been difficult to produce the right kind of
replacement tissues from ES cells because the
"differentiation", or cell-type specification
process, takes many days to weeks, during which
time many different stimuli and signaling
molecules need to be physically applied to the
stem cells. This process of "stem cell
differentiation" is slow, costly, laborious, variable,
prone to error and contamination, and ultimately
rate-limiting in the long road leading to clinical
translation. We propose to develop and apply
fast, inexpensive, and robust optical technologies
to the fundamental problem of stem cell
differentiation and regenerative medicine, with
particular focus on CNS disease.                         $3,154,719
There remains an urgent and critical need for a
cell-based cure of diabetes, one of the most
costly diseases in California. Islet transplantation
with persistent immune suppression has shown
promise in curing type 1 diabetes (TID). However,
one major obstacle towards large scale
implementation of this approach is the shortage
of engraftable islets. Human ES cells (hESCs),
which can undergo unlimited self-renewal and
differentiate into all cell types in the body, have
the potential to become an unlimited source of
pancreatic β cells. Significant challenges,
including the lack of chemical defined conditions
for reproducibly differentiating hESCs into
endocrine precursors (EPs), lack of strategy to
purify these EPs to avoid teratoma risk, and
destruction of engrafted islets by allogeneic and
autoimmune rejection despite persistent immune
suppression, hinder clinic development of this
promising hESC based therapy.




Ongoing research in our laboratories is directed
at developing novel strategies to derive β-cells
from hESCs. Of the several genetic factors that
contribute to stem cells differentiation, miRs
(microRNAs) are emerging as important
determinants. We hypothesize that identification
and validation of the temporal expression of miRs
at discrete, functionally defined and genetically
marked stages of hESC differentiation to insulin-
producing cells, when combined with a
computational/systems biology approach, will
create a population of cells of significant
therapeutic impact. The proposed studies will
translate basic large-scale analysis of miR and
mRNA from pancreatic precursors derived from
hESC into a fundamental understanding of
differentiation. This in turn will ultimately lead to
novel treatments for T1D.
In this project we will elucidate the importance of
miRs in pancreatic cell differentiation through
functional testing, genetic marking, deep
sequencing, computational analysis, and
validation. Within the context of the above-
stated general aims the sequencing studies will
be initiated for 3 reasons: 1) to establish on site
the most powerful approaches currently available
for measuring gene identity and expression 2) to
ensure that novel and established miRs are
evaluated for changes in expression during hESC
differentiation 3) to validate targets of miR
action. Application of this emerging technology to
β-cell genesis will allow the generation of miR
and mRNA profiles from uniform cell populations
and validation through functional assays.
Together, this information will help to better
understand, describe, and ultimately optimize
hESC differentiation. Basic research from this
project has the potential to create a paradigm
shift in understanding the cellular ontogeny of
the pancreas and help identify which cell types
can be used for transplantation therapy in T1D.       $1,313,649 Diabetes
Diabetic foot ulcers (DFU), chronic, non-healing
wounds on the feet of diabetic patients, present a
serious challenge to global health. These ulcers
affect between 15-25% of the 18-21 million
Americans who have diabetes (world-wide
incidence of diabetes: 366 million people). DFUs
have a huge impact on our health care system,
not only in terms of economic cost, but also from
a psychosocial perspective, associated with
significant morbidities, decrease in quality of life,
prolonged hospitalization and importantly, often
result in the amputation loss of lower extremity.
In the United States, persons with diabetes are at
twice the risk for amputation compared to non-
diabetic individuals. According to recent census,
DFU is the leading cause of lower limb
amputation and greater than 85% of amputations
are preceded by an active foot ulcer. Treatments
for curing DFU are very far from optimal. Current
standard of care can cure only about 30% of DFU
and even the most advanced therapies, cell-
based devices containing skin-derived
keratinocytes and fibroblasts, boost the cure rate
only to about 50%, leaving a tremendous unmet
need for new effective cures for DFU. The
research that we propose with our collaborative         $4,526,900 Skin Disease
The proposed CIRM Bridges to Stem Cell Research
Award will support and enhance further
development of an existing stem cell biology
training program that includes a wide range of
internship opportunities, a rigorous curriculum,
substantive auxiliary training opportunities, and
stem cell techniques coursework at a CIRM-
funded Shared Research Laboratory. Based upon
the applicant institution’s demographics (nearly
76% minorities, 45% low-income, and 47% first-
generation) and their experience in
biotechnology training, it is anticipated that CIRM
Bridges interns recruited for the project will
represent the diversity of California’s population.
The grant project will build upon existing
partnerships between the home institution and
three outstanding host institutions that have
collaborated on earlier projects to enhance stem
cell research. Potential interns will be recruited
through strong community outreach, including
dissemination of General Education modules for
stem cell education, inviting students from other
colleges and universities to attend seminars and
programs, advertising through campus and
community media outlets, and support from
established biotechnology research and training       $3,609,138
Congestive heart failure afflicts 4.8 million
people, with 400,000 new cases each year.
Myocardial infarction (MI), also known as a
"heart attack", leads to a loss of cardiac tissue
and impairment of left ventricular function.
Because the heart does not contain a significant
number of multiplying stem, precursor, or reserve
cells, it is unable to effectively heal itself after
injury and the heart tissue eventually becomes
scar tissue. The subsequent changes in the
workload of the heart may, if the scar is large
enough, deteriorate further leading to congestive
heart failure. Many stem cell strategies are being
explored for the regeneration of heart tissue,
however; full cardiac tissue repair will only
become possible when two critical areas of tissue
regeneration are addressed: 1) the generation of
a sustainable, purified source of functional
cardiac progenitors and 2) employment of cell
delivery methods leading to functional
integration with host tissue. This proposal will
explore both of these 2 critical areas towards the
development of a living cardiac patch material
that will enable the regeneration of scarred
hearts.                                                $1,706,255 Heart Disease
The Burnham Institute proposes a CIRM type II
program to train pre-doctoral PhD students and
post-doctoral scientists. Currently, Burnham
Institute faculty direct a large stem cell research
and teaching enterprise that comprises over 100
biologists, chemists, engineers and clinicians with
extensive expertise in stem cell biology and in
allied disciplines dedicated to stem cell-based
therapies for cardiovascular, neurodegenerative,
hematopoietic and metabolic disorders.
Additionally, the Institute has made substantial
technology, recruitment and infrastructure
investments as part of its commitment to stem
cell biology. Our training curriculum will
incorporate 1) an intensive hESC training course
that has been run for two years and offers
practical, hands-on instruction, 2) additional
courses in stem cell, development, animal models
of disease, bioinformatics and chemical biology,
3) training in ethical and legal implications of
stem cells, and 4) laboratory research. Courses
will be open to other CIRM program trainees in
the La Jolla area and students will benefit from
our inter-institutional research and training
collaborations. PhD degrees will be granted
through our existing training partnership with        $1,489,640
Stem cell research has the potential to improve
the health care of all Californians. To achieve this
goal and maintain state government and public
support in California for stem cell research, stem
cell education needs to be made accessible to all
California university students since some of them
will become part of the stem cell workforce and
many others will make up the large body of
future governing officials and voting voices of
California. Two Bacchalaureate/Master's degree
universities will collaborate in the development
of a stem cell program to do this. To prepare
students to enter the California stem cell
workforce, we will provide research internship
opportunities at major research-intensive
institutions for qualified undergraduate and
Master's degree students. Since our large pool of
candidates includes many under-represented
minority students, the program will make a
significant contribution to the training and
diversity of California's future stem cell research
workforce. To give the large, ethnically diverse
California student population a basic
understanding of stem cell research, stem cell
curriculum for both life science majors and non-
majors will also be developed. An online stem cell     $3,008,975
The field of stem cell biology has developed into a
rapidly expanding technology offering novel
therapeutic approaches to human disease.
California has taken the lead in the development
and expansion of these technologies. There is
critical need to recruit, educate, and train the
next generation of scientists that will work on
achieving these goals. The focus of our program
will be to recruit students from California’s large
and diverse population, and to provide them with
the educational and technical skills that will allow
them to pursue careers in stem-cell research. The
strength of our proposal include our ability to
effectively utilize our geographical location by
recruiting students from our home institution and
community college partners and train them
effectively to carry out successful research
internships with our host institutions. The
greatest key to the success of our plan relies on
our geographical location and the collaborations
and partnerships we established throughout our
region. We have established partnerships with
the leaders in stem cell research in academia
including the [REDACTED]. In addition, or
students will have the option to intern in
premiere biotechnology companies including             $3,613,311
The ability to direct the differentiation of resident
mesenchymal stem cells (MSCs) towards the
cartilage lineage offers considerable promise for
the regeneration of articular cartilage after
traumatic joint injury or age-related osteoarthritis
(OA). MSCs can be stimulated in vitro to form
new functional cartilage. In the OA-affected joint,
the repair is insufficient, leaving a damaged
matrix, suggesting that key factors are missing to
properly direct the regenerative process.
Molecules that activate the chondrogenic
potential of cartilage stem cells may potentially
prevent further cartilage destruction and
stimulate repair of cartilage lesions. Currently
there are no disease-modifying therapeutics
available for the 40 million Americans suffering
from OA. Therapeutic options are limited to oral
and intra-articularly injected pain medications
and joint replacement surgery. The primary
objective of this project is to develop a non-
invasive, therapeutic for the regeneration of
cartilage in OA. This new therapy will target the
resident MSCs in the joint, stimulate production
of new cartilage matrix, promote repair and thus
limit additional joint damage and improve joint         $6,792,660 Arthritis, Bone or Cartilage Disease
The present planning grant application lays the
groundwork for a collaborative heart disease
regenerative medicine team. We plan to develop
sequential preclinical and clinical investigations
directed at regenerative stem cell-based
approaches to treating the following major
cardiovascular diseases: heart attack and its
sequelae; congestive heart failure; and heart
block requiring a pacemaker. The basic
foundation necessary to justify focused preclinical
studies has been achieved by members of the
collaborative team and by investigators
elsewhere. We will plan detailed milestone-driven
studies aimed at direct clinical applications in the
above-mentioned cardiovascular diseases.
Autologous adult cardiac stem cells (CSCs) will be
used to treat myocardial infarction as well as
cardiomyopathy. Cell delivery will be via
catheters like those used to perform angioplasties
on diseased coronary arteries. This work needs
minimal additional preclinical work in large
animals in order to be ready for regulatory filings
in anticipation of human studies. To treat heart
block, we will develop human embryonic stem
cell (hESC)-derived biological pacemakers as a
clinical product. Work to date has demonstrated        $46,886
Diabetes exacts a tremendous toll on patients,
their families, and society in general.
Autoimmune Type 1 diabetes, often called
juvenile-onset diabetes, is caused by a person's
own immune system mistakenly destroying their
insulin-producing cells in the pancreas, known as
beta cells. When those beta cells are lost, the
ability to produce insulin in response to food
intake is lost, and blood sugar can increase to
toxic levels. Although not due to autoimmunity,
Type 2 diabetics often lose their ability to
produce insulin as well. While pharmaceutical
insulin is commonly used to control both types of
diabetes, it does not sufficiently replace beta
cells, and the adverse short- and long-term
effects of diabetes remain, including dangerous
episodes of low blood sugar, nerve damage,
blindness, kidney damage, foot ulcers leading to
amputations, and cardiovascular disease. Ideally,
one would like to replace lost beta cells, and
attempts to do so have included the use of
pancreatic transplants, beta cell (islet)
transplants, and transplants of animal cells or
tissues. Unfortunately, those approaches are
hindered by 1) the limited amount of donor           $19,999,937 Diabetes


Human embryonic stem (ES) cells have the
capacity to self-renew but also give rise to other
cell types. How this capacity is regulated and
what factors determine one fate over another is
an active area of research. This is because by
understanding the decision making process the a
stem cell goes through, we might be able to
manipulate the process and make stem cells
generate more of themselves or other cell types
of interest. Preliminary studies indicate that one
important determinant of stem cell fate is its         $641,047
Pluripotent stem cells have a remarkable
potential to develop into virtually any cell type of
the body, making them a powerful tool for the
study or direct treatment of human disease.
Recent demonstration that induced pluripotent
stem (iPS) cells may be derived from
differentiated adult cells offers unprecedented
opportunities for basic biology research,
regenerative medicine, disease modeling, drug
discovery and toxicology. For example, using
patient-derived iPS cells, one can model diseases
in vitro and screen for drugs in ways never before
possible, enabling the identification of promising
new therapeutic candidates earlier in the drug
discovery process. In addition, iPS cell derivatives
represent an ideal source for autologous cell
replacement therapies, as they would not be
rejected upon transplantation back into the
patient. While it is clear that iPS cells hold great
promise for finding therapies for diseases, there
are significant hurdles that need to be overcome
before full clinical potential is realized. The
mechanism of iPS cell derivation is largely elusive,
and the process used to generate them is very
inefficient and needs to be improved in significant     $1,458,000
There is a group of brain diseases that are caused
by functional abnormalities. The brains of
patients afflicted with these diseases which
include autism spectrum disorders,
schizophrenia, depression, and mania and other
psychiatric diseases have a normal appearance
and show no structural changes. Neurons, the
cellular units of the brain, function by making
connections (or synapses) with each other and
exchanging information in form of electric
activity. Thus, it is believed that in those diseases
many of these connections are not working
properly. However, using current technology,
there is no way to investigate individual neuronal
synapses in the human brain. This is because it is
not ethical to biopsy the brain of a living person if
it is not for the direct benefit to the patient.
Therefore, scientists cannot study synaptic
function in psychiatric diseases. Because of the
limited knowledge about the functional
consequences in the affected brains, there is no
cure for these diseases and the few existing
therapies are often associated with severe side
effects and cannot restore the normal function of
the brain. Therefore, it is of great importance to      $1,906,494 Autism, Rett's Syndrome
Despite therapeutic advances, cardiovascular
disease remains a leading cause of mortality and
morbidity in both California and Europe. New
insights into disease pathology, models to
expedite in vitro testing and regenerative
therapies would have an enormous societal and
financial impact. Although very promising,
practical application of pluripotent stem cells or
their derivatives face a number of challenges and
technological hurdles. For instance, recent
reports have demonstrated that cardiac
progenitor cells (CPCs), which are capable of
differentiating into all three cardiovascular cell
types, are present during normal fetal
development and can be isolated from
pluripotent stem cells. induced pluripotent stem
cell (iPSC)-derived CPC therapy after a myocardial
infarction would balance the need for an
autologous, multipotent stem cell myocardial
regeneration with the concerns of tumorigenicity
using a more primitive stem cell. However,
translating this discovery into a clinically useful
therapy will require additional advances in our
understanding of CPC biology and the factors that
regulate their fate to develop optimized cell
culture technology for CPC application in




                                                      $1,181,306
Cardiac cell therapy with hiPSC-derived cells, will
require reproducible production of large numbers
of well-characterized cells under defined
conditions in vitro. This is particularly true for the
rare and difficult to culture intermediates, such as
CPCs. Our preliminary data demonstrated that a
CPC niche exists during cardiac development and
that CPC expansion is regulated by factors found
within the niche microenvironment including
specific soluble factors and ECM signals.
However, our current understanding of the
cardiac niche and how this unique
microenvironment influences CPC fate is quite
limited. We believe that if large scale production
of hiPSC-derived CPCs is ever to be successful,
new 3D cell culture technologies to replicate the
endogenous cardiac niche will be required. The
goals of this proposal are to address current
deficiencies in our understanding of the cardiac
niche and its effects on CPC expansion and
differentiation as well as utilize novel
bioengineering approaches to fabricate synthetic
niche environments in vitro. The development of
advanced fully automated in vitro culture systems
that reproduce key features of natural niche
microenvironments and control proliferation              $1,181,306
Stem cells are the building blocks during
development of organisms as varied as plants and
humans. In addition, adult or “tissue” stem cells
provide for the maintenance and regeneration of
tissues, such as blood and skin throughout the
lifetime of an individual. The ability of stem cells
to contribute to these processes depends on their
unique ability to divide and generate both new
stem cells (self-renewal) as well as specialized cell
types (differentiation). In some tissues, cells that
have already begun to specialize can revert or “de-
differentiate” and assume stem cell properties,
including the ability to self-renew. De-
differentiation of specialized cells could provide a
“reservoir” of cells that could act to replace stem
cells lost due to wounding or aging. This proposal
seeks to uncover the mechanisms that are
utilized to regulate the process of de-
differentiation and to compare these to the
mechanisms that endow stem cells with the
ability to self-renew. A thorough understanding
of the factors that regulate self-renewal programs
will be essential for the expansion and long-term
maintenance of adult stem cells in culture, a
necessary step towards the successful use of stem       $2,675,234 Aging
Adult heart muscle cells retain negligible
proliferative capacity and this underlies the
inability of the heart to replace muscle cells that
are lost to injury, such as infarct, and underlies
progression to heart failure. To date, no stem cell
therapiy has produced significant cardiomyocyte
replacement. Instead, transplanted cells, if they
persist at all, produce endothelial cells or
fibroblasts and the ameliorating effects on heart
function that have been reported have been
achieved by improving contractility, perfusion or
other processes that are impaired in the failing
heart. This proposal is to develop specific
reagents and ultimately drugs to stimulate
regeneration. Our approach integrates advances
in stem cell biology, high-throughput (HT)
biology, informatics and proteomics to identify
small molecules, proteins and signal transduction
pathways that control heart muscle formation
from human embryonic stem cells (hESCs). High
throughput assays will be developed and
implemented to identify genes, signaling
proteins, and small molecules that that control
important steps in the differentiation,
proliferation, and maturation of cardiac cells.         $3,036,002 Heart Disease
This Level II Training Grant will support seven PhD
Post-Doctoral and three MD Clinical Fellows for
training in stem cell biology, and the clinical and
ethical implications of stem cell research. The
program is based in one of the top six of the
nation’s pediatric stand alone Institutions. Over
the past 25 years, we have built an internationally
renowned research program in stem cell biology
and its clinical applications. The program was
founded on the fields of human hematopoietic
stem cell biology, transplantation and gene
therapy. In the past two decades, integration of
research in developmental biology and tissue
regeneration have expanded the reach of the
program into other types of somatic stem cells
including lung, pancreas, liver, gut, bladder and
mesenchymal tissue. In the past 6 years, we have
developed expertise in human embryonic stem
cell (hESC) culture and differentiation and have
established an hESC tissue culture core. A unique
focus of Stem Cell Training will be on applications
to pediatric disorders such as diabetes,
monogenic inherited disorders (cystic fibrosis,
muscular dystrophy, sickle cell disease, etc), and
congenital birth defects. It is our central
hypothesis that childhood disorders will be           $5,103,441

The proposed program is a collaboration between
two institutions that collectively represent a
range of exciting stem cell research opportunities.
The proposed program augments an established
summer research program that has been
providing biomedical research experiences to
high school and college students for 30 years. The
objectives of the program are to:

1) Recruit 4 high school students, including those
from socioeconomically disadvantaged
backgrounds


2) Match the students with mentors to undertake
a stem cell biology project over an eight-week
period, culminating in presentation of their work
in a research symposium

3) Stimulate students' interests and enhance
exposure to stem cell issues
4) Engage the students in a secondary enriching
discipline

5) Provide students with academic and
psychosocial support



The proposed program will inform and increase
the awareness of high school students in stem
cell research during a formative time of their
lives. It is anticipated that a positive and
nurturing summer experience will help stimulate
their interest to pursue a career in stem cell
research. Across California, the CIRM Creativity
program will contribute toward producing a
generation of stem cell researchers who can
approach problems in new ways, which will be
necessary for new breakthroughs and to keep
California competitive internationally in the stem
cell field.                                               $115,500
FACILITY The Buck Institute for Age Research
proposes to develop a CIRM Major Facility to
investigate the role of stem cells in aging and in
the pathogenesis, diagnosis and treatment of age-
related disease. A new building devoted to
human embryonic stem cell (hESC) research will
be constructed adjacent to space earmarked for
our CIRM Shared Research Laboratory and Stem
Cell Techniques Course. The project will be
expedited by our recent experience completing a
NCRR Center for Integrative Studies of Aging on
time and within budget. The CIRM Major Facility
will contain laboratories for 12 principal
investigators (PIs) and space for cell culture,
shared equipment and research cores. The cores
will be devoted to cell sorting, imaging, genomics,
proteomics, high-throughput screening (HTS),
electrophysiology and bioinformatics/statistics,
and will be fiscally separate satellites of existing,
NIH-supported cores. The CIRM Major Facility will
be closely integrated with our CIRM Shared
Research Laboratory, which will house another 4
PIs. Core support within the Institute but outside
the Facility will include the vivarium and the
transgenic and animal-behavior cores. PROGRAM
The Buck Institutes                                     $20,500,000
Children born with sickle cell anemia (SCA),
caused by a genetic defect in hemoglobin, have
severe anemia and damage to virtually all the
body organs: the damage begins in infancy, and is
frequently fatal by early adulthood. This is one of
the most common inherited diseases in the
world: because of California’s ethnic diversity it is
relatively common here, often in underserved
populations. Our research team is dedicated to
the treatment and, when possible, cure of this
devastating disease. We and others have shown
that transplantation of blood stem cells from
bone marrow can cure SCA, and this type of stem
cell therapy also is used in treating other blood
and genetic diseases. Unfortunately, not all
individuals are cured after bone marrow
transplantation, as this is a risky treatment. We
have carried out pioneering work showing that
blood from the umbilical cord (“cord blood”) of a
newborn sibling can be used to cure blood
disease in the affected sibling. A significant part
of our effort is devoted to discovering ways to
improve and extend the use of cord blood for
blood cell transplantation and make this
treatment less risky. Most recently, we have              $55,000
The promise of stem cell-based therapies is
critically dependent upon being able to direct
stem cell decisions (i.e., pancreatic cells for
diabetes, cardiac cells for cardiac diseases, neural
cells for neurodegenerative disease, etc.). A
fundamental understanding of the cues in the
microenvironment that guide stem cell fate
decisions is essential to develop strategies for
disease-directed regenerative medicine.
Development of robust, reproducible protocols
for stem cell differentiation therapy is dependent
upon a fundamental scientific understanding of
the variables that influence stem cell fate
decisions. The unique theme of our stem cell
research program is quantitative analysis of single
cells at the micro/nano-scale level using
innovative molecular, cellular and bioengineering
approaches to interrogate and manipulate
individual cells in precisely controlled
microenvironments. The proposed Stem Cell
Instrumentation Foundry (SCIF) will provide stem
cell researchers throughout California access to
advanced instruments, techniques and
collaborators for single cell analysis. The SCIF will
be housed in a 5,420 asf facility which includes        $4,359,480
The San Diego Consortium for Regenerative
Medicine ("SDCRM") is a nonprofit organization
formed to marshal the intellectual resources of
four world-leaders in life sciences research,
including the Burnham Institute for Medical
Research, the Salk Institute for Biological Studies,
The Scripps Research Institute and the University
of California, San Diego. In addition to the
collective strength of its members, SDCRM has
established an extensive network of academic
and industrial collaborators to efficiently and
effectively expand the breadth and depth of its
scientific, technological capabilities and
resources. The SDCRM research program goals
are, consistent with those of the California
Institute for Regenerative Medicine ("CIRM"), to
invent research tools and technologies to hasten
the pace of stem cell research progress and to
discover and develop diagnostics, therapies and
cures to relieve human suffering from chronic
disease and injury. The research interests of
SDCRM member scientists are extraordinarily
broad and deep and exceed what SDCRM can
pursue in its initial resident basic research,
preclinical research and preclinical development
programs. That notwithstanding, resident and           $43,000,000
The Stem Cell Center is a cornerstone program of
campus biomedical research that capitalizes on
our strengths in basic and preclinical research, as
well as collaborations with neighboring research
institutions, to support high impact investigations
with several major emphases: (1) stem cell self-
renewal, (2) hematopoietic differentiation, (3)
neural differentiation and neurodegeneration, (4)
cardiovascular and skeletal muscle
differentiation, and (5) cancer and cancer stem
cells. The proposed CIRM Center of Excellence
(CoE) will be the focal point for these efforts and
will be critical to our ability to expand this
program of world class basic and preclinical stem
cell research. The CoE will assemble a critical
mass of investigators who will promote
interdisciplinary collaborations among campus
biologists, engineers, and physical scientists to
make important discoveries that lay the
foundation for developing new therapies for
human disease. Basic investigations of genes that
control stem cell self-renewal and pluripotency
will aid the engineering of synthetic
microenvironments for the large scale, safe
expansion of human embryonic and other stem
cells for cell replacement therapies and diagnostic   $20,183,500
The proposed new CIRM Stem Cell Institute, to be
located at a major public university, will be the
center of scientific and clinical activity to bring
stem cell therapies to patients in the State of
California. This institution has a long-standing
reputation for being highly collaborative, sharing
resources and infrastructure, and for providing
outreach and expertise to other educational and
medical facilities. Our geographical location and
service to diverse communities will ensure that
stem cell treatments are provided to patients that
desperately need them. The rapid renovation of
undeveloped space in a large existing building
adjacent to our medical center and clinics will
establish a new home to co-locate disease teams
that span basic, translational, and clinical
strengths. This setting for disease team-based
research will forge collaborative networks,
promote communication, and accelerate
development of clinical trials for the treatment of
human diseases. The disease teams include, but
are not limited to, investigators working together
toward therapies for liver, kidney, heart, and lung
diseases; bladder reconstruction; peripheral
vascular disease; neurodegenerative disorders         $20,082,400
The Stem Cell Research Program will build upon a
long history of achievement in regeneration and
developmental biology. Program scientists have
made key contributions to developing stem cells,
understanding how and why cells are lost in
aging, understanding how tissues regenerate, and
developing methods to make high purity cells
from human embryonic stem (hES) cells for
treating diseased or damaged tissue. The
program consists of basic scientists carrying out
research to elucidate the fundamentals of stem
cells; translational scientists testing the feasibility
of moving basic studies to the clinic; and clinical
scientists who study specific diseases and
afflicted patients. The new CIRM Institute will
help spawn a new paradigm in medicine, namely
interdisciplinary disease-focused teams consisting
of basic, translational and clinical scientists.
Disease-focused teams will guide discoveries from
the lab bench to the bedside. The program will
focus on neuromotor disorders such as those
caused by spinal cord injury, multiple sclerosis,
and stroke; neurodegenerative disorders such as
ALS (Lou Gerhrig                                          $27,156,000
OVERVIEW: The CIRM Facility will support ~19K+
ASF of laboratory and vivarium not subject to
federal human embryonic stem cell (hESC)
restrictions including: 1. Research labs, 2. Core
facilities, and 3. Career Development space. The
Facility is adjacent to biology, chemistry,
engineering, medicine, and clinical/translational
programs, including our Stem Cell Center (SCC),
FDA compliant GMP facility & CIRM Shared
Research Laboratory (SRL), our Hospital, Cancer
Center, Professional Schools, AIDS Institute, and
the College of Letters and Science and formal
inter-institutional scientific collaborations.
MAJOR PROGRAMS across Elements X, Y, and Z,
include: 1. role of stem cells in hematopoiesis,
vascular biology, immunotherapy for cancer and
related diseases, and immune deficiencies, 2.
analyses of hESC, epigenetic regulation and
pluripotency, and 3. understanding epithelial
stem cells including neural, cardiovascular, and
skin types in normal and abnormal development.
Programs include our engineered immunity
consortium that will express T cell receptor genes
in hematopoietic stem cells to produce cellular
immunity to combat cancer and related diseases.
Our neural stem cell group uses hESC derived
cells to model genetic and injury-induced            $19,854,900
We propose a CIRM Special Program (Research
Element X), supporting basic and discovery
research that will fund renovation of space to
provide for the establishment of a new Center for
Stem Cell Biology and Engineering. CIRM funding
will allow us to expand our growing basic
research on human embryonic stem cells (hESC)
by creating a state-of-the-art facility for new
faculty, for collaborative work and for core
facilities. We will transform antiquated,
inadequate laboratory space to allow research
that will be free of federal restrictions. Research
in the proposed Center will focus on two areas of
basic and discovery stem cell research: Molecular
Mechanisms and Bioengineering. First, studies
will focus on the fundamental molecular
mechanisms of stem cell growth and
differentiation, using hESC and stem cells in
simpler organisms that are useful models of
developmental processes and disease
pathobiology. The second goal will be to
investigate novel methods for stem cell growth,
differentiation, sorting and delivery, using
synergistic cell biological, biomaterial, and
bioengineering technologies. The long-term goal
will be the application of results to the             $7,191,950
We propose a 13,200 square foot research facility
dedicated to basic and discovery research in stem
cell biology on the top floor of a planned, state-
funded biomedical research building. The facility
is designed to house six stem cell faculty and to
support all institute affiliates through the
establishment of several core facilities, including
cell culture, cell sorting, microscopy,
electrophysiology, a sequencing center, and
dedicated space in a new animal facility in the
same building. Other institute affiliates will be
located on other floors of the building or in
buildings nearby. The facility will house the
Institute for the Biology of Stem Cells (IBSC), an
interdisciplinary program currently involving 18
faculty from 5 departments and numerous
collaborators from other institutions. The IBSC
combines the unique strengths of a diverse group
of researchers to address many of the most
challenging problems in stem cell biology. Some
of the projects IBSC faculty are undertaking
include: * Developing computer programs and a
database to analyze the wealth of data being
generated in stem cell research labs throughout
California, and making the data available on a         $34,862,400
The CIRM Facility, at the School of Medicine of
the Lead Institution, will be the home of the
Southern California Stem Cell Scientific
Collaboration (SC3), a comprehensive and
integrated program of basic, pre-clinical and
clinical stem cell research arising from scientific
collaboration between six institutions. The
scientists of SC3 bring together a diverse set of
skills and expertise in stem cell biology,
chemistry, engineering, and medicine, and the
CIRM Facility will be a focal point that catalyzes
interdisciplinary work to accelerate their
discoveries towards cures. SC3 is committed to
the development of a stem cell program,
eventually comprising eighteen research teams,
that will be housed in the new Facility and will
form the core of the research activity. The Facility
will also devote a significant amount of space for
scientists from other departments at SC3
institutions to train in stem cell research and
carry out pilot research projects that will explore
promising new ideas. By sharing facilities,
reagents, and discoveries, SC3 scientists will make
efficient use of state stem cell resources and
accelerate the progress of research to the clinic.     $26,972,500
Leukemias are cancers of the blood forming cells
that afflict both children and adults. Many drugs
have been developed to treat leukemias and
related diseases, but in many cases of adult
leukemia, the diseases are not curable, and cause
disability and eventual death. More than in other
cancers, scientists understand the exact
molecular changes in the blood forming cells that
cause leukemias, but it has been very difficult to
translate the scientific results into new and
effective treatments. The main difficulty has been
the failure of existing agents to eliminate small
numbers of leukemia stem cells that persist in
patients, despite therapy, and that continue to
grow, spread, invade and kill normal cells. In fact,
the models used for drug development in the
pharmaceutical industry have not been designed
to detect drugs or drug combinations capable of
destroying the leukemia stem cells. Drugs against
leukemia cell stems may already exist, or could be
simple to make, but there is not an easy current
way to identify them. Recently, physicians and
scientists at universities and research institutes
have developed tools to isolate and to analyze
leukemia stem cells taken directly from patients.      $55,000
We propose to sponsor a CIRM Research Training
Program in stem cell and regenerative medicine,
which will provide six postdoctoral Ph.D. or M.D.
(Type III) trainees per year with state-of-the-art
stem cell-related research experience and
coursework in a rich scientific environment. The
goal is to prepare trainees for productive,
independent research careers in stem cell and
regenerative medicine, with an emphasis on
training individuals from scientifically and
demographically diverse backgrounds. Consistent
with our mission, the program will focus on stem
cells in aging and age-related disease, with
particular concentration in neurodegenerative
disorders. Required courses will be offered in
Stem Cell Biology; Neurodegenerative Disorders;
Legal, Ethical and Social Issues in Stem Cell
Research; and Career Development. Trainees will
also be invited to participate in other courses and
related activities at the Institute, including weekly
laboratory meetings, a weekly journal club in
stem cell and regenerative medicine, a special
lecture series titled Seminars in Stem Cell Biology,
professional development workshops, and a
Summer Scholars Program for high school and
college students, whom trainees will participate        $3,178,692
Our plan is to establish a ~ 4,700 sq. ft. shared
research laboratory dedicated to the
experimental manipulation and ultimate clinical
application of human embryonic stem cells
(hESC). This Shared Research Laboratory (SRL) is
centrally located on the main campus. The SRL
will be used by researchers focused on
understanding how hESCs are induced to
generate specialized tissues used for regeneration
of the blood forming, nervous, and
musculoskeletal systems. The SRL will be a state
of the art facility accommodating a hierarchy of
functions that includes: ~ 1659ASF of general
hESC, multi-user laboratory space will be assigned
on a time share basis to investigators who do not
have the capacity, or cannot due to federal
restrictions, conduct research with hESC in their
own research laboratory. In addition to cell
culture facilities that will allow multiple groups to
work simultaneously, space in this area includes
an hESC analytic laboratory for the basic
characterization of hESC and their derivatives. ~
2245ASF of space will be used to establish a hESC
GTP suite in which hESC free of infectious agents
can be experimentally manipulated in a manner           $3,740,497
Our CIRM High School Summer Research and
Creativity Program will be an 8-week hands-on
inquiry based mentored research experience
integrated with our existing High School Summer
Research Program. Our Summer Research
Program for high school students has been in
existence for 22 years and has a proven track
record of success in mentored scientific research
and literacy, communication and advancement to
top tier research universities. The programmatic
components include a week-long hands-on stem
cell biology workshop followed by the 10 interns
joining a research team within the Stem Cell
Center or one of the 50 Associate laboratories,
biweekly progress update meetings, a mid-
program social event to create a CIRM student
network, and a program-end research seminar by
all CIRM high school student interns. Using the
rich resources of our institution, the local
community and the CIRM network, a forum
entitled “Stem Cells, Creativity and the Public”
will serve as a platform to integrate stem cell
biology research conducted at the bench with
expression in the humanities, communication to
the public and public policy decision-making.            $264,000
This is a proposal for a Type I Comprehensive
Training Program in Stem Cell Biology to be based
at University of Southern California. Our program
will train post-doctoral and clinical fellows across
27 departments at USC. Pre-doctoral trainees will
be recruited from 11 Ph.D. programs in the
Schools of Medicine and Gerontology and in the
College of Letters, Arts and Sciences. We have
assembled a team of world-class scientists to
teach two new courses developed through this
initiative: an interdisciplinary, USC -based course
in the social, legal and ethical implications of
stem cells, and a joint course among USC, its
affiliate, Children                                    $3,158,532
This is a proposal to renew funding for the host
institution’s Type I Comprehensive Training
Program in Stem Cell Biology. Since funding was
first applied for in the summer of 2005, stem cell
research at the host institution has undergone a
major transformation: a center for regenerative
medicine and stem cell research was established,
and a world class stem cell biologist was recruited
to be its director. Seven new faculty, representing
a wide spectrum of stem cell-related disciplines,
have been recruited as members of the Center.
Groundbreaking for construction of a CIRM Stem
Cell Facility took place in early [REDACTED] 2008.
This initiative was launched with a multi-million
dollar gift from a private foundation, and was
recently matched with a Major Facilities Award
from CIRM. Also with CIRM funding, the host
institution has developed a Training Program in
Stem Cell Biology which has thus far supported 24
individuals. Key features of this program are a
flagship course in stem cell biology, co-taught
with two neighboring institutions, as well as
courses in stem cell ethics, developmental biology
and a practical course in the culture of human ES
cells. A yearly retreat was instituted and created
a website created, which will soon be the              $6,162,053
The proposed project has three major goals. The
first is educating the public about the medical,
biological, and technological advances of stem
cell research and recruiting new scientists into
the workforce. The second is training the
students in the theory and techniques of stem
cell research. The third is retaining these trainees
in the California workforce by providing
specialized training and laboratory internships,
which will lead to long-term career opportunities
in stem cell research in California. To educate non-
scientists and to increase the number of informed
California citizens in the theory and potential of
stem cell research, a new general education
course will be developed at a local community
college as a bridge to our comprehensive
university program. A new module also will be
added to our existing large, lower division,
general education lecture course “Introduction to
Human Diseases.” This course may be the only
life sciences many students will learn in college
and could initiate a life-long appreciation of the
biological sciences, including stem cell
technologies. Such an appreciation will have a
significant impact on our society given the role of    $3,042,698
The aim of the UCLA Type1, Comprehensive
Training Program is to train basic scientists,
engineers and physicians to become leaders in
stem cell research and clinical programs in
academia and industry. A distinctive feature of
the UCLA program is that Scholars will be trained
from a multidisciplinary perspective, which is
possible because faculty from the College of
Letters and Science, and the Schools of Dentistry,
Engineering, Law, Nursing, Medicine, and Public
Affairs are located in close proximity on the same
campus and have developed a tradition of multi-
disciplinary teaching and research collaboration.
The recently established UCLA Institute for Stem
Cell Biology and Medicine (ISCBM) has been built
on this foundation and has received strong
campus-wide support as evidenced by the
allocation of 12 new faculty positions in stem cell
biology and a major space commitment. The
ISCBM will coordinate the training of 5 pre-
doctoral, 5 post-doctoral, and 6 clinical Scholars,
each of whom will be presented with numerous
training options. Some may choose to work with
UCLA faculty who are leaders in cell and
molecular biology, while others will elect to
receive training in gene medicine, cell-based         $3,750,000
The proposed project will build on a robust stem
cell technician training program already in place
at the home institution, expanding and enhancing
student training through the implementation of
10 internship experiences each year as well as a
range of other support activities. Specifically, the

internships to 10 students each year in CIRM-
funded research laboratories or industry labs
working with stem cells. Participating laboratories
include both academic and industry labs
throughout the region. Interns will be recruited
from the pool of students who have completed a
series of cell culture courses at the home
institution and will engage in a six-month
internship for which they will earn college credit.

24 instructional hours, that will prepare students

and update all existing cell culture courses with
cutting-edge information, techniques, and
equipment, serving approximately 60 community

twice each semester through an existing
infrastructure that hosts lectures and events for
community college students, faculty, and staff as      $2,454,307
The mission of the Research Training Program in
Stem Cell Biology is to train CIRM Scholars
scientists at the predoctoral and postdoctoral
levels in the fundamental biology of stem cells
and strategies for translating this knowledge
towards treatment of diseases. By developing
effective scientists and leaders in the stem cell
field, this training will enhance stem cell-based
biomedical research efforts in academia and
industry, and promote the development of novel
therapies for previously intractable diseases. Our
institution is in a particularly advantageous
position to undertake this training because of our
tradition of programs in which research efforts
cross-fertilize with experimental medicine and
clinical practice. As an institution with emerging
stem cell research programs, we are proposing a
Type III training program for two predoctoral and
four postdoctoral CIRM Scholars. To prepare
CIRM Scholars to be productive researchers in
collaborative and disease-oriented research
environments in academia or in industry, we
propose a program of course work and
independent research. The didactic curriculum
will be administered under the auspices of the
Graduate School of Biological Sciences, which        $2,500,143
There are over 1.5 million osteoporotic fractures
annually in the USA alone, at a cost of
approximately $15 billion each year. The majority
of these fractures occur in the spine, followed by
the hip and wrist. Incidence varies according to
age; vertebral fracture rates increase rapidly by
the sixth decade of life, whereas the risk of hip
fracture rises markedly by the eighth decade and
beyond.
Current treatment is focused on prevention using
osteoclast inhibitors, hormone therapy, diet and
exercise. When a fracture occurs current
therapies involve injection of cement into the
vertebral body and/or open surgery with
implants. Unfortunately, these procedures do not
regenerate bone tissue, often fail and incur risks
of leakage and emboli. The clinical and economic
impact associated with these fractures is
substantial. Following a fragility fracture,
significant pain, disability, and deformity can
ensue. If fracture union is not achieved, the
patient may suffer long-term disability. This is
exacerbated because there is a five-fold increase
in the risk for sustaining a subsequent vertebral
fracture and the odds that a neighboring
vertebrae will fail within one year is >20%. We
propose to add a noninvasive anabolic option to
the treatment and prevention of osteoporotic
fractures. This therapy utilizes a novel small
molecule Wnt pathway activator that drives the
endogenous stem cells in the bone compartment
to differentiate into bone forming osteoblasts
thereby increasing bone mass and reducing the
risk of fracture. This therapy will be administered   $99,110 Bone or Cartilage Disease
Chronic skin wounds affect a large number of
patients every year who suffer from diabetes,
burns, venous disease leg ulcers, arterial disease
leg ulcers, pressure ulcers, and ulcers from spinal
diseases. The annual health care costs for wound
care in the United States is $15 billion. The
purpose of our CIRM Disease Team Planning
Award Proposal is to create an investigative team
across the academic departments of Pathology,
Dermatology, Surgery, Dermatology and Cell and
Neurobiology who will work together using stem
cell technology to study regenerative wound
healing of the skin in which there is restoration of
the skin’s normal architecture, lack of fibrosis and
regeneration of skin appendages – hair follicles,
sebaceous glands and eccrine glands. This type of
healing takes place in Nature such as the
regeneration of the limb of a newt, but does not
occur normally in post-natal human beings. Our
team consists of (i) a NIH-funded Plastic Surgeon
who runs the {REDACTED} Burn Unit and has
performed many wound healing clinical trials; (ii)
a NIH-funded Pathologist with expertise in
epidermal-mesenchymal interactions and skin
appendage formation; (iii) an accomplished stem
cell biologist; (iv) a NIH-funded clinical               $42,574
We are proposing to expand our "safe haven"
human embryonic stem cell laboratory to
accommodate the enormous interest in scientific
research in this field, and to provide an
environment that is conducive to the goals of the
CIRM                                                   $4,762,725
A drug was identified through the use of muscle
stem cells that can enhance the effectiveness of
exon skipping by antisense oligonucleotides to
the DMD gene to restore dystrophin expression
and at least partially correct the defect
responsible for loss of muscle function in
Duchenne. We propose to test the effectiveness
of this drug in combination with antisense
oligonucleotides as a novel therapeutic strategy
for Duchenne muscular dystrophy (DMD). DMD is
the most common muscular dystrophy and leads
to progressive muscle loss in boys resulting in
severe weakness, and is caused by mutations in
the DMD gene. DMD generally leads to death in
the teens or early 20's, making Duchenne one of
the most severe disorders in humans. Further,
Duchenne occurs in 1/3500 boys, making it one of
the most common genetic disorders. There are no
highly effective therapies. Thus, there is an urgent
need to develop new and highly effective
therapies. We propose to perform the necessary
studies using DMD patient-derived iPS and animal
models to perform safety studies that will permit
regulatory approval to test the safety and efficacy
of the combination therapy in Duchenne
muscular dystrophy. The goal of the treatment is       $86,414 Muscular Dystrophy
Various cells and organs in the human body
originate from a small group of primitive cells
called stem cells. Human cancer cells were also
recently found to arise from a group of special
stem cells, called cancer stem cells (CSCs). At
present, cancer that has spread throughout the
body (metastasized) is difficult to treat, and
survival rates are low. One major reason for
therapeutic failure is that CSCs are relatively
resistant to current cancer treatments. Although
most mature cancer cells are killed by treatment,
resistant CSCs will survive to regenerate
additional cancer cells and cause a recurrence of
cancer. As opposed to other human stem cells,
CSCs have their own unique molecules on their
cell surface. This project aims to develop agents
that specifically target the unique cell surface
molecules of CSCs. These agents will have the
potential to eradicate cancer from the very root,
i.e., from the stem cells (CSCs) that produce
mature cancer cells. In this project, we will
develop agents that specifically target leukemia
stem cells to determine the feasibility of our
approach. Leukemia is the fourth most common
cause of cancer death in males and the fifth in       $2,567,397 Blood
The aim of California Stem Cells Initiative is to
develop new therapeutical approaches by
utilizing human embryonic stem cells (hESCs) to
renew themselves and to differentiate into a
variety of cell types, thus enabling the
engineering of specific tissues to treat diseases
that cannot be currently cured. To realize the
potential of hESCs in regenerative medicine will
require (1) the establishment of conditions for
the expansion of these cells into a sufficiently
large quantity and (2) the development of
protocols to differentiate them into specific cell
types and generate the desired tissues.
Experimental manipulation of the environmental
cues, such as chemical signals and physical
stresses, to which stem cells are exposed, will
lead to the discovery of conditions that
specifically direct hESC growth and
differentiation. Studies on factors affecting stem
cell growth and differentiation tend to focus on
one or a few elements in the microenvironment,
e.g., some proteins in the matrix underlying the
cell or growth factors brought to the cell from the
circulation or neighboring cells. The proposed
research will develop a platform that will allow       $638,140
The United States government does not fund
research involving human embryos or cells that
were grown from them after August 9, 2001. In
addition, other restrictions have been imposed
that make these types of experiments extremely
difficult to do. For example, work cannot be
conducted alongside research that is funded by
government agencies, the typical mode in which
academic research laboratories operate. In
practical terms, this means that duplicate
facilities must be created to do the large amount
of research that is needed to turn human
embryonic stem cells (hESCs) into robust
experimental tools that will enable us to
understand disease processes, the first step in
curing them. These onerous regulations,
unprecedented in our country, have stifled
progress in this exciting new area of medical
research. Thus, there is a great deal of basic work
that remains to be accomplished. Our group is
focusing on one particular area--the enigmatic
process that occurs when an embryo--which
would otherwise be discarded at the conclusion
of an in vitro fertilization (IVF) treatment--is
donated for research and grown in a laboratory.       $2,532,388
We understand little about human development
especially at the earliest stages. Yet human
developmental biology is very important to stem
cell biology and regenerative medicine for two
reasons: 1) Understanding human developmental
pathways especially of embryonic differentiation
will inform our efforts to derive pluripotent stem
cells and differentiate them to stable progenitors
that are suitable for transplantation or
pharmaceutical applications. Clearly, human
development follows well-defined pathways that
we are just beginning to elucidate. 2)
Understanding human development will allow us
to translate findings to the clinic to alleviate
common problems of women's and children's
health. Errors in the earliest stages of
development are the most common cause of all
birth defects in the human population and yet we
know little of the fundamental ways in which
errors occur. Our lack of knowledge is likely
enhanced by the complete ban of federal funding
for this research in spite of the fact that each year
there is increased clinical use of procedures such
as IVF.


Thus, here we seek to build a map of human
development that combines imaging
(microscopic) data, molecular data, genetic and
epigenetic data to describe human pluripotent
blastomeres (cells) and their potentials. We note
that events in the first few cell divisions, even
before human embryos turn on their own genes,
have repercussions to later generations of cells
and the overall health and welfare of the embryo
and fetus (and likely adult).
Our goals are based on our research over several
years in which we initiated construction of a map
of pathways and programs that function during
embryo development. Our studies provide
methods and algorithms for early diagnosis of
embryo potential in clinics and should be
extended to the diagnosis of the general health of
pluripotent stem cell populations. We expect that
via translation of our basic studies to the clinic,
we will improve outcomes of IVF in terms of birth
of healthy offspring and decrease devastating and
common adverse outcomes such as multiple
births with attending complications to organ
development, epigenetic errors that may result in
miscarriage, and need to reduce fetal number to
increase odds of survival of siblings and/or
mother. Thus, this research may yield benefits to
both maternal/fetal health and stem cell biology
and regenerative medicine.                            $1,425,600
We propose a CIRM Creativity Award program
that builds on our existing summer research
program for undergraduate and high school
students by offering additional elements tailored
to Creativity Award students, including: (a) a
lecture series highlighting local young
investigators, ethical issues, and future
undergraduate educational opportunities, (b) a
series on "The Art in Science", and (c) a project
challenging their creativity and executed
individually or in small groups.



The CIRM Creativity Award program will expose
the next generation of California professionals to
evidence-based stem cell research at an early
time in their scientific development. The actual
practice of scientific research will broaden their
general education at the pre-college stage. CIRM
Creativity Award students may not necessarily
gravitate to scientific research, but their
understanding of stem cell biology and scientific
research will shape their thinking as they move
into the diverse career options that will be
available to them.                                     $211,200
Parkinson's Disease (PD) is the most common
neurodegenerative movement disorder. It is
characterized by motor impairment such as
slowness of movements, shaking and gait
disturbances. Age is the most consistent risk
factor for PD, and as we have an aging
population, it is of upmost importance that we
find therapies to limit the social, economic and
emotional burden of this disease. Most of the
studies to find better drugs for PD have been
done in rodents. However, many of these drugs
failed when tested in PD patients. One problem is
that we can only investigate the diseased neurons
of the brain after the PD patients have died. We
propose to use skin cells from PD patients and
reprogram these into neurons and other
surrounding cells in the brain called glia. This is a
model to study the disease while the patient is
still alive. We will investigate how the glial
surrounding cells affect the survival of neurons.
We will also test drugs that are protective for glial
cells and neurons. Overall, this approach is
advantageous because it allows for the study of
pathological development of PD in a human
system. The goal of this project is to identify key     $2,336,404 Parkinson's disease
The Bridges to Stem Cell Research Training
Program will provide a practical laboratory
training experience in stem cell biology with
integrated educational seminars and mentored
guidance for highly qualified and culturally
diverse senior undergraduate and Master’s level
students. Our internship-host institution provides
mentors who are world-leaders in stem cell
research. There is a great scientific variety of
available hands-on training environments in
embryonic, induced pluripotent, and adult stem
cell biology, spanning the basic to translational
investigative spectrum. Our partnership achieves
the major Bridges Program objectives including:
1) training laboratory personnel in current stem
cell research techniques, policies, and ethics, and
2) facilitating the entry of an ethnically and
culturally diverse student population into the
emerging world of stem cell biology and
regenerative medicine. Ten Bridges trainees will
study the latest advances in stem cell biology and
will present their own work in a setting in which
they can obtain constructive feedback. They will
interact with their peers in formal and informal
forums and will meet leaders in the field. Bridges      $3,382,877
Our Bridges to Stem Cell Research program will
have 7 components: 1) Partnership with two local
community colleges to diversify the potential
population of interns, 2) Internships at three host
institutions, one a public research university, one
a private research institute, and one a
commercial company. This will provide research
experiences that occur in diverse environments,
each with their own institutional emphasis. 3)
Students will receive academic course credit that
will allow them to continue earning credit
towards their degrees while conducting their
internship research. 4) Development of cell
culture courses on the student’s campuses to
provide them with training prior to entering their
internship. 5) Development of a Stem Cell
Techniques training course at a Shared Research
Laboratory to provide advanced training in
embryonic stem cells prior to entering their
internship. 6) Development of two general
education course modules to educate the
broader population in stem cells. 7) Mentorship
of students, including academic counseling,
preparation for application to advanced
programs, and opportunities for presentation of
research results. Over the three year period of       $2,607,705
The primary aim of this project is to develop
treatments for incurable diseases of the blood
and immune system. X-linked Severe Combined
Immunodeficiency (X-SCID) and Fanconi anemia
(FA) are two blood diseases where mutations in a
single gene results in the disease. XSCID, more
commonly known as the “bubble boy” disease, is
characterized by a complete failure of the
immune system, and typically results in early
childhood fatality. The most common treatment
for X-SCID is bone marrow transplant using a
matched sibling donor. Unfortunately, the lack of
suitable donors limits the application of this
treatment. In 2000, the first gene therapy
"success" resulted in X-SCID patients with a
functional immune system. These trials were
stopped when it was discovered that several
patients in one trial had developed lymphoma, a
blood related cancer resulting from unintended
consequences of the therapy. FA is a disease
where the stability of the genome is
compromised and results in premature cell death
and lethal anemia. Gene therapy trials for such
patients have been largely unsuccessful due to
the inability to culture the cells long enough for
the correction of the gene. Like XSCID there is a


From this study and others we have learned 1)
gene therapy can work to cure certain diseases,
2) adequate safeguards must be developed to
prevent unintended cancer formation, and 3) we
need better sources of matched cells and tissues
to avoid the problems of rejection.
Our proposal will be using one of the most
exciting new developments in regenerative
medicine, that is the ability to reprogram a
patient’s skin, or even hair follicle back to an
induced pluripotent stem (iPS) cell, which is
similar to embryonic stem cells, without involving
embryo destruction. The iPS cell is a good
candidate for repair of the specific genetic
defects that cause diseases like X-SCID and FA.
The reprogrammed, genetically corrected cells
are a perfect match for transplantation therapy
since they come from the patient. At this stage
the corrected cells will be augmented with
additional safety factors that work to avoid the
downstream potential for cancer. These safe and
genetically corrected cells will then be coaxed
back into the cells that form the blood and
immune systems and used for transplant therapy.


In this work we will be using mouse models that
mimic the human diseases of X-SCID and FA and
are amenable to treatment with human
hematopoietic stem cells. We will be working
with human patient and disease-specific cells to
demonstrate the feasibility and evaluate the
safety in a pre-clinical setting to advance these
pioneering new techniques that combine the
latest developments in regenerative medicine
and gene therapy. Our proposed work will also
benefit the successful stem cell based therapies
for many other diseases like Parkinson’s and
diabetes.                                            $6,649,347 Blood Disorders, Immune Disease
The effective implementation of numerous
research programs in stem cell technology funded
by the California Institute for Regenerative
Medicine, created after the approval of
Proposition 71 by California citizens, has led to a
rapid growth of research communities in
California. Consequently, an urgent and long-
term need for qualified technical personnel to
support these research activities has become
apparent. Stem cell technology is a relatively new
field. The management of stem cells in the
laboratory is difficult and arduous. It requires an
experienced and knowledgeable technical
workforce. Few individuals in California are
currently trained to provide research teams with
high-quality and routine management of stem
cell culture facilities. California does not have any
program for advanced training in stem cell
technology and stem cell lab management. Our
proposal for the CIRM Bridges Award addresses
the demand for well-trained professionals
capable of managing stem cell culture facilities.
We propose to extend our current MS
Biotechnology and Bioinformatics program to
include comprehensive training in Stem Cell
Technology and Laboratory Management. Several           $3,614,553
GOALS We propose to determine the effects of
different forms of apoE on the development of
induced pluripotent stem (iPS) cells into
functional neurons. In Aim 1, iPS cells will be
generated from skin cells of adult knock-in (KI)
mice expressing different forms of human apoE
and in humans with different apoE genotypes. In
Aim 2, the development of the iPS cells into
functional neurons in culture and in mouse brains
will be compared. In Aim 3, the effects of
different forms of apoE on the functional
recovery of mice with acute brain injury treated
with iPS cell–derived neural stem cells (NSCs) will
be assessed. RATIONALE AND SIGNIFICANCE The
central nervous system (CNS) has limited ability
to regenerate and recover after injury. For this
reason, recovery from acute and chronic
neurological diseases, such as stroke and
Alzheimer’s disease (AD), is often incomplete and
disability results. Embryonic stem cells have great
promise for treating or curing neurological
diseases, but their therapeutic use is limited by
ethical concerns and by rejection reactions after
allogenic transplantation. The generation of iPS
cells from somatic cells offers a way to potentially   $2,847,600 Stroke
The development of methods to "reprogram"
adult cells such as skin cells by simultaneously
expressing four specific factors - Oct3/4, Sox2, c-
Myc and Klf4 - in order to create cells resembling
embryonic stem (ES) cells is a major breakthrough
in stem cell biology. Our ability to generate these
cells, which are known as induced pluripotent
stem (iPS) cells, will allow us to obtain stem cells
capable of maturing into any tissue type, which is
critical for research and has great therapeutic
potential, without the controversial use of
embryos. We envision that human iPS cells
generated from a patient could be used to
generate specific cells or tissues for cell
replacement therapies for that individual patient,
without stimulating an adverse immune
response. Certain disease-specific iPS cells could
also be differentiated into diseased tissues to
study the causes of those diseases or to screen
for drugs to treat them. Differentiated cells from
iPS cells could also be used for toxicology tests
before a drug is given to patients. Therefore, iPS
cell technology may make individualized medicine
a reality in the future. However, molecular
changes that underlie reprogramming of body            $1,332,379
The field of regenerative medicine revolves
around the capacity of a subset of cells, called
stem cells, to become the mature tissues of the
adult human body. By studying stem cells, we
hope to develop methods and reagents for
treating disease. For instance, we hope to
develop methods for making stem cells become
cardiovascular cells in the lab which could then
be used to rapidly screen large numbers drugs
that may be used to treat cardiovascular disease.
In another example, if we are able to create bone
in the lab from stem cells, we may be able to help
treat people with catastrophic skeletal injuries
such as wounded soldiers. Until recently, the
most flexible type of stem cell known was the
embryonic stem cell. Embryonic stem cells are
pluripotent, meaning they can give rise to all of
the adult tissues. In contrast, stem cells found in
the adult are considered only multipotent, in that
they can only become a limited number of
mature cells. For example, bone marrow stem
cells can give rise to all of the components of the
blood, but cannot make nerves for a spinal chord.
Breakthroughs in the past couple of months have
indicated that it is possible to "reprogram" adult
skin cells and make them become pluripotent,          $1,424,412 Heart Disease
Cancer is the leading cause of death for people
younger than 85 (1). High cancer mortality rates
underscore the need for more sensitive
diagnostic techniques as well as therapies that
selectively target cells responsible for cancer
propagation (1) Compelling studies suggest that
human cancer stem cells (CSC) arise from
aberrantly self-renewing tissue specific stem or
progenitor cells and are responsible for cancer
propagation and therapeutic resistance (2-9).
Although the majority of current cancer therapies
eradicate rapidly dividing cells within the tumor,
the rare CSC population may be quiescent and
then reactivate resulting in disease progression
and relapse (2-9). We recently demonstrated that
CSC are involved in progression of chronic phase
chronic myelogenous leukemia (CML), a disease
that has been the subject of many landmark
discoveries in cancer research(19-30), to a more
aggressive and therapeutically recalcitrant
myeloid blast crisis (BC) phase. These CSC share
the same cell surface markers as granulocyte-
macrophage progenitors (GMP) but have
aberrantly gained the capacity to self-renew as a
result of activation of the Wnt/                     $642,500 Blood
Facioscapulohumeral muscular dystrophy (FSHD)
is the third most common hereditary muscular
dystrophy. It is autosomal dominant, meaning
that if one of the parents has the disease, their
children have a 50:50 chance of getting it, too.
FSHD is characterized by progressive weakness
and atrophy of facial, shoulder and upper arm
musculature, which can spread to other parts of
the body. In some cases, it is accompanied by
hearing loss and, in severe cases, mental
retardation. There is no cure or treatment of this
disease since the gene(s) responsible for this
disease has not been identified. One thing that is
clear is that the majority of FSHD is linked to a
decrease in the number of repeats of a DNA
sequence called D4Z4 located at the end of
chromosome 4. When shortening of this repeat
region occurs in either chromosome 4, the person
gets FSHD. However, it is unclear how shortening
of this repeat leads to the disease. We found that
this D4Z4 repeat cluster contains
"heterochromatin" structure, which is associated
with gene silencing. This heterochromatin
structure includes specific methylation of histone
H3 and the recruitment of heterochromatin              $632,500 Genetic Disorder, Muscular Dystrophy
Cancer is the leading cause of death for people
younger than 85. High cancer mortality rates
related to resistance to therapy and malignant
progression underscore the need for more
sensitive diagnostic techniques as well as
therapies that selectively target cells responsible
for cancer propagation. Compelling studies
suggest that human cancer stem cells (CSC) arise
from aberrantly self-renewing tissue specific stem
or progenitor cells and are responsible for cancer
propagation and resistance to therapy. Although
the majority of cancer therapies eradicate rapidly
dividing cells within the tumor, the rare CSC
population may be quiescent and then reactivate
resulting in disease progression and relapse. We
recently demonstrated that CSC are generated in
chronic myeloid leukemia by activation of beta-
catenin, a gene that allows cells to reproduce
themselves extensively. However, relatively little
is known about the sequence of events
responsible for leukemic transformation in more
common myeloproliferative disorders (MPDs)
that express an activating mutation in the JAK2
gene. Because human embryonic stem cells
(hESC) have robust self-renewal capacity and can      $3,240,572 Blood
This is an unprecedented time in stem cell biology
and regenerative medicine. Today, we have cell
lines and tools that did not exist just a few years
ago. Indeed, human embryonic stem cells (hESCs)
were derived from pre-implantation embryos just
10 years ago; more recently in the past year, cells
with extensive similarities to ESCs have been
derived via genetic reprogramming of ordinary
fetal and adult skin cells in both mice and
humans. These induced-pluripotent stem cells
(IPSCs) have been shown to have many properties
similar to hESCs. Also recently, and surprisingly in
mice, a new source of cells that does not require
genetic manipulation has been identified, namely
mouse spermatogonial stem cells (mSSCs). These
cells also demonstrate extensive similarity to
mouse ESCs. However, human SSCs (hSSCs) have
not yet been reported though our preliminary
data presented here lends credence to their
derivation. Our goal is to derive hIPSCs and hSSCs
– two pluripotent cell types – from the same men
and compare key characteristics to those of
hESCs. We suspect human pluripotent cell types
derived from these three different sources may
differ in key characteristics including their ability
to contribute to both the germ cell (egg and            $1,410,042
The inner workings of the nervous system which
regulate normal body movements, thought
processes, feelings and senses are highly
complex. How the nervous system relays and
receives this variety of information is little
understood, although significant inroads are
being made to deduce underlying causes of many
forms of neurological disorders. Many forms of
retardation are caused directly by a failure of the
cells within the nervous system to survive or work
properly. One of the biggest limitations in this
research is the inability to study the disease in
the laboratory over the course of the disease.
This is because neuronal or brain cells cannot be
examined experimentally and ethically until
postmortem tissues are obtained. Human
embryonic stem cells (hESCs) can differentiate in
the laboratory into many of the neural tissues
within the human brain and spinal cord. Thus,
they are a key to exploring human neurogenesis
in vitro. In this proposal, we explore yet another
vital use of hESCs, which is to study how
neurogenesis is effected in vitro with cells
carrying mutations that cause different forms of
neurological dysfunction. To date, most of the
hESC field has been devoted to deriving purified      $1,424,412 Genetic Disorder, Neurological Disorders

Parkinson                                             $2,507,223 Parkinson's disease
Recent studies in the derivation of rodent
pluripotent epiblast stem cells and their
molecular characterizations have provided strong
evidence that the conventional human embryonic
stem cells may represent a distinct, later
developmental stage, i.e. late epiblast stage, than
the conventional murine embryonic stem cells,
which is a “capture” of the ICM stage. Those two
stages (i.e. ICM/pre-implantation stage vs.
epiblast/post-implantation stage) of pluripotent
stem cells are typically maintained in their self-
renewal state by different sets of exogenous
signaling molecules. Meanwhile, other studies
have suggested that rather than exogenously
activating multiple additional pathways to
achieve a fine balanced self-renewal state, a more
fundamental approach to main self-renewal of
stem cells is to inhibit endogenously expressed
differentiation-inducing protein activity. In
addition, cell-permeable small molecules have
the unique advantage of acting intracellularly to
inhibit differentiation without requirement of
expression of the desirable membrane receptors
by cells for transducing differentiation-inhibiting
signals by the desirable exogenous growth factors
in the culture media. Those studies together          $1,719,468
Parkinson's disease (PD) is currently the most
common neurodegenerative movement disorder,
severely debilitating approximately 1-2% of the
US population. The disease is caused by a
selective loss of dopamine-producing neurons
located in a specific region of the brain. This loss
leads to significant motor function impairment
and age-dependent tremors. Unfortunately there
is currently no cure for PD, however a synthetic
dopamine treatment (L-DOPA), temporarily
alleviates symptoms. The mechanisms of PD
progression are currently unknown. However,
genetic studies have identified that mutations
(changes) in seven genes, including alpha-
synuclein, LRRK2, uchL1, parkin, PINK1, DJ-1 and
ATP13A2 cause familial PD. Although the familial
form of PD only affects a small portion of PD
cases, uncovering the function of these genes
may provide insight into the mechanisms that
lead to the majority of PD cases. One of the best
strategies to study PD mechanisms is to generate
experimental models that mimic the initiation
and progression of PD. A number of cellular and
animal models have been developed for PD
research. However, a model, which closely
resembles the human degeneration process of            $1,589,760 Parkinson's disease
Parkinson’s disease (PD) is a devastating
movement disorder caused by the death of
dopaminergic neurons (a type of neurons in the
central nervous system) present in the midbrain.
These neurons secrete dopamine (a signaling
molecule) and are a critical component of the
motor circuit that ensures movements are
smooth and coordinated. All current treatments
attempt to overcome the loss of these neurons by
either replacing the lost dopamine, or modulating
other parts of the circuit to balance this loss or
attempting to halt or delay the loss of
dopaminergic neurons. Cell replacement therapy
(e.g. transplantation of dopaminergic neurons
into the brain to replace lost cells and restore
function) as proposed in this application attempts
to use cells as small pumps of dopamine that will
be secreted locally and in a regulated way, and
will therefore avoid the complications of other
modes of treatment. Indeed, cell therapy using
fetal tissue-derived cells have shown varying
success in multiple transplant studies. Work in
the field has been limited however, partially due
to the limited availability of cells for
transplantation. We believe that human               $55,000
Autism and autism spectrum disorders (ASD) are
complex neurodevelopmental diseases that affect
1 in 150 children in the United States. Such
diseases are mainly characterized by deficits in
verbal communication, impaired social
interaction, and limited and repetitive interests
and behavior. Because autism is a complex
spectrum of disorders, a different combination of
genetic mutations is likely to play a role in each
individual. One of the major impediments to ASD
research is the lack of relevant human disease
models. ASD animal models are limited and
cannot reproduce the important language and
social behavior impairment of ASD patients.
Moreover, mouse models do not represent the
vast human genetic variation. Reprogramming of
somatic cells to a pluripotent state (induced
pluripotent stem cells, iPSCs) has been
accomplished using human cells. Isogenic
pluripotent cells are attractive from the
prospective to understanding complex diseases,
such as ASD. Our preliminary data provide
evidence for an unexplored developmental
window in ASD wherein potential therapies could
be successfully employed. The model
recapitulates early stages of ASD and represents a   $1,491,471 Autism


Elucidating how genetic variation contributes to
disease susceptibility and drug response requires
human Induced Pluripotent Stem Cell (hIPSC)
lines from many human patients. Yet, current
methods of hIPSC generation are labor-intensive
and expensive. Thus, a cost-effective, non-labor
intensive set of methods for hIPSC generation
and characterization is essential to bring the
translational potential of hIPSC to disease
modeling, drug discovery, genomic analysis, etc.
Our project combines technology development
and scaling methods to increase throughput and
reduce cost of hiPSC generation at least 10-fold,
enabling the demonstration, and criterion for
success, that we can generate 300 useful hiPSC
lines (6 independent lines each for 50 individuals)
by the end of this project. Thus, we propose to
develop an efficient, cost effective, and minimally
labor-intensive pipeline of methods for hIPSC
identification and characterization that will
enable routine generation of tens to hundreds of
independent hIPSC lines from human patients.
We will achieve this goal by adapting two simple
and high throughput methods to enable analysis
of many candidate hIPSC lines in large pools.
These methods are already working in our labs
and are called "fluorescence cell barcoding" (FCB)
and expression cell barcoding (ECB).




To reach a goal of generating 6 high quality hIPSC
lines from one patient, as many as 60 candidate
hIPSC colonies must be expanded and evaluated
individually using labor and cost intensive
methods. By improving culturing protocols, and
implementing suitable pooled analysis strategies,
we propose to increase throughput at least 10-
fold with a substantial drop in cost. In outline, the
pipeline we propose to develop will begin with
the generation of 60 candidate hIPSC lines per
patient directly in 96 well plates. All 60 will be
analyzed for diagnostic hIPSC markers by FCB in 1
pooled sample. The 10 best candidates per
patient will then be picked for expression and
multilineage differentiation analyses with the
goal of finding the best 6 from each patient for
digital karyotype analyses. Success at 10-fold
scaleup as proposed here may be the first step
towards further scaleup once these methods are
fully developed.
Aim 1: To develop a cost-effective and minimally
labor-intensive set of methods/pipeline for the
generation and characterization high quality
hIPSC lines from large numbers of human
patients. We will test suitability/develop a set of
methods that allow inexpensive and rapid
characterization of 60 candidate hIPSC lines per
patient at a time.


Aim 2: To demonstrate/test/evaluate the success
and cost-effectiveness of our pipeline by
generating 6 high quality hIPSC lines from each of
50 human patients from [REDACTED]. We will
obtain skin biopsies and expand fibroblasts from
50 patients, and generate and analyze a total of 6
independent hIPSC lines from each using the
methods developed in Aim 1.                             $1,816,157 Alzheimer's disease


One of the most exciting and challenging frontiers
in neuroscience and medicine is to repair
traumatic injuries to the central nervous system
(CNS). Most spinal cord and head injuries result in
devastating paralyses, yet very limited clinical
intervention is currently available to restore the
lost abilities. Traumatic injuries of the spine cause
fractures and compression of the vertebrae,
which in turn crush and destroy the axons, long
processes of nerve cells that carry signals up and
down the spinal cord between the brain and the
rest of the body. It follows that the best chance
for promoting functional recovery is identifying
strategies that enable lesioned axons to
regenerate and reconnect the severed neural
circuits. Even minor improvements in voluntary
motor functions after spinal cord injury could be
immensely helpful for increasing the quality of
life, employability, and independence, especially
for patients with injuries at the upper spinal level.
Thus, our overall research program centers on
axon regeneration in general, with a focus on
regenerating descending axons from the brain
that control voluntary motor and other functions.
We recently made breakthrough discoveries in
identifying key biological mechanisms stimulating
the re-growth of injured axons in the adult
nervous system, which led to unprecedented
extents of axon regeneration in various CNS
injury models. While our success was compelling,
we found that many regenerated axons were
stalled at the lesion sites by the injury-induced
glial scars. Furthermore, it is unclear whether the
regenerated axons can form functional synaptic
connections when they grow into the denervated
spinal cord. This proposed research program is
aimed at solving these obstacles by using human
stem cell technologies. In the first aim, we will
use human neural stem cells to engineer
“permissive cell bridges” that can guide the
maximum number of regenerating axons to grow
across injury sites. In the second aim, we will test
the therapeutic potential of human stem cell-
derived neurons in forming “functional relays”
that could propagate the brain-derived signals
carried by regenerating axons to the injured
spinal cord. Together, our research program is
expected to develop a set of therapeutic
strategies that have immediate clinical                $5,609,890 Spinal Cord Injury
Canavan disease is a devastating disease of
infants which affects their neural development
and leads to mental retardation and early death.
It occurs in 1 in 6,400 persons in the U.S. and
there is no treatment so far. We propose to
generate genetically-repaired and patient-specific
stem cells (called iPSCs) from patients' skin cells,
and then coax these stem cells into specific types
of corrective neural precursors using methods
established in our laboratories in order to
develop a therapeutic candidate for this disease.
By use of a mouse model of Canavan disease, we
will determine the ability of these genetically
corrected cells to successfully treat the disease.
These results will form the basis for an eventual
clinical trial in humans, and if successful, would
be the first treatment for this terrible disease.
There are many families affected by this disease,
and other diseases similar to it. Results from this
work could have applications to this and other
similar genetic diseases. Through the proposed
research, maybe no parents will have to watch
their child suffer and die as a result of these
dreadful diseases in one day. What a wonderful
day that would be!                                     $1,731,750 Genetic Disorder, Neurological Disorders
Human embryonic stem cells (hESCs) can undergo
unlimited self-renewal and differentiate into all
the cell types in the human body, and thus hold
great promise for cell replacement therapy.
However, one major problem for hESC-based
therapy is that the cells derived from hESCs will
be rejected by the recipient and can only be
tolerated under persistent immunosuppression,
which itself can cause cancer and infection.
Recent development of induced pluripotent stem
cells (iPSCs), which are generated from somatic
cells of individual patient with defined factors and
very similar to hESCs, could provide ideal cell
source for transplantation by avoiding graft
rejection in the patient. In addition, the disease-
specific iPSCs can be used as human disease
models for more reliable testing of the efficacy
and toxicity of drugs. However, there are several
major bottlenecks that prevent the development
of iPSCs in human therapy and drug discovery.
The overall goal of this proposal is to resolve the
major bottlenecks remained in human iPSC
biology to make it feasible for human therapy
and drug discovery. We propose to develop safe
and efficient approach to generate iPSCs from           $5,165,028 Diabetes
Supported in part by a previous CIRM Tools and
Technologies Grant [REDACTED], we have
optimized and scaled up highly advanced
(microfluidic) cell culture chips into
manufacturable form, produced prototype
instruments to drive these chips, and
demonstrated that we can culture cells, dose
them with combinations of reagents, and export
them back off the chip.


Since a cell's state is controlled by multiple genes,
experiments to control cell state (e.g. to turn skin
cells into stem cells, or to turn stem cells into
nerve cells) will almost always involve multiple
factors as well. We believe the ability to do multi-
factor experiments more quickly, easily, and
reproducibly will be enabling for the stem cell
field.
The research we propose here will push the
capabilities of this system even further by
producing a set of three complementary
commercial instruments: a Controller (capable of
full fluidic and environmental control on one
chip), a Hotel (capable of limited fluidic and
environmental control on multiple chips), and a
Reader (capable of imaging the cells in the chip in
phase contrast and fluorescence modes). The
idea is to load cells and dose them with different
drugs/chemicals on the Controller, transfer them
to the Hotel for culture and maintenance, and
transfer them to the Reader for periodic imaging,
allowing therefore running multiple sets of
experiments in parallel and increasing even more
the throughput of the system.


We are also proposing two sets of experiments to
demonstrate what the system can do: in the first
one, we will develop new methods to turn IPS
cells (stem cells obtained by reprogramming non-
stem cells - skin cells for instance) into neural
progenitor cells - cells which can become
different types of neural cells. These cells could
be used to study diseases such as Parkinson's or
Alzheimer's. In the second set of experiments, we
will develop methods to make these cells
proliferate without turning into specific types of
neural cells. Since these types of cells are
potentially useful to treat neurodegenerative
diseases (e.g. Parkinson's and Alzheimer's) and
spinal cord injury, developing methods to make
more of them could advance the field a step
closer to clinical application. In both cases, we
will avoid using serum and animal products, since
methods which use these products cannot be
used clinically.                                      $1,943,904
The surgical tools currently available to transplant
cells to the human brain are crude and
underdeveloped. In current clinical trials, a
syringe and needle device has been used to inject
living cells into the brain. Because cells do not
spread through the brain tissue after
implantation, multiple brain penetrations (more
than ten separate needle insertions in some
patients) have been required to distribute cells in
the diseased brain region. Every separate brain
penetration carries a significant risk of bleeding
and brain injury. Furthermore, this approach does
not result in effective distribution of cells. Thus,
our lack of appropriate surgical tools and
techniques for clinical cell transplantation
represents a significant roadblock to the
treatment of brain diseases with stem cell based
therapies. A more ideal device would be one that
can distribute cells to large brain areas through a
single initial brain penetration. In rodents, cell
transplantation has successfully treated a great
number of different brain disorders such as
Parkinson's disease, epilepsy, traumatic brain
injury, multiple sclerosis, and stroke. However,
the human brain is about 500 times larger than         $1,831,723
With a current prevalence of greater than 170
million individuals world-wide, diabetes has
attained epidemic proportions. The widespread
secondary complications this disease extract a
relentless and costly toll on the patients and
health care establishment required for their
treatment. To date, cellular replacement
therapies for the treatment of diabetes has been
performed either by transplantation of whole
pancreas, or via infusion of isolated primary
pancreatic islets into the portal vein . While
effective, the availability of such procedures is
severely limited for the treatment of the general
diabetes population since it relies upon the
extremely limited supply of organs from deceased
donors. One approach to overcoming the
problem of insufficient organ and islet supply is to
generate glucose responsive human insulin
secreting pancreatic islet cells from stem cell
populations. Only human embryonic stem cells
(hES cells) demonstrate sufficient cell expansion
capacity to achieve production levels needed to
treat patients with diabetes. Furthermore, hES
cells are capable of efficiently and rapidly
progressing through a series of defined steps to
generate most cell types found in the human            $48,950
Stroke is the leading cause of adult disability.
Most patients survive their initial stroke, but do
not recover fully. Because of incomplete
recovery, up to 1/3 of stroke patients are taken
from independence to a nursing home or assisted
living environment, and most are left with some
disability in strength or control of the arms or
legs. There is no treatment that promotes brain
repair and recovery in this disease. Recent studies
have shown that stem cell transplantation into
the brain can promote repair and recovery in
animal models of stroke. However, a stem cell
therapy for stroke has not reached the clinic.
There are at least three limitations to the
development of a human stroke stem cell
therapy: most of the transplanted cells die, most
of the cells that survive do not interact with the
surrounding brain, and the process of injecting
stem cells into the brain may damage the normal
brain tissue that is near the stroke site. The
studies in this grant develop a novel investigative
team and research approach to achieve a solution
to these limits. Using the combined expertise of
engineering, stem cell biology and stroke
scientists the studies in this grant will develop     $1,825,613 Stroke
Stem cells are unique among cell types found in
the human body: These cells are pluripotent; that
is, they can develop into any of the more than
200 cell types in the human body. A major goal of
stem cell research is to develop treatments for
patients who suffer from devastating and
currently incurable conditions such as AIDS,
Alzheimer’s, liver disease, diabetes, Parkinson's
disease, muscular dystrophies, spinal cord
injuries, and inborn errors of metabolism. These
patients might be treated with gene-modified or
gene-corrected patient-specific human embryonic
stem cells (hESCs). In the hESCs used for
treatment, the bad or defective gene must be
either replaced or repaired with a good or
effective gene. In some cases, it may be
important that the patient’s hESCs be provided
with a disease-fighting gene. Here, the genes
need to be placed in safe sites in the genome. For
example, we might be able to treat AIDS patients
using hESCs modified to contain a gene to make
them resistant to the HIV-1 virus or patients with
Alzheimer’s disease might be treated with neural
stem cells equipped with a new gene that fights
the development of Alzheimer plaques                  $1,146,312
Stroke is the leading cause of adult disability. As
Californians adopt health measures that minimize
stroke risk factors, such as high blood pressure
and smoking, the number one risk factor for
stroke cannot be controlled: age. As the
population ages the incidence of stroke is
expected to markedly increase to almost 1.2
million cases per year in the United States, with a
disproportionate increase in stroke in California
with its relative population growth in older age
groups. Because most of the cost in stroke is in
the chronic care of disabled survivors, studies
indicate that this increase in stroke incidence may
cause the total cost of caring for stroke victims in
the next quarter century in the United States to
top $1 trillion dollars. Stroke induces a limited
degree of functional recovery. In humans, this
recovery is associated with functional re-
organization of the tissue adjacent to the stroke
site. Recent studies have shown that stem cell
transplantation enhances functional recovery in
animal models of stroke. However, these stem
cell therapies in animal models of stroke have not
translated into new clinical therapies for several
important reasons. First, most studies have            $44,792
Age related macular degeneration (AMD) is a
blinding disease of the elderly affecting nearly
one in three individuals over the age of 75.
Central vision is lost in AMD, severely impairing
the ability to read, watch television, or drive. The
epicenter of AMD is the retinal pigment
epithelium (RPE), a single layer of cells in the
retina adjacent to the photoreceptor cells. A
recent breakthrough in AMD research showed
that this disease is caused in about 50% of cases
by the innate immune system (complement
system) inappropriately attacking RPE cells.
Specifically, AMD results when regulators of the
complement system, which normally protect the
RPE, are weakened by mutations. This sickens
and later kills the RPE, causing secondary
degeneration of photoreceptors in the central
retina (macula). The goal of this proposal is to
develop a strategy for transplanting stem-cell
derived RPE cells into the eyes of patients with
AMD. In the past, transplantation of RPE cells
from postmortem donors yielded encouraging
initial therapeutic effects that subsequently failed
due to immune rejection. Current stem-cell
technology offers the opportunity to avoid this
complication. We plan to generate functional RPE       $5,503,069 Vision Loss
Drug-induced liver toxicity, including that from
FDA-approved drugs, is the leading cause of liver
failure in the US. One of the biggest road blocks
to testing drug-induced liver toxicity prior to
clinical studies or release of the drug into the
market is the absence of a good model of human
drug metabolism in the liver. Development of a
clinically predictive drug screening system would
allow earlier detection of drug-induced liver
toxicity, thus decreasing drug costs, decreasing
the scale of pre-clinical animal testing, and
increasing drug safety. Unfortunately, use of
primary human liver cells for drug screening is
hampered by their limited availability and poor
viability in culture. Human embryonic stem (hES)
cells, however, could provide a renewable,
scalable, relevant source of liver cells since they
can be induced to turn into these types of cells.
Unfortunately, though, current hES protocols
yield primarily immature liver cells, even though
mature adult-like liver cells would be needed for
drug screening. Here we propose development of
a new hES cell line tool that attaches a
fluorescent molecule to a protein found in              $971,558 Liver Disease, Toxicity
Human embryonic stem cells (hESCs) are an ideal
tissue source for cell replacement therapy (CRT).
They have the potential for limitless self-renewal
while retaining their ability to differentiate into a
wide variety of cells and tissues. Since their first
derivation in 1998, hESCs have been used in
many studies in order to evaluate their potential
therapeutic utility in humans. These have
included animal models of myocardial infarction,
Parkinson's disease, spinal cord injury, and bone
marrow deficiency. Results so far have been
promising, and many groups are advancing
studies in support of clinical trials of hESC-derived
cells. However, these studies have depended on
either the use of immunosuppressed animals to
avoid allogeneic or xenogeneic graft rejection or
the coadminstration of highly toxic
immunosuppressive drugs. Thus, a key limitation
in transplanting hESC-derived cells remains their
potential to elicit a host immune response with
subsequent graft rejection due to immune
mismatch between host and donor cells. In fact,
recent studies showed that a single minor
histocompatability antigen mismatch led to the
rejection of allogeneic ESCs. In order to realize        $1,453,040
Stem cells are powerful undifferentiated cells that
are able to both regenerate themselves and
differentiate into different mature cell types, such
as lung cells or liver cells. The ability to edit stem
cell genomes is useful for both understanding
stem cells at a fundamental level as well as for
practical and therapeutic purposes, such as
regenerative medicine. However, there is a
current lack of tools available for targeting these
cells in a specific and efficient way. Our proposal
is to utilize a genetic scissor, which has the ability
to target specific sites in the genome, and an
engineered delivery vehicle, to site-specifically
alter genes of interest in stem cells. This would
enable us to correct genetic mutations or
deficiencies at known and targeted points in the
stem cell genome, which is much more efficient
and safer than current methods, which involve
random insertion. The random placement of a
gene into the stem cell genome could potentially
disrupt the production of necessary cellular
proteins, which could result in death of the stem
cell, or even lead to the development of a
cancerous stem cell. Thus, targeting DNA to a
specific site has an important advantage over             $951,104
The long term goal of our research program is
regeneration of the diseased eye. Age-related
macular degeneration, diabetic retinopathy, and
retinitis pigmentosa are leading causes of
blindness for which there are no effective
treatments for the majority of cases. Loss of
vision is due to progressive degeneration of the
photoreceptor cells, or loss of cells that support
the photoreceptors, such as retinal pigment
epithelial (RPE) cells or cells in the retinal blood
vessels. The RPE is a pigmented cell layer that lies
just behind the retinal and is necessary for
photoreceptor survival. One possible strategy for
treatment of these blinding diseases is to replace
cells that are lost via transplantation. My work
explores this approach, with the object of first
identifying and characterizing sources of cells,
determining the optimal parameters for
transplantation, and investigating molecular,
cellular and behavioral events that occur upon
transplantation in animal models of retinal
degeneration. In the case of age-related macular
degeneration, there is a solid body of evidence
that RPE cell loss is often an early event in disease
progression. We have shown that RPE can be               $4,880,116
Leukemias are cancers of the blood forming cells
that afflict both children and adults. Many drugs
have been developed to treat leukemias and
related diseases. These drugs are often effective
when first given, but in many cases of adult
leukemia, the disease returns in a form that is not
curable, causing disability and eventual death.
During the last few years, scientists have
discovered that some leukemia cells possess stem
cell properties that make them more potent in
promoting leukemia growth and resistance to
common types of treatment. These are called
leukemia stem cells (LSC). More than in other
cancers, scientists also understand the exact
molecular changes in the blood forming cells that
cause leukemias, but it has been very difficult to
translate the scientific results into new and
effective treatments. The main difficulty has been
the failure of existing drugs to eliminate the small
numbers of LSC that persist in patients, despite
therapy, and that continue to grow, spread,
invade and kill normal cells. In fact, the models
used for drug development in the pharmaceutical
industry have not been designed to detect drugs
or drug combinations capable of destroying the          $19,999,826 Blood
Alzheimer disease (AD) is a progressive
neurodegenerative disorder that currently affects
over 4.5 million Americans. By the middle of the
century, the prevalence of AD in the USA is
projected to almost quadruple. As current
therapies do not abate the underlying disease
process, it is very likely that AD will continue to
be a clinical, social, and economic burden.
Progress has been made in our understanding of
AD pathogenesis by studying transgenic mouse
models of the disease and by utilizing primary
neuronal cell cultures derived from rodents.
However, key proteins that are critical to the
pathogenesis of this disease exhibit many species-
specific differences at both a biophysical and
functional level. Additional species differences in
other as yet unidentified AD-related proteins are
likely to also exist. Thus, there is an urgent need
to develop novel models of AD that recapitulate
the complex array of human proteins involved in
this disease. Cell culture-based models that allow
for rapid high-throughput screening and the
identification of novel compounds and drug
targets are also critically needed. To that end we
propose to model both sporadic and familial            $492,750 Alzheimer's disease
Human embryonic stem cells (hESC) hold great
promise in regenerative medicine and cell
replacement therapies because of their unique
ability to self-renew and their developmental
potential to form all cell lineages in the body.
Traditional techniques for generating hESC rely
on surplus IVF embryos and are incompatible
with the generation of genetically diverse, patient
or disease specific stem cells. Recently, it was
reported that adult human skin cells could be
induced to revert back to earlier stages of
development and exhibit properties of authentic
hES cells. The exact method for “reprogramming”
has not been optimized but currently involves
putting multiple genes into skin cells and then
exposing the cells to specific chemical
environments tailored to hES cell growth. While
these cells appear to have similar developmental
potential as hES cells, they are not derived from
human embryos. To distinguish these
reprogrammed cells from the embryonic sourced
hES cells, they are termed induced pluripotent
stem (iPS) cells. Validating and optimizing the                  Amyotrophic Lateral Sclerosis, Autism, Blood
reprogramming method would prove very useful                     Disorders, Rett's Syndrome, Neurological
for the generation of individual cell lines from      $1,737,720 Disorders
Optimal cardiac function depends on the properly
coordinated cardiac conduction system (CCS). The
CCS is a group of specialized cells responsible for
generating cardiac rhythm and conducting these
signals efficiently to working myocardium. This
specialized CCS includes the sinoatrial node,
atrioventricular node and His-Purkinje system.
These specialized pacemaking /conducting cells
have different properties from the surrounding
myocytes responsible for the contractile force.
Genetic defects or postnatal damage by diseases
or aging processes of these cells would result in
impaired pulse generation (sinus node
dysfunction, SND) or propagation (heart block).
Implantation of an electronic cardiac pacemaker
is necessary for intolerant bradycardia to restore
cardiac rhythm. However, the electronic
implantable pacemaker has multiple associated
risks (e.g. infections) and requires frequent
generator changes due to limited battery life.
Sinus node dysfunction is a generalized
abnormality of cardiac impulse formation and
accounts for >30 percent of permanent
pacemaker placements in the US. A perfect
therapy to SND will be to repair or replace the
defective sinus node by cellular or genetic           $744,639 Heart Disease
Despite significant advances in treatment and
prevention programs, HIV infection with
progression to Acquired Immunodeficiency
Syndrome (AIDS) is still prevalent in California.
The CDC Estimates >56,000 new cases of HIV
infection each year in the US with over 148,000
cumulative cases reported in California alone (as
of 2009). Multi-drug therapy has been helpful in
reducing the severity of disease and prolonging
lifespan but sixteen of every one hundred HIV
patients will eventually fail to control the virus
after attempting at least 2 drug treatment
regimens. The Centers for Disease Control (CDC)
recently estimated the lifetime cost of medical
care for AIDS to be in excess of $600,000 per
patient, over 85% of which is attributable to
prescription drug costs. Additionally, medication
non-compliance, intolerance of drugs due to side
effects and the development of resistant strains
of virus are all complicating factors in obtaining
consistent clinical benefit with lifelong drug
therapy. Therefore, there is a need to provide a
longer lasting, cost effective therapy for this
disease. Our project builds on prior work from
our laboratories in which genetically engineered         $3,124,130 HIV/AIDS, Immune Disease
Clinical application of cell transplantation therapy
requires a means of non-invasively monitoring
these cells in the patient. Several imaging
modalities, including MRI, bioluminescence
imaging, and positron emission tomography have
been used to track stem cells in vivo. For MR
imaging, cells are pre-loaded with molecules or
particles that substantially alter the image
brightness; the most common such labelling
strategy employs iron oxide particles. Several
studies have shown the ability of MRI to
longitudinally track transplanted iron-labeled
cells in different animal models, including stroke
and cancer. But there are drawbacks to this kind
of labeling. Division of cells will result in the
dilution of particles and loss of signal. False signal
can be detected from dying cells or if the cells of
interest are ingested by other cells. To overcome
these roadblocks in the drive toward clinical
implementation of stem cell tracking, it is now
believed that a genetic labeling approach will be
necessary, whereby specific protein expression
causes the formation of suitable contrast agents.
Such endogenous and persistent generation of
cellular contrast would be particularly valuable to      $1,930,608
Autism Spectrum Disorders (ASDs) are a heritable
group of neuro-developmental disorders
characterized by language impairments,
difficulties in social integrations, and the
presence of stereotyped and repetitive behaviors.
There are no treatments for ASDs, and very few
targets for drug development. Recent evidence
suggests that some types of ASDs are caused by
defects in calcium signaling during development
of the nervous system. We have identified cellular
defects in neurons derived from induced
pluripotent stem cells (iPSCs) from patients with
Timothy Syndrome (TS), caused by a rare
mutation in a calcium channel that leads to
autism. We propose to use cells carrying this
mutant calcium channel to identify drugs that act
on calcium signaling pathways that are involved
in ASDs. Our research project has three aims.
First, we will determine whether known channel
modulators reverse the cellular defects we
observe in cells from TS patients. It is possible
that we will find that existing drugs already
approved for use in humans might be effective
for treating this rare but devastating disorder.
Our second aim is to determine whether screens
using neuronal cells derived from ASD patients       $1,884,808 Autism
hESCs represent an important source of cell
therapies in regenerative medicine and the study
of early human development. A number of hESC-
based therapies are nearing clinical trials. To
bring these to clinical trials requires the scale-up
production, or “banking”, of large numbers of the
desired hESC cell. The current lack of large scale
hESC culture methods presents a serious
challenge to ensuring progression of new
therapies into clinical testing. In addition, current
characterization methods are inadequate to
monitor genetic and epigenetic changes that may
occur during the long term culture required for
banking. Finally, the lack of well characterized
hESC research banks limits the comparability of
research between laboratories. We propose to
address these issues by adapting three
representative cell lines to scalable suspensions
culture, develop epigenetic and genetic
“fingerprinting” methods and generate well
characterized Master Cell Banks of the three hESC
lines for use by all CIRM investigators. Procedures
typically used in adherent hESC cell banking
involve feeder cell layers, undefined media
and/or mechanical manipulation. Banking of cell         $882,929
Currently, many chronic diseases and injuries do
not have effective cures; millions of people suffer
from disabilities while carrying on daily lives
without appropriate medical assistance.
Advances in human pluripotent stem cells (hPSCs)
research have provided the potential hope for
significant improvements of disease treatment
and management. The success of stem cell-based
therapy will have major impacts on the quality of
life of people with chronic health problems such
as cancer, cardiovascular diseases, and
neurodegenerative disorders (e.g. Alzheimer's
and Parkinson's diseases). The California Institute
of Regenerative Medicine was established to
develop such novel cell-based therapies to treat
disorders that are presently incurable. HPSCs
process the enormous potential to be directed to
all cell types in the human body as the "raw
material" for many cell-based therapies. The
realization of the full potential of hPSCs in
regenerative medicine requires, among other
things, the establishments of well-defined culture
conditions for their growth and differentiation
and cost-effective protocols for their expansion.
In this grant application, we propose a series of
experiments to develop a novel technology
Due to the high cost and limited range of testing
capability, previous studies on factors affecting
stem cell growth have focused on only one or a
few elements of the cellular microenvironment,
e.g., individual extracellular matrix components
or growth factors. In addition, most protocols for
hPSC culture use non-human products such as
animal supporting materials and recombinant
proteins isolated from bacterial culture, which
represent potential complications for clinical
usage. Our proposed research will develop a high-
throughput cellular microarray screening tool
that incorporates synthetic materials, including
polymers and peptides, to select the optimal
matrix for supporting self-renewal and
differentiation of hPSCs. This tool and technology
will allow the concomitant screening of the
effects of thousands of conditions on growth,
maintenance and differentiation of hPSCs with a
cost-effective approach. The results from our
studies will provide fully defined and optimized
culture conditions for the expansion and
differentiation of hPSCs without exposure to
animal-derived products.



In summary, we will develop a comprehensive
approach to elucidate the responses of hPSCs to
microenvironmental factors in a combinatorial
and systematic manner. Application of this novel
and powerful technology will lead to the
definition of the optimal synehtic matrices for the
control of hPSC growth and differentiation and
the production of hPSCs without contamination
by non-human products.                                $1,832,515
There are several challenges to the successful
implementation of a cellular therapy for insulin
dependent diabetes derived from Human
Embryonic Stem Cells (hESCs). Among these are
the development of functional insulin-producing
cells, a clinical delivery method that eliminates
the need for chronic immunosuppression, and
assurance that hESC-derived tumors do not
develop in the patient. We have recently
developed methods to efficiently generate such
insulin-producing cells from Human Embryonic
Stem Cells that can prevent diabetes in mouse
models of the disease. The results demonstrated
for the first time that Human Embryonic Stem
Cells could indeed serve as a source of cellular
therapy for diabetes. However, the clinical use of
Human Embryonic Stem Cell-derived cell products
is hampered by safety concerns over the
potential growth of unwanted cell types and the
formation of tumors. Encapsulation of cellular
transplants has the potential to reduce or
eliminate the need for immunosuppression.
Moreover, a durable immunoprotective device
which prevented cell escape could serve as a
platform for safely administering Human
Embryonic Stem Cell-derived therapies. The           $827,072 Diabetes
Acute myeloid leukemia (AML) is a cancer of the
blood and bone marrow that is rapidly fatal
within months if untreated. Even with aggressive
treatment, including chemotherapy and bone
marrow transplantation, five-year overall survival
rates range between 30-40%. Evidence indicates
that not all cells in this cancer are the same, and
that there is a rare population of leukemia stem
cells (LSC) that are responsible for maintaining
the disease. Thus, in order to cure this cancer, all
LSC must be eliminated, while at the same time
sparing the normal blood forming stem cells in
the bone marrow. We propose to develop
therapeutic antibodies directed against surface
markers present in much larger amounts on LSC
than on the surface of normal blood forming
stem cells. We recently identified and validated
several such protein markers including CD47,
which we determined contributes to leukemia
development by blocking the ingestion and
removal of leukemia cells by immune system cells
called macrophages. In this way, CD47 acts as a
"don't eat me" signal on LSC. Moreover, we
determined that monoclonal antibodies (mAbs)
directed against CD47, able to block its
interaction with macrophages, mask the "don't          $19,999,996 Blood
Augmentation or replacement of the bladder is
often necessary for the treatment of adults with
bladder cancer and children with spinal cord
injury or spina bifida. Current surgical techniques
utilize segments of intestine or stomach as a
substitute for bladder wall. Use of intestinal
segments is associated with many complications
including infection, stones, salt imbalance, and
most concerning, cancer. An ideal substitute for
bladder wall would be bioengineered bladder
tissue. Ideally, a bioengineered graft would
consist of cells that are genetically normal and
free of cancerous mutations, promote blood
vessel growth, survive long-term and regenerate.
Stem cells appear to be the ideal solution for
bioengineering tissue. Preliminary clinical trials
have demonstrated the feasibility of using
bioengineered tissue for bladder augmentation.
The bladder is lined by a very unique cell type
called "urothelium". The ability to induce human
embryonic stem cells (hESC) or induced
pluripotent stem cells (iPSC) into urothelium
would provide a major advancement in the tissue
engineering field, scientifically and clinically. In
addition, deciphering the mechanisms of hESC to
urothelial differentiation would facilitate            $885,600
The roughly 25 feet of intestine in the adult
human play numerous essential roles in daily life,
such as nutrient absorption, secretion of
hormones, and serving as a barrier to infection.
Commensurate with these diverse roles, diseases
of the intestine are a considerable source of
human morbidity and mortality. Indeed,
numerous pathologic conditions including
inflammatory bowel diseases, mesenteric
ischemia, congenital syndromes and trauma, with
or without concomitant intestinal resection, all
impair intestinal function to the extent that
"short-gut" syndromes develop-- resulting in
effective intestinal failure. Current therapies rely
on supportive measures such as total parenteral
nutrition, in which patients receive all of their
nutrition intravenously, or even intestinal
transplantation. The adult intestine is populated
by specialized but highly active intestinal stem
cells, which ideally could be harnessed for stem
cell therapies of these disabling conditions.
However, despite intensive research, no methods
currently exist for identifying, isolating, and
growing these intestinal stem cells for therapeutic
purposes. Our goal is to develop technologies
enabling human embryonic stem (hES) cells to be        $578,943 Intestinal Disease, Pediatrics, Trauma
Human embryonic stem cells (hESCs) and induced
pluripotent stem (iPS) cells have considerable
potential as sources of differentiated cells for
numerous biomedical applications. The ability to
introduce targeted changes into the DNA of these
cells – a process known as gene targeting – would
have very broad implications. For example,
mutations could readily be introduced into genes
to study their roles in stem cell propagation and
differentiation, to analyze mechanisms of human
disease, and to develop disease models to aid in
creating new therapies. Unfortunately, gene
targeting efficiency in hESCs is very low. To meet
this urgent need, we propose to develop new
molecular tools and novel technologies for high
efficiency gene targeting in hES and iPS cells.
Importantly, this approach will be coupled with
genome-wide identification and functional
analysis of genes involved in the process in
dopaminergic neuron development, work with
fundamental implications for Parkinson’s disease.
Barriers to targeted genetic modification include
the effective delivery of gene targeting constructs
into cells and the introduction of defined changes
into the genome. We have developed a high
throughput approach to engineer novel                 $918,000 Parkinson's disease
Great progress has been made in the last decades
to derive many types of human stem cells for
potential therapeutic uses. However, practical
clinical use is severely limited by several
challenges. One of which is the poor homing and
integration of transplanted cells with the targeted
host tissues - only very few transplanted stem
cells integrate structurally and functionally to the
damaged or diseased tissues. We recently
demonstrated that at wounds and damaged
tissue sites there are naturally occurring electric
fields, which may send a signal to guide cell
migration. Excitingly, applied EFs guide migration
and division of murine embryonic stem
cells(mESCs) and nerve stem cells (mNSCs). We
hypothesize that EFs are an effective signal to
direct migration of human embryonic stem cells
(hESCs), and nerve stem cells (hNSCs) to, as well
as engagement and interaction with, sites of
tissue damage. In this proposal, we will establish
EFs as a novel signalling mechanisms to guide
human stem cells homing and integration. We
will optimize electric stimulations to direct
migration of hESCs and hNSCs. We will combine
the electric stimulation with other treatment to       $1,052,715
This work is directly relevant to human embryonic
stem cell (hESC) research because it brings new
ideas about novel compounds to affect
cardiomyogenesis. The work addresses an urgent
need to develop new agents to treat
cardiovascular disease. We will develop potent
and selective drug-like molecules as
cardiomyocyte differentiation agents. Heart
disease is the leading cause of mortality and
decline in the quality of life in the developed
world. The ability of hESCs to form
cardiomyocytes has spawned hope that these
cells may be used to replace damaged
myocardium. Despite their ability to form
cardiomyocytes, efficient and controlled
cardiomyogenesis in ESC cultures has not been
achieved due to the unavailability of
differentiation agents and an incomplete
understanding of the pathways that regulate
cardiac development. Success has been achieved
in developing a robust and dependable high-
throughput assay to study the effects of small
molecules on cardiomyocyte differentiation.
Powerful cell-based assays were developed and
provided readouts that led to high-content
results because multiple signals were probed. The   $714,654 Heart Disease
We have assembled a team of investigators with
complementary expertise in applying the state-of-
the-art “one-bead-one-compound” (OBOC)
combinatorial library methods to identify
synthetic chemical molecules that bind to unique
receptors (protein molecules) on the surface of
human embryonic stem cells and induced
pluripotent stem cells. In this technology, stem
cells will be mixed with huge number of chemical-
beads (1,000,000 or more), and those beads
coated by the stem cells will be isolated for
chemical analysis. We believe some of the
chemical molecules identified by this method will
support the growth and proliferation of stem cells
while maintaining their “stemness” nature (self-
renewal). Other molecules may induce directed-
differentiation into specific desirable cell types
such as heart cells for damaged heart and brain
cells for patients who suffer stroke. Once these
molecules are identified, we shall incorporate
them into an artificial gel that can support large
scale stem cell growth and directed-
differentiation. Such artificial gels are free of
animal products and viruses, making them safe
for therapeutic use in human. We shall take
advantage of these novel molecules and gels to       $835,540

The CIRM Basic Biology Award III was developed
to support basic research that enables the
realization of the full potential of human stem
cells and reprogrammed cells for therapies and as
tools for biomedical innovation. This is
particularly important since many fundamental
issues related to the regulation of stem cell fate
and reprogramming, especially with regard to
human cells, remain to be resolved. X
chromosome inactivation (XCI) is one of those
fundamental processes of human development
related to stem cell biology and reprogramming,
that we know surprisingly little about, and we
therefore propose to study the regulation of XCI
in human cells in this proposal using human
induced pluripotent stem cells (iPSCs) as model
system.
A normal female has two X chromosomes and no
Y chromosome and males have one X and one Y
chromosome. To be equal with males, females
must shut off one of two X chromosomes during
embryonic development by inducing XCI, such
that only one X chromosome remains active in
every cell of the female body. Females even
become genetic mosaics by randomly inactivating
either the X chromosome inherited from the
father or the mother, which has important
consequences for the clinical phenotype of X-
linked diseases between the two sexes.


Studies on XCI in the mouse model system have
revealed that female embryonic stem cells (ESCs)
carry two active X’s and that XCI must be
initiated when these cells are induced to
differentiate. XCI is an epigenetic phenomenon
that occurs without alterations in the primary
sequence of DNA by formation of a repressive
heterochromatin structure. Intriguingly, this
heterochromatin structure can be erased when
adult murine cells are reprogrammed to the ESC-
like state of iPSCs.




                                                   $1,364,598
Findings in the human system are less clear as
typical female human ESCs and iPSC lines have an
inactive X chromosome that can change its
composition with extended culturing indicating
potential epigenetic instability. It is now also
thought that these cells don't represent the same
developmental state as mouse ESCs and iPSCs. In
agreement with this notion, human pluripotent
cells with two active X chromosomes have
recently been generated that appear to resemble
the mouse ESC state. Thus, there are now at least
two different human pluripotent states that also
differ in their X chromosome status. We believe
that our proposed studies of XCI regulation
during differentiation and reprogramming in
human cells and in these different human ESC
states will not only unveil mechanisms underlying
this fundamental silencing process and human
development, but also be instrumental for the
careful characterization of these different human
pluripotent states. This is particularly important
given that human ESCs and iPSCs carry a
tremendous promise for therapeutic applications
and for modeling of human development and
diseases, and that the XCI status in these cells
also will have specific implications for modeling of   $1,364,598
A major issue in the use of stem cells or in organ
transplantation in general is the need to
overcome graft rejection. Unfortunately, the only
means currently available involves the use of
systemic immunosuppression which leaves the
recipient at risk for opportunistic infections. This
proposal will seek to use the donor's immune
cells to prevent rejection. Using a concept in
which the donor immune cells (in this case,
natural killer cells) are infused first, the recipient's
immune cells will specifically seek to attack and
reject it. The donor natural killer cells will be
activated and thereby act as a "veto cell" and
"attack the attacker" resulting in the eradication
of only the host immune cells which would
recognize the donor graft. Once eradicated, we
will then infuse the donor stem cells which should
now engraft without the need for extensive
immunosuppression with the goal that the
recipient will now become tolerant of the donor
cells. This proposal will also examine the impact
of recipient age on this process as the vast
majority of patients in need of such therapy will
be more advanced in age and this can impact
both their rejection ability and the ability to            $1,317,569
Human Leukocyte Antigens (HLA) are proteins
that are expressed on the surface of almost all
cells in the body. Because HLA sequences are
highly variable and each person generally has a
different set of HLA gene sequences, these cell
surface markers serve as the identifiers of "self"
vs. "non-self". If immune cells in the body
encounter foreign cells transplanted from a
different individual, in most cases these foreign
cells are recognized due to their display of a
different "non-self" HLA on their cell surfaces,
and attacked by the immune system. However,
because it is difficult to obtain donors with
precise matches, many patients succumb to their
disease while on a waiting list for matched bone
marrow or organs. Even one mismatch in HLA can
result in immune responses against the
transplant graft, making it necessary to
administer immunosuppressive drugs for the
lifetime of the patient. Initially it was thought
that human embryonic stem cell (hESC)-derived
cells and tissues might not be attacked by the
immune system because these cells do not have
much HLA on their surfaces in their primitive
state. However, it is now known that once hESC              $469,219
Critical limb ischemia (CLI) represents a significant
unmet medical need without any approved
medical therapies for patients who fail surgical or
angioplasty procedures to restore blood flow to
the lower leg. CLI affects 2 million people in the
U.S. and is associated with an increased risk of leg
amputation and death. Amputation rates in
patients not suitable for surgery or angioplasty
are reported to be up to 30-50% after 1 year.
Patients who are not eligible for revascularization
procedures are managed with palliative care, but
would be candidates for the proposed phase I
clinical trial.


In an effort to combat CLI, prior and ongoing
clinical trials that our group and others have
conducted have evaluated direct injection of
purified growth factors into the limb that has low
blood flow. Some trials have tested plasmids that
would produce the blood vessel growth factors
for a short period of time. These therapies did
show benefit in early stage clinical trials but were
not significantly better than controls in Phase III
(late stage) trials, probably due to the short
duration of presence of the growth factors and
their inability to spread to the areas most
needed. Other clinical trials ongoing in our
vascular center and others are testing the
patient's own stem cells, moved from the bone
marrow to the damaged limb, and those studies
are showing some benefit, although the final
assessments are not yet completed. Stem cells
can have benefit in limb ischemia because they
can actively seek out areas of low oxygen and will
produce some growth factors to try to encourage
blood vessel growth. But in cases where the
circulation needs very high levels of rescue, this
strategy might not be enough.
As an improved strategy we are combining the
stem cell and growth factor approaches to make
a more potent therapy. We have engineered
human Mesenchymal Stem Cells (MSCs) to
produce high levels of the strong angiogenic
agent VEGF for this novel approach (MSC/VEGF).
We and others have documented over the past
20+ years that MSC are capable of sustained
expression of growth factors, migrate into the
areas of lowest oxygen in the tissues after
injection, and wrap around the damaged or tiny
blood vessels to secrete their factors where they
are needed most.



These MSC/VEGF cells are highly potent, safe and
effective in our preclinical studies. These human
stem cells designed to produce VEGF as
"paramedic delivery vehicles armed with growth
factor to administer" rapidly restored blood flow
to the limbs of rodents who had zero circulation
in one leg. With funding that could be potentially
obtained through the proposed application we
will follow the detailed steps to move this
candidate therapy into clinical trials, and will
initiate and complete an early phase clinical trial
to test safety and potential efficacy of this
product that is designed to save limbs from
amputation.                                           $76,861 Heart Disease
Leukemia is the most frequent form of cancer in
children and teenagers, but is also common in
adults. Chemotherapy has vastly improved the
outcome of leukemia over the past four decades.
However, many patients still die because of
recurrence of the disease and development of
drug-resistance in leukemia cells. In preliminary
studies for this proposal we discovered that in
most if not all leukemia subtypes, the malignant
cells can switch between a "proliferation phase"•
and a "quiescence phase". The "proliferation
phase" is often driven by oncogenic tyrosine
kinases (e. g. FLT3, JAK2, PDGFR, BCR-ABL1, SRC
kinases) and is characterized by vigorous
proliferation of leukemia cells. In this phase,
leukemia cells not only rapidly divide, they are
also highly susceptible to undergo programmed
cell death and to age prematurely. In contrast,
leukemia cells in "quiescence phase" divide only
rarely. At the same time, however, leukemia cells
in "quiescence phase" are highly drug-resistant.
These cells are also called 'leukemia stem cells'
because they exhibit a high degree of self-
renewal capacity and hence, the ability to initiate
leukemia. We discovered that the BCL6 factor is
required to maintain leukemia stem cells in this      $3,607,305 Blood
Stroke is the third leading cause of death and the
leading cause of disability in this country,
affecting about 650,000 people in the US each
year. Currently approved therapies for stroke are
directed toward acutely restoring blood flow
(using drugs that break up clot). A new approach
is to use stem cells to regenerate portions of the
brain that are damaged in a stroke. Stem cells can
be obtained from adult individuals, or from
embryos. Studies using adult stem cells have
shown that only a small fraction of these cells are
capable of transforming into brain cells. Another
problem is that in patients with stroke, many
different types of brain cells must be replaced.
Furthermore, the replacement cells must
reconstitute the normal architecture of the lost
brain. Additionally, the stem cells must overcome
the hostile metabolic milieu in the ischemic brain,
which includes poor blood flow, as well as the
adverse metabolic environment that caused the
stroke in the first place (eg. high blood sugar, high
cholesterol, high blood pressure). So in this
proposal we are taking a different approach. We
will develop methods to make blood vessels using
human embryonic stem cells (HESC). HESC                  $658,125
The goal of this proposal is to establish a novel
research tool to explore the molecular basis of
Parkinson's disease (PD) - a critical step toward
the development of new therapy. To date, a small
handful of specific genes and associated
mutations have been causally linked to the
development of PD. However, how these
mutations provoke the degeneration of specific
neurons in the brain remains poorly understood.
Moreover, conducting such genotype-phenotype
studies has been hampered by two significant
experimental problems. First, we have historically
lacked the ability to model the relevant human
cell types carrying the appropriate gene
mutation. Second, the genetic variation between
individuals means that the comparison of a cell
from a disease-carrier to a cell derived from a
normal subject is confounded by the many
thousands of genetic changes that normally
differentiate two individuals from one another.
Here we propose to combine two powerful
techniques - one genetic and one cellular - to
overcome these barriers and drive a detailed
understanding of the molecular basis of PD.
Specifically, we propose to use zinc finger             $1,327,983 Parkinson's disease
Familial hypertrophic cardiomyopathy (HCM) is
the leading cause of sudden cardiac death in
young people, including trained athletes, and is
the most common inherited heart defect. Until
now, studies in humans with HCM have been
limited by a variety of factors, including variable
environmental stimuli which may differ between
individuals (e.g., diet, exercise, and lifestyle), the
relative difficulty in obtaining human cardiac
samples, and inadequate methods of maintaining
human heart tissue in cell culture systems.
Cellular reprogramming methods that enable
derivation of human induced pluripotent stem
cells (hiPSCs) from adult cells, which can then be
differentiated into cardiomyocytes (hiPSC-CMs),
are a revolutionary tool for creating disease-
specific cell lines that may lead to effective
targeted therapies.



In this proposal, we will derive hiPSC-CMs from
patients with HCM and healthy controls, then
perform a battery of functional and molecular
tests to determine the presence of
cardiomyopathic disease and associated
abnormal molecular programs. With these
preliminary studies, we believe hiPSC-CMs with
HCM phenotype will dramatically enhance the
ability to perform future high-throughput drug
screens, evaluate gene and cell therapies, and
assess novel electrophysiologic interventions for
potential new therapies of HCM. Because HCM is
not a rare disease but rather the leading cause of
inherited heart defects, we believe the findings
here should have broad clinical and scientific
impact toward understanding the molecular and
cellular basis of HCM.                                   $1,425,600 Heart Disease
Cardiovascular disease (CVD) is the leading cause
of death in the United States. Over one million
Americans will suffer from a new or recurrent
heart attacks this year and over 40 percent of
those will die suddenly. In addition, about two-
thirds of the patients develop congestive heart
failure; and in people diagnosed with CHF,
sudden cardiac death occurs at 6-9 times the
general population rate. Heart transplantation
remains the only viable solution for severely
injured hearts; however, this treatment is limited
by the availability of donor hearts. Therefore,
alternative strategies to treat end stage heart
failure and blocked blood vessels are needed. The
objective of this proposal is to determine
whether human embryonic stem (hES) cell can be
used for repairing the heart. Our collaborator
Advanced Cell Technology (ACT) has recently
succeeded in identifying conditions for the
reproducible isolation of hES cells which have the
characteristics of cells which form blood vessels
and heart muscle. This proposal will assess
whether the hES cells can form new functional
blood vessels and repair injured heart muscle in a
rat model of heart attacks. Results from these       $2,524,617 Heart Disease
The function of the immune system throughout
life is essential for protection from infections and
cancer. T lymphocytes are white blood cells that
choreograph the multiple responses that the
body uses to control infection. T lymphocytes are
produced in the thymus, a specialized organ
located in the chest in front of the heart. The
production of new T lymphocytes
("thymopoiesis") is abnormal in some children
with genetic defects in the development of the
thymus (DiGeorge syndrome [DGS]), but even in
healthy people, thymic function declines with
age. Thymic insufficiency, the decreased ability of
the thymus to make new T lymphocytes, is a
serious health problem. For example, if the T
lymphocytes that have been previously made
were to be destroyed by HIV infection,
chemotherapy or radiation therapy, or
hematopoietic stem cell transplantation, the
restoration of immune function requires the
production of new T lymphocytes to replace
those that were lost. For this reason, adults with
such conditions have poorer recovery of immune
function than children and the elderly have
increasing risk of severe infection with age. For
example, 10-40% of the elderly do not respond to       $658,057 Immune Disease
A stroke kills brain cells by interrupting blood
flow. The most common "ischemic stroke" is due
to blockage in blood flow from a clot or
narrowing in an artery. Brain cells deprived of
oxygen can die within minutes. The loss of
physical and mental functions after stroke is
often permanent and includes loss of movement,
or motor, control. Stroke is the number one
cause of disability, the second leading cause of
dementia, and the third leading cause of death in
adults. Lack of movement or motor control leads
to job loss and withdrawal from pre-stroke
community interactions in most patients and
institutionalization in up to one-third of stroke
victims. The most effective treatment for stroke,
thrombolytics or "clot-busters", can be
administered only within 4.5 hours of the onset
of stroke. This narrow time window severely
limits the number of stroke victims that may
benefit from this treatment. This proposal
develops a new therapy for stroke based on
embryonic stem cells. Because our (and others')
laboratory research has shown that stem cells can
augment the brain's natural repair processes
after stroke, these cells widen the stroke           $20,000,000 Stroke
The goals of this proposal are to investigate
endodermal differentiation and proliferation in
human ES cell cultures. Endodermal cells give rise
to the epithelial lining of the respiratory and
digestive tract as well as to the liver and
pancreas. The future treatment of diseases such
as type I diabetes using stem cell therapy relies
on our ability to differentiate stem cells into
endoderm, a prerequisite step to forming
pancreatic beta cells. In 2005, D                      $635,242 Diabetes
Cardiovascular diseases remain the major cause
of death in the western world. Stem and
progenitor cell-derived cardiomyocytes (SPC-
CMs) hold great promise for myocardial repairs.
However, most SPC-CMs displayed
heterogeneous and immature
electrophysiological (EP) phenotypes with
variable automaticity. Implanting these
electrically immature and inhomogeneous CMs
into hearts might carry arrhythmogenic risks.
Human embryonic stem cell-derived
cardiomyocytes (hESC-CMs) provide a model
system to study the development of
cardiomyocytes (CMs), in part because they are
an immature population of CMs that could
continue to mature in the embryoid body (EB)
environment. Elucidating cellular factors and
molecular pathways governing electrical
maturation of early hESC-CMs would enable
engineering microenvironment to create
electrophysiologically compatible hESC-CMs for a
safe, cell-based therapy of cardiovascular
diseases. Many temporal and regional cues from
neighboring extra-cardiac cells or non-CMs direct
the specification and maturation of CMs during
normal cardiac development. How these regional
and temporal cues influence EP maturation of        $1,823,362
Stem cell therapies have the potential to
transform medicine by allowing the regeneration
of tissues or organs damaged by disease or
trauma. In order for stem cell therapies to
proceed, it will be essential that the regulation of
immune responses to the stem cell derived
tissues be achieved. While the function of the
immune system in protection from infections is
essential throughout life, some immune reactions
are undesirable. Illnesses due to autoimmunity, in
which the immune system attacks one's own
body, instead of only germs that cause infection,
are common. Examples of autoimmune diseases
that are amenable to stem cell based therapies
include Type I diabetes caused by abnormal
immune responses directed against the insulin
producing cells and multiple sclerosis (MS) caused
by immune responses that attack the nervous
system. Another type of undesirable immune
response is the attack on transplanted tissues,
leading to rejection. Control of immune reactions
is the major impediment to successful organ
transplantation, and is highly likely to be an
obstacle to therapeutic uses of stem cells. T
lymphocytes are white blood cells that
choreograph the multiple responses that the            $1,415,836
Cardiovascular disease (CVD) affects more than
71 million Americans and 1.7 million Californians.
Recently, engineered cardiovascular tissue grafts,
or "patches", including one made from mouse
embryonic stem cells (ESC), have shown
promising results as a future therapy for CVD. Our
overall goal is to extend these recent results to
human ESC as follows. Aim 1: Apply mechanical
stretch and electrical pacemaker-like stimulation
to hESC-derived heart cells in order to make them
stronger and beat at the same time. Current
methods to turn hESC into heart cells do not
result in the organization required to generate
enough strength to support a weak heart and to
avoid irregular heart beats. We will use specially
engineered devices to apply mechanical stretch
and electrical pacemaker-like stimulation to hESC-
derived heart cells in order to strengthen them
and make them beat in unison. Aim 2: Engineer a
cardiovascular patch from hESC-derived heart
cells in order to make a potential new therapy for
heart disease. Recently, heart cells from mouse
ESC, supporting structures called scaffolds, and
mechanical stretch have successfully been
combined to engineer a cardiovascular patch. We      $2,618,704 Heart Disease
Human pluripotent stem cells (hPSC) have the
capacity to differentiate into every cell in the
adult body, and they are thus a highly promising
source of differentiated cells for the investigation
and treatment of numerous human diseases. For
example, neurodegenerative disorders are an
increasing healthcare problem that affect the
lives of millions of Americans, and Parkinson's
Disease (PD) in particular exacts enormous
personal and economic tolls. Expanding hPSCs
and directing their differentiation into
dopaminergic neurons, the cell type
predominantly lost in PD, promises to yield cells
that can be used in cell replacement therapies.
However, developing technologies to create the
enormous numbers of safe and healthy
dopaminergic neurons required for clinical
development and implementation represents a
bottleneck in the field, because the current
systems for expanding and differentiating hPSCs
face numerous challenges including difficulty in
scaling up cell production, concerns with the
safety of some materials used in the current cell
culture systems, and limited reproducibility of
such systems. An emerging principle in stem cell
engineering is that basic advances in stem cell        $1,493,928 Parkinson's disease
Stem cells, like all transplants not derived from an
identical twin, are subject to scrutiny by the
immune system and, without medical
interventions that suppress the immune system,
are usually killed after transplantation. However,
rare exceptions to this rule exist because a small
fraction of transplant patients has been able to
maintain their transplant in the absence of
immunosuppressive drug therapy and developed
"operational tolerance" towards the foreign graft.
Our team has extensively studied these patients
and identified a number of genes that are
characteristically overexpressed or silenced in
these patients. Other instances of tolerance
towards foreign cells also occur naturally, e.g.
during pregnancy. While numerous genes that
correlate with operational tolerance are known, it
is less clear whether they actively contribute to
tolerance and how they compare in their
effectiveness. We will therefore transfer this
collection of genes, one-by-one or as
combinations, into mouse embryonic stem cells
using gene therapy methods and identify those
genes that can best protect the cells from
rejection by the immune system. To accurately          $1,447,956
A healthy immune system produces T cells that
can recognize and react against foreign molecules
(antigens) to protect against infection, while
leaving normal host cells with "self antigens"
undamaged. All T cells are produced in the
thymus from blood stem cells that migrate from
the bone marrow. "Tolerant" T cells are those
that have been "educated" to not react against
self antigen on host cells. The key cells in the
thymic microenvironment that control T cell
production and tolerance are the thymic
epithelial cells (TECs). When TECs are lost or
become dysfunctional, T cell production is poor
and patients are at risk for a wide range of
infections. When tolerance is lost, T cells react to
host tissues as if they were foreign, producing
inflammation and damage and causing
autoimmune diseases such as Type I Diabetes,
multiple sclerosis, rheumatoid arthritis and
systemic lupus erythematosus. The ability of a
patient to accept cells or an organ transplant
from another person also requires tolerance to
occur, or the graft will be rejected. The goal of
our studies is to develop a method for
engineering and transplanting new, healthy             $1,357,398
Less than 2% of the human genome encodes
protein coding genes. But many trait-specific and
disease specific mutations seem to map away
from such coding sequences. This paradox is
partially resolved by observation that some of the
noncoding sequences are involved in regulation
of when and where in the developing organism
genes are to be turned on and off. One class of
such regulatory sequences is called enhancers,
since they have a property to greatly enhance
gene expression. Genomic DNA in the cells is
physically organized in the form of chromatin,
which consists of DNA wrapped around histone
proteins. Specific combinations of chemical
modifications of histones form a basis of
epigenetic marking system, which helps to
organize the genome into functional domains,
some of which are active, while others are
silenced.




In human embryonic stem cells two different
epigenetic signatures are associated with, and
specifically distinguish, two classes of enhancer
elements. One signature marks enhancers that
are actively turned on in embryonic stem cells,
and another marks class of enhancers that we
dubbed "poised enhancers", which are not active,
but are kept in a state of anticipation that allows
them to become rapidly activated when stem
cells undergo a decision to differentiate. Here we
propose a series of experiments aimed at
elucidating why and how the poised enhancer
signature is formed, and how it transitions to an
active signature during differentiation and does
so in a cell-type specific manner. Results of such
experiments will greatly extend our
understanding of how the genomic information is
interpreted to form the multitude of human
tissues during development.
Why is enhancer regulation important for stem
cell biology and its biomedical applications? Basic
research on enhancer regulation in embryonic
cell types proposed here is important for
uncovering fundamentals of early human
development and understanding of nature of
pluripotency and commitment. In addition to
novel insights into developmental gene
regulation in humans this work may have
unexpected, immediate and broad applications
for regenerative medicine. For example, discovery
of poised enhancer signature in embryonic stem
cells identified a set of over 2,000 putative early
developmental enhancers in a single study,
thereby creating an invaluable resource for
generation of reporters for lineage tracking and
isolation of transient cell populations
representing early steps of human development.         $1,425,600
Human embryonic stem cell (hESC) research
promises to be of fundamental importance in the
study and treatment of various human diseases,
including cancer, neurodegenerative disorders
and organ failure. In recent years we have made
great strides in advancing hESC research as
documented by the large number of successful,
high-impact laboratories and breadth of research
projects here. In addition, we are situated among
several other first-rate institutions, all of which
have joined in an unparalleled research
environment for hESC research. Since the
creation of the California Institute for
Regenerative Medicine, we have devoted both
space and financial resources to promote hESC
research. Our institutional commitment has as a
cornerstone the creation of a core facility for
hESC research to foster and promote hESC
research at this and surrounding institutions. To
date the facility has served to (1) train scientists
in the basic methodologies to conduct hESC
research (2) facilitate hESC research for many
investigators, both established and beginning
scientists, and (3) provide a "safe haven" that is
sheltered from any federal funding sources thus
allowing unimpeded hESC research. However,             $3,711,102
All adult tissues contain stem cells. Some tissues,
like bone marrow and skin, harbor more adult
stem cells; other tissues, like muscle, have fewer.
When a tissue or organ is injured these stem cells
possess a remarkable ability to divide and
multiply. In the end, the ability of a tissue to
repair itself seems to depend on how many stem
cells reside in a particular tissue, and the state of
those stem cells. For example, stress, disease, and
aging all diminish the capacity of adult stem cells
to self-renew and to proliferate, which in turn
hinders tissue regeneration. Our strategy is to
commandeer the molecular machinery
responsible for adult stem cell self-renewal and
proliferation and by doing so, stimulate the
endogenous program of tissue regeneration. This
approach takes advantage of the solution that
Nature itself developed for repairing damaged or
diseased tissues, and controls adult stem cell
proliferation in a localized, highly controlled
fashion. This strategy circumvents the
immunological, medical, and ethical hurdles that
exist when exogenous stem cells are introduced
into a human. When utilizing this strategy the
goal of reaching clinical trials in human patients                 Bone or Cartilage Disease, Stroke, Heart Disease,
within 5 years becomes realistic. Specifically, we      $5,767,050 Neurological Disorders, Skin Disease
Although ESC-based therapies hold great promise
for the cure of a wide diversity of degenerative
diseases, rapid progress to actual human clinical
trials is hindered by the lack of preclinical data for
specific ESC-based therapies. I aim to move the
process forward by establishing a protocol in
which immune system cells are reproducibly
produced from ESC and tested in vivo for the
induction of and maintenance of immunological
tolerance to therapeutic ES-derived cells. I will
use the mouse as a model system to test this
protocol, as the mouse is the model system of
choice for study of the immune system due to the
availability of genetically identical strains and well-
studied models of human disease. Moreover, my
protocol design will be reflect strategies already
used for successful organ transplantation, making
the protocol suitable for clinical use. The immune
system is the primary barrier to the acceptance of
any embryonic stem cell (ESC)-based therapy.
Immune system cells are derived from a stem cell
in the blood which has the potential to
differentiate into a number of mature cell types,
such as red blood cells, macrophages,
granulocytes, B lymphocytes (B cells) and T               $1,581,056
The clinical application of cell replacement
therapy in the US is dependent on the FDA's
approval, and the primary objective of the FDA is
to protect patients from unsafe drugs and
procedures. The FDA has a specific mandate for
human gene and cell therapy and since the
unexpected deaths in early trials of gene therapy
trials the bar for safety in these areas is unusually
high. This is a summary of the key findings from
the FDA's report on human embryonic stem cell
therapy (April 2008): "From the perspective of
toxicology, the proliferative potential of
undifferentiated human embryonic and
embryonic germ cells evokes the greatest level of
concern. A characteristic of hESCs is their capacity
to generate teratomas when transplanted into
immunologically incompetent strains of mice.
Undifferentiated hESCs are not considered as
suitable for transplantation due to the risk of
unregulated growth. Before clinical trials are
begun in humans, the issue of unregulated
growth potential and its relationship to stem cell
differentiation must be evaluated". In order to
overcome the concerns about the safety of
pluripotent stem cell therapy, we have designed a         $6,292,290
Human embryonic stem cells (hESCs) have the
potential to become all sorts of cells in human
body including nerve cells. Moreover, hESCs can
be expanded in culture plates into a large
quantity, thus serving as an ideal source for cell
transplantation in clinical use. However, the
existing hESC lines are not fully characterized in
terms of their potential to become specific cell
types such as nerve cells. It is also unclear if the
nerve cells that are derived from hESCs are totally
normal when tested in cell transplantation
experiments. One of the goals for our proposal is
to compare the quality and the potential of eight
lines of hESCs in their capacity to become nerve
cells. To measure if the nerve cells that are
derived from hESCs are normal when compared
to the nerve cells in normal human beings, we
will examine the levels of gene expression and
the mechanisms that control gene expression in
hESC-derived nerve cells. Specifically, we will
examine the pattern of DNA modification, namely
DNA methylation, in the DNA of nerve cells. This
DNA modification is involved in the inhibition of
gene expression. It is known that if DNA
methylation pattern is abnormal, it can lead to        $2,516,613 Stroke
Cancer is responsible for approximately 25% of all
deaths in the US and other developed countries.
For women, breast and lung cancers and for men,
cancers of prostate and lung are the most
prevalent and the most common cause of deaths
from cancer. While a large number of treatment
modalities such as surgery, chemotherapy,
radiation therapy, etc. have been developed, we
still are far from finding a cure for most cancers.
So, more research is needed to understand the
basic processes that are subverted by cancer cells
to gain a proliferative advantage. In addition,
cancer patients show a great deal of
heterogeneity in the course and outcome of the
disease. Therefore it is important to be able to
predict the clinical outcome of the patients so
that appropriate therapies can be administered.
Clinical outcome prediction is based generally on
tumor burden and degree of spread with
additional information provided by histological
type and patient demographics. However,
patients with similar tumor characteristics still
show heterogeneity in the course and outcome of
disease. Thus, accurate sub-classification of
patients with similar clinical outcomes is required
for development of more efficacious therapies.        $3,238,450 Solid Tumor
Alzheimer’s disease is the most common cause of
dementia in the elderly, affecting over 5 million
people in the US alone. Boosting immune
responses to beta-Amyloid (A?) has proven
beneficial in mouse models and Alzheimer's
disease (AD) patients. Vaccinating Alzheimer’s
mice with A? improves cognitive performance
and lessens pathological features within the
brain, such as A? plaque loads. However, human
trials with direct A? vaccination had to be halted
to brain inflammation in some patients. We have
demonstrated that T cell immunotherapy also
provides cognitive benefits in a mouse model for
Alzheimer's disease, and without any detectable
brain inflammation. Translating this approach
into a clinical setting requires that we first
develop a method to stimulate the proliferation
of A?-specific T cells without triggering
generalized inflammatory response, as happens
with vaccinations. Adaptive immune responses
are provided by T cells and B cells, which are
regulated by the innate immune system through
antigen presenting cells, such as mature dendritic
cells. We propose to leverage the power of
embryonic stem (ES) cells by engineering
dendritic cells that express a recombinant           $2,120,833 Aging, Alzheimer's disease
We propose to generate induced pluripotent
stem (iPS) cells from skin cells derived from
human subjects with frontotemporal dementia
(FTD). FTD accounts for 15–20% of all dementia
cases and, with newly identified genetic causes, is
now recognized as the most common dementia in
patients under 65 years of age. FTD patients
suffer progressive neurodegeneration in the
frontal and temporal lobes and other brain
regions, resulting in behavioral changes and
memory and motor neuron deficits. The median
age of onset for this devastating disease is 58
years, and disease progression is rapid, with
death in 3–8 years. Compared with other age-
dependent neurodegenerative diseases, the
molecular, cellular, and genetic bases of FTD
remain poorly understood. Genetic causes are
estimated to account for ~40% of FTD. In addition
to tau identified in 1998, mutations in three
causative genes have been identified during the
last three years. The identification of FTD
mutations opens exciting new avenues for
understanding the causes of FTD. Research on
these mutations will help to identify effective
therapies. However, the ability to study the
functions of these factors is severely limited due    $1,708,560 Dementia
Human embryonic stem cells (hESC) have the
potential to differentiate into all of the cell types
that make up the body. Therefore, hESCs are
promising tools for the treatment of degenerative
diseases and for use in regenerative medicine.
One highly desirable use of hESCs is to treat
cardiovascular disease. Cardiovascular disease is a
leading cause of mortality and morbidity in the
state and country. Cardiovascular disease is
caused by damage to blood vessels and the ability
to repair this damage will improve disease
outcomes. However, the ability to efficiently
differentiate hESCs down cardiovascular lineages
to generate large numbers of cells on a
therapeutically relevant scale is lacking. The goal
of this project is to develop a protocol for the
differentiation of hESCs into vascular endothelial
cells for the treatment of cardiovascular disease.
Initially we will study the expression of vascular
precursor cell genes during embryoid body
formation from hESCs. Then, using gene transfer
technology and regulatable gene expression of
transcription factors that induce the vascular cell
lineage, we will “tune―   treated hESCs to
optimize derivation of endothelial cells. We will
then use these cells in a pre-clinical mouse model      $1,382,400

The proposed project is designed to assess the
safety and preliminary activity of escalating doses
of human embryonic stem cell (hESC) derived
oligodendrocyte progenitor cells for treatment of
spinal cord injury. Oligodendrocyte progenitor
cells have two important functions: they produce
neurotrophic factors which stimulate the survival
and growth of neurons (nerve cells) after injury,
and they mature in the spinal cord to produce
myelin, the insulation which envelops neuronal
axons (nerve cell bodies responsible for
conduction) and facilitates unimpeded nerve
impulse conduction. After extensive efficacy and
safety testing, clinical testing of this product was
initiated in 2010.
Clinical testing is being initiated in paraplegic
patients with neurologically complete thoracic
injuries (i.e., those in which no motor or sensory
function remains below the level of the injury). In
the first cohort, a dose equivalent to the lowest
efficacious dose observed in preclinical rodent
studies is being administered. During the course
of the proposed program, clinical safety studies
testing increasing doses will be conducted. Upon
demonstration of safety, clinical testing will be
expanded to tetraplegic patients (complete
cervical injuries) and to patients with incomplete
thoracic injuries for additional safety testing. In
each of the proposed studies, preliminary
evidence of activity will be monitored using
measures of improved neurological function and
performance of daily living activities.


The project plan also includes the manufacture of
cells to be used in the clinical trials and additional
supporting activities. By completion of the
proposed project, we expect to have
accumulated substantial safety data and
preliminary efficacy data in three different
patient subpopulations. This data will provide key
information to inform the design and execution
of advanced efficacy studies.                            $0 Spinal Cord Injury
Human embryonic stem cells (hESCs) are cells
derived from human embryos early in
development before their fate has been sealed.
These cells grow and differentiate in response to
a variety of stimuli to eventually give rise to all of
the differentiated tissues in the body. By
exploiting the remarkable potential of hESCs to
differentiate into multiple cell lineages, medicine
stands to benefit enormously. To do so requires a
comprehensive understanding of the optimal
conditions to grow and differentiate these cells.
What is known is that the physical environment
in which hESCs reside plays an important role in
regulating their tissue-specific differentiation.
Recent work has highlighted the importance of
the composition and structure of the extracellular
matrix (ECM), within which hESCs exist in vivo, in
directing hESC differentiation during embryonic
development. In an embryo, hESCs differentiate
in a dynamic and structurally distinct three-
dimensional (3D) ECM, rich in nutrients and
exogenous stimuli (force). Mechanical stimulation
(via matrix compliance and externally applied
force) dramatically influences the formation and
development of the embryo. Despite these
compelling observations, information regarding           $561,082
The clinical potential of pluripotent stem cells for
use in regenerative medicine will be realized only
when the process by which tissues are generated
from these cells is significantly more efficient and
controlled than is currently the case.
Fundamental questions remain about the
mechanisms by which pluripotent stem cells
differentiate into mature tissue. The overall goal
of this research proposal is to discover if the cell
types produced during differentiation of PSC
produce the microenvironment needed for
specialized tissue stem cells to develop. To
approach this question we will use the
hematopoietic ("blood-forming") system as our
model, as it is the best characterized tissue in
terms of differentiation pathways and offers a
range of unique technical tools with which to
rigorously study questions of differentiation.
Adult hematopoietic stem cells survive and grow
in the bone marrow only if they are physically
close to specialized cell types, the so-called
hematopoietic stem cell "niche". We hypothesize
that hematopoietic stem cells are not produced
from pluripotent cells because the cells that form
the niche and provide the necessary signals are        $1,375,983


One of the most potentially powerful aspects of
regenerative medicine is stem cell therapy. In this
therapy, healthy tissues derived from stem cells
will be implanted into patients with damaged
tissue in order to restore function. However,
there is currently a risk of immune rejection.
Human induced pluripotent stem (hiPS) cells have
the potential to revolutionize regenerative
medicine. By reprogramming a patient's own cells
into pluripotent stem cells, stem cell therapies
can be performed with little to no risk of
rejection. However, this nuclear reprogramming
process is not well understood at a mechanistic
level. Also, all procedures developed to date use
cancer-related genes. This has raised fears that
current hiPS cells could potentially have a high
cancer risk if used therapeutically. In this
proposed research, we intend to study the
mutation load associated with reprogramming
and the functional consequences of the
mutations. We will use the obtained knowledge
about transformation to develop safer methods
of generating hiPS cells.
We will perform large-scale screening of somatic
mutations that have potential deleterious effects
during the reprogramming of human primary
cells into hiPS cells, and the differentiation of hiPS
cells into somatic cell types. We will also
characterize whether mutations occurred have
any function, including the increase of cancer
risk. These information will help us to understand
how do the mutations occur and propagate.


This proposed project will not only help us to gain
additional mechanistic insights on nuclear
reprogramming, but also allow great progress
towards functional stem cell therapy, as safe hiPS
cells will be available for therapeutic use.             $1,382,140

Regenerative medicine holds the promise that
tissues can be engineered in vitro and then
transplanted into patients to treat debilitating
diseases. Human Embryonic Stem Cells
differentiate into a wide array of adult tissue
types and are thought to be the best hope for
future regenerative therapies. This grant has
three main goals: 1. The creation of new human
embryonic stem cells in animal free conditions
which will allow for future therapeutic uses. 2.
The creation of human embryonic stem cell that
contain mutations in their genomes that cause
diseases, including cystic fibrosis, muscular
dystrophy, Downs Syndrome and many others.
These lines can be used to study these diseases
and to test potential therapies 3. A close
biological assessment of one of the first tissues to
arise during differentiation of human embryonic                     Genetic Disorder, Muscular Dystrophy, Pediatrics,
stem cells                                               $2,628,635 Respiratory Disorders
Nearly one out of every two Californians born
today will develop cancer at some point in their
lives, and it is likely that one in five persons will
die of the disease. We propose to study the
mechanisms of action of the RB gene, which is
mutated in a broad range of human cancers,
including pediatric cancers of the eye and the
bone, and adult tumors such as lung, breast,
prostate and liver cancers. RB normally acts as a
tumor suppressor. When RB is mutated, cells lose
the ability to sense when to cycle or not and they
divide too much, thereby initiating cancer.
Because RB is mutated in so many human
cancers, therapies that could re-introduce RB
function in cancer cells would benefit a great
number of cancer patients. A key question is to
determine in which cell type loss of RB function is
most detrimental. Knowing the answer to this
question would help to diagnose cancer early and
target specific cells within tumors, making
treatment more effective. Recent evidence
suggests that loss of RB may initiate cancer in
stem cells . Because human embryonic stem cells
(hESCs) give rise to any other stem cells, we will      $520,777
More than 600 disorders afflict the nervous
system. Common disorders such as stroke,                         Amyotrophic Lateral Sclerosis, Spinal Muscular
epilepsy, Parkinson                                     $807,749 Atrophy, Neurological Disorders
Stem cell research holds great promise for
neurological disease. One in three Americans will
suffer from diseases of the nervous system
ranging from stroke to Alzheimer's disease to
epilepsy. Very few treatments for neurological
disease exist, in part because of he lack of
suitable in vitro models with which to test
therapeutics. In addition, many neuronal
disorders, including Parkinson's disease and ALS,
are characterized by loss of important
subpopulations of neurons. In affected patients,
the only way to restore function may be to
provide them with replacement neurons. Many
researchers are already working on methods to
generate replacement neurons from human
embryonic stem cells or to generate accurate in
vitro models of neurological diseases. Here, we
propose to perform the reverse experiment; we
aim to generate pluripotent cell lines directly
from neurons, using two novel technologies. The
first goal of these experiments is to generate cell
lines so that we can compare the chromosomes
of neurons with those of neurons derived from ES
cells. If differences exist, and are important for
the proper function of neurons, it is essential to
identify these changes. Similarly, if neurons in      $2,803,375
A major goal of stem cell research is to generate
various functional human cell types that can be
used to better understand how these cells work
and to use them directly in therapies. There are
currently no effective treatments, let alone a
cure, for many neurological conditions. Two
particular devastating neurological conditions,
spinal cord injury and amyotrophic lateral
sclerosis (ALS, or Lou Gehrig's disease) share a
common element. That is, in both conditions, the
corticospinal motor neurons that control skilled
voluntary movement are severely damaged,
leading to significant loss of motor control. There
has been extensive research on spinal cord injury
and ALS in recent years. In the field of spinal cord
injury, much effort has been devoted to repairing
the damaged nerve paths, but this has turned out
to be extremely challenging. The work on ALS, on
the other hand, has mostly focused on the spinal
motor neurons (often referred to as the lower
motor neurons in the context of ALS). Our
proposed study focuses on the corticospinal
motor neurons (or the upper motor neurons)
and, more broadly, the subcerebral projection
neurons. Taking clues from studies in mice, we
aim to understand how the subcerebral                  $1,355,063 Neurological Disorders
The therapeutic use of stem cells depends on the
availability of pluripotent cells that are not
limited by technical, ethical or immunological
considerations. The goal of this proposal is to
develop and bank safe and well-characterized
patient-specific pluripotent stem cell lines that
can be used to study and potentially ameliorate
human diseases. Several groups, including ours
have recently shown that adult skin cells can be
reprogrammed in the laboratory to create new
cells that behave like embryonic stem cells. These
new cells, known as induced pluripotent stem
(iPS) cells should have the potential to develop
into any cell type or tissue type in the body.
Importantly, the generation of these cells does
not require human embryos or human eggs. Since
these cells can be derived directly from patients,
they will be genetically identical to the patient,
and cannot be rejected by the immune system.
This concept opens the door to the generation of
patient-specific stem cell lines with unlimited
differentiation potential. While the current iPS
cell technology enables us now to generate
patient-specific stem cells, this technology has                Amyotrophic Lateral Sclerosis, Melanoma,
not yet been applied to derive disease-specific      $1,382,400 Muscular Dystrophy, Neurological Disorders
The ability to target a specific locus in the mouse
genome and to alter it in a specific fashion has
fundamentally changed experimental design and
made mice the preeminent model for studying
human diseases . However, pathogenesis in
humans have unique pathways that may not be
revealed by only using mouse or other animal
models. An approach that combines the
advantages of mouse models with parallel
experiments in human embryonic stem cells
(hESCs) offers significant advantages over current
methodologies. With the large number of hESC
lines available, the ability to grow cells in defined
media, the development of drug resistant feeders
and the reports of strategies to insert DNA with
increasing efficiency into hESC, it would only be a
matter of time to obtain homologous
recombinants in hESCs. In order to provide direct
clues to pathogenesis in human tissues, we
propose to use homologous recombination to
establish in vitro human disease models in hESCs.
As a proof of principle, we have chosen Lou
Gehrig's disease (or amyotrophic lateral sclerosis,
ALS). ALS is a disease that progressively and
selectively attacks motoneurons in the brain and
the spinal cord. It becomes fatal when
motoneurons controlling breathing are affected.         $869,262 Amyotrophic Lateral Sclerosis
The goal of this proposal is to generate forebrain
neurons from human embryonic stem cells. Our
general strategy is to sequentially expose ES cells
to signals that lead to differentiation along a
neuronal lineage, and to select for cells that
display characteristics of forebrain neurons.
These cells would then be used in transplantation
experiments to determine if they are able to
make synaptic connections with host neurons. If
successful these experiments would provide a
therapeutic strategy for the treatment of
Alzheimer's disease and other disorders that are
characterized by loss of forebrain neurons.
Currently there is no effective treatments for
Alzheimer's disease, and with an aging baby-
boomer population, the incidence of this disease
is likely to increase sharply. One of the few
promising avenues to treat Alzheimer's is the
possibility of cell replacement therapy in which
the neurons lost could be replaced by
transplanted neurons. Embryonic stem cells,
which have the ability to differentiate into
various cells of the body, could be a key
component of such a therapy if we can
successfully differentiate them into forebrain        $612,075 Aging, Alzheimer's disease
Hearing loss is the leading birth defect in the
United States with ~3 children in 1,000 born with
partial to profound compromise of auditory
function. Debilitating hearing loss is estimated to
affect ~4% of people under 45 years of age, and
34% of those 65 years or over. A major cause of
why acquired hearing loss is permanent in
mammals lies in the incapacity of the sensory
epithelia of the inner ear to replace damaged
mechanoreceptor cells, or hair cells. Sensory hair
cells are mechanoreceptors that transduce fluid
movements generated by sound into
electrochemical signals interpretable by the
brain. Degeneration and death of hair cells is
causal in >80% of individuals with hearing loss. In
this grant application, we propose to explore, in
comparative manner, the potential of at least five
human ESC lines to develop into hair cells. We
strive to use recently derived human embryonic
stem cells for this purpose to avoid problems
caused by potential chromosomal abnormalities
and nonhuman or viral contaminants, which
greatly restrict the use of these stem cells and
render their derivatives unacceptable for in vivo
studies. Federal funding cannot be used for
research with these embryonic stem cell lines.           $2,469,373 Hearing Loss


For many therapeutic reasons it is important to
have available large numbers of blood cells.
However, it is difficult to generate large numbers
of specialized blood cells that have the ability to
neutralize autoimmunity and response to tumor
cell growth. In this study we would develop a
technique that would allow the production of
large numbers of different types of blood cells
from human embryonic stem cells. For example, a
subset of white blood cells, called dendrititc cells,
is currently manipulated in the laboratory in a
manner that allows them to attack cancer cells.
The same cells also are altered in the laboratory
to counter-act the development of autoimmune
diseases. A problem with these experiments is
that it is difficult to isolate large numbers of these
cells, since they are relatively rare. With the
technology that is described in this grant
application we would be able to generate large
numbers of such cells in the laboratory using as a
starting point, human embryonic stem cells.               $538,211 Blood Disorders
Human embryonic stem cells (hESCs) hold
significant promise for regenerative medicine. In
this application our goal is to derive hESC lines
from pre-implantation embryos to generate a
source of low passage lines that can be used in
research and to develop the procedures required
to generate a clinic grade cell-based product. In
this application we will develop the procedures
for deriving, expanding and banking using current
good manufacturing practices (cGMP), which are
necessary for producing a clinic grade line. We
aim to do this using chemically defined media and
surfaces in consultation with the Director of
Regulatory Compliance at our Institution.
Secondly, we aim to derive hESC lines from
embryos that have genetic disorders. These
genetic aberrations are identified following pre
implantation genetic diagnosis (PGD) or pre
implantation genetic screening (PGS) of
consented embryos from couples undergoing in
vitro fertilization (IVF). Deriving hESC lines from
these embryos will be essential for understanding
the underlying causes of spontaneous
miscarriage, or as a tool to improve the quality of
life of individuals born with these chromosomal       $1,177,648 Genetic Disorder, Pediatrics
The goal of our research is to develop efficient
methods for making a particular class of immune-
system cells known as regulatory T cells (Tregs).
Tregs have the potential to be useful in a wide
variety of clinical situations. For instance, they
could be used to control the harmful immune
responses seen in patients with autoimmune
diseases such as childhood (Type I) diabetes,
rheumatoid arthritis, multiple sclerosis and
inflammatory bowel disease; and to suppress
rejection of transplanted organs in patients given
heart, liver or kidney transplants. These patients
are normally treated with toxic
immunosuppressive drugs to prevent transplant
rejection, but nevertheless tend to lose the
organs and need to get on a long waiting list all
over again. Treating them with Tregs might
preserve the transplant, possibly indefinitely, and
is expected to be much less toxic because it
would decrease or eliminate the need for the
immunosuppressive drugs. Bone marrow
transplants are a special case. Stem cells present
in the bone marrow give rise to all types of blood
cells, including red blood cells which carry
oxygen, platelets which are necessary for blood
clotting so that one does not bleed to death from     $1,503,998
Genetic dissection of mesodermal commitment
to hematopoietic fates. Hematopoietic cell
transplantation is the gold standard for cell-based
therapy and is routinely used to treat a wide
variety of blood disorders and cancer. A major
limitation exists, however, in finding donors
whose immune systems are compatible with
those of the patients requiring transplantation.
The recent creation of human embryonic stem
cell (hESC) lines holds great promise for new cell-
based therapies. ES cells can generate all cell
types in the body and can be stored indefinitely.
Large banks of genetically diverse or genetically
engineered hESC cells could thus be used to
match donor and host immune systems. For
hematopoietic cell transplantation, ESCs must be
coaxed to differentiate into hematopoietic stem
cells (HSCs). This is currently not possible, due in
large part to a lack of understanding of the
molecular cues required to generate HSCs during
development. In the vertebrate embryo, two
waves of blood cell production occur. The first
generates only erythroid cells and the second
HSCs. Understanding the development of these
two waves is important since ES cells have been
shown to normally generate only the first. In this     $2,185,369
Embryonic stem cells have the capacity to self-
renew and differentiate into other cell types.
Understanding how this is regulated on the
molecular level would enable us to manipulate
the process and guide stem cells to generate
specific types of cells for safe transplantation.
However, complex networks of intracellular
cofactors and external signals from the
environment all affect the fate of stem cells.
Dissecting these molecular interactions in stem
cells is a very challenging task and calls for
innovative new strategies. We propose to
genetically incorporate novel amino acids into
proteins directly in stem cells. Through these
amino acids we will be able to introduce new
chemical or physical properties selectively into
target proteins for precise biological study in
stem cells. Nurr1 is a nuclear hormone receptor
that has been associated with Parkinson’s disease
(PD), which occurs when dopamine (DA) neurons
begin to malfunction and die. Overexpression of
Nurr1 and other proteins can induce the
differentiation of neural stem cells and embryonic
stem cells to dopamine (DA) neurons. However,
these DA neurons did not survive well in a PD           $2,626,937 Parkinson's disease
The overall goal of the proposed studies is to
utilize human gene therapy approach using
human embryonic stem cells to direct our body's
defenses to specifically attack melanoma tumor
cells. Current technologies try to accomplish this
by genetically manipulating certain circulating T
lymphocytes, such that they will target tumor
cells. T lymphocytes are the major cell type of our
body's immune system. However it is likely that
this type of approach will not result in the
presence of stable, lifelong genetically modified T
cells. In contrast, a potentially more long-lasting
approach would be to genetically modify human
embryonic stem cells with the same therapeutic
gene. Stem cells have the ability to form any type
of blood cell, including T cells. Importantly, stem
cells can persist for the life of the individual, and
thus have the potential to produce genetically
modified T cells for many years. In addition, these
new tumor specific cells should expand in the
body in response to the presence of the tumor,
thus a large supply of tumor-fighting cells should
be available as long as needed. This project
proposes to develop novel means to introduce
the anti-cancer gene into human embryonic stem           $642,501 Melanoma
The advent of human embryonic stem cells
(hESCs) has offered enormous potential for
regenerative medicine and for basic
understanding of human biology. On the one
hand, hESCs can be turned into many different
cell types in culture dish, and specific cell types
derived from hESCs offer an almost infinite
source for cellular replacement therapies. This is
the primary reason for which hESCs have received
much attention from the general public. On the
other hand, scientists can study the properties of
hESCs and their derivatives, and determine the
effect of genes and molecules on such properties
either in culture dish or with transplantation
studies in live animals. This second aspect of hESC
research would not only significantly enhance our
understanding of the function of human genes,
but will greatly augment our ability to apply
hESCs in transplantation therapies and
regenerative medicine. To attain the full potential
of hESCs, genetic manipulation of hESCs is
essential. In this proposal, we will establish the
methods to genetically manipulate an
increasingly used, non-federally approved hESC
line, the HUES-9, and assess the feasibility to use              Amyotrophic Lateral Sclerosis, Spinal Cord Injury,
genetically modified HUES-9 cells in cell               $642,361 Neurological Disorders

The proposed studies describe the genetic
approaches utilizing human embryonic stem cells
to suppress and/or eliminate the expression of
the human protein CCR5. CCR5 is found on the
surface of white blood cells. HIV-1 attaches to
CCR5 and uses CCR5 to enter into its target cells.
Our approach is to utilize established as well as
new non-established approaches to prevent CCR5
from appearing on the surface of the cells. If
CCR5 is not present, HIV-1 cannot infect the cells.
Interestingly, this concept has already been
proven in nature. Approximately 1% of the
Caucasian population is genetically deficient for
CCR5 and these individuals are resistant to HIV-1
transmission. Their white blood cells, when
placed in culture, also resist HIV-1 infection in the
laboratory. As such, we believe that our approach
can be used to protect high risk individuals from
HIV-1 infection as well as impede or stop
progression of disease in those individuals
already infected.                                       $642,652 HIV/AIDS, Immune Disease
Science has made great progress in the treatment
of certain cancers with targeted and combination
therapies, yet prolonged remissions or cures are
rare because most cancer therapies only inhibit
cell growth and/or reduce such growth but do
not stop the cancer.



The study investigators propose to develop an
Investigational New Drug (IND) and fully accrue a
phase I clinical trial within the grant period to
genetically redirect the patient's immune
response to specifically attack the cancer starting
from hematopoietic (blood) stem cells (HSC) in
patients with advanced forms of the aggressive
skin cancer malignant melanoma. Evaluation of
immune system reconstitution, effectiveness and
immune response during treatment will use
imaging with Positron Emission Tomography
(PET) scans.



The HSC treatment approach has been validated
in extensive studies in the laboratory. The
investigators of this grant have recently initiated
a clinical trial where adult immune cells obtained
from blood are genetically modified to become
specific killer cells for melanoma. These cells are
administered back to patients. The early data
from this study is encouraging in terms of the
ability to generate these cells, safely administer
them to patients leading to beneficial early
clinical effects. However, the adult immune cells
genetically redirected to attack cancer slowly
decrease over time and lose their killer activity,
mainly because they do not have the ability to
self-renew.
The advantage of the proposed HSC method over
adult blood cells is that the genetically modified
HSC will continuously generate melanoma-
targeted immune killer cells, hopefully providing
prolonged protection against the cancer. The IND
filing with the FDA will use the modified HSC in
advanced stage melanoma patients. By the end of
year 4, we will have fully accrued this phase 1
clinical trial and assessed the value of genetic
modification of HSCs to provide a stable
reconstitution of a cancer-fighting immune
system. The therapeutic principles and
procedures we develop will be applicable to a
wide range of cancers and transferrable to other
centers that perform bone marrow and HSC
transplants.

The aggressive milestone-driven IND timeline is
based on our:

1) Research that led to the selection and
development of a blood cell gene for clinical use
in collaboration with the leading experts in the
field,

2) Our wealth of investigator-initiated cell-based
clinical research and the Human Gene Medicine
Program (largest in the world with 5% of all
patients worldwide),


3) Experience filing a combined 15 investigator
initiated INDs for research with 157 patients
enrolled in phase I and II trials, and


4) Ability to leverage significant institutional
resources of on-going HSC laboratory and clinical
research and contribute ~$1M of non-CIRM funds
to pursue the proposed research goals, including
the resulting clinical trial.                        $110,000 Melanoma
Osteoporosis is an unsolved and highly prevalent
health care problem: 10 million Americans suffer
from the disease, and an additional 34 million
have low bone mass. Roughly half of all women
and a fourth of all men older than 50 years will
sustain an osteoporosis-related fracture at some
time in their lives, and when such a fracture
occurs, the chances of death within 12 months
are about 1 in 5. Osteoporotic fractures can take
several forms, but VCFs (vertebral compression
fractures) occur at a rate of 700,000 per year-
twice the rate of hip fractures. The economic
burden of osteoporotic fractures is tremendous.
In 2001, there were approximately 1.5 million
osteoporosis-related fractures in the US at a cost
of $17 billion, or approximately $47 million per
day. Currently, treatment is focused primarily on
prevention. When fractures occur in patients with
osteoporosis, treatment options are limited
because open surgery with implants often fails.
Recently, new therapies involving injection of
cement into the vertebral body were developed.
Unfortunately, these procedures do not
regenerate bone tissue, but do incur risks of
leakage and emboli. Moreover,recent                  $109,743 Bone or Cartilage Disease
Our proposal details assembly of a
multidisciplinary Disease Team whose goal will be
to take into the clinic a novel and promising stem
cell-based strategy for selectively targeting
invasive tumor cells in high-grade glioma. These
tumor cells form small foci scattered throughout
the brain that are resistant to standard
treatments and are the tumor in large part
responsible for the poor prognosis of glioma
patients. Therapies to eliminate invasive brain
tumor cells while sparing normal brain are
urgently needed to address this clinical gap. The
therapy we intend to develop is centered on our
initial preclinical results demonstrating that
neural stem cells (NSCs) can be used to target and
deliver chemotherapeutic agents to tumors and
infiltrative microfoci. Only cell-based therapies
have the capability to actively seek out tumor
cells, a property essential to targeting dispersed
invasive glioma microfoci. Our fundamental
observation and lead approach has been
established in pre-clinical glioma models: a well-
characterized immortalized human neural stem
cell line will localize to tumor sites, track invading
tumor cells, and deliver therapeutically effective
drug. We are now uniquely poised to take this            $55,000
Human embryonic stem cells (hESCs) have
important potential in the treatment of human
disease. Because they can change into a large
number of different cell types, they may be useful
in restoring a variety of damaged tissues. One
potentially harmful side effect of hESC therapy is
cancer due to unregulated growth of the hESCs
introduced in the body. hESCs have the potential
to grow almost indefinitely. Therefore if they
should become "transformed" into cancer cells
while being cultured in the laboratory, they may
cause cancer in the individuals into which they
are injected. Transformation of normal cells into
cancer cells can occur through changes in their
DNA, which contains the information telling cells
to grow or not to grow. Because multiple changes
must occur for cells to begin the unchecked
growth of cancer cells, the likelihood of cancer is
low. However, some cellular changes can increase
the rate at which subsequent changes occur,
which greatly increases the probability that a cell
will acquire all of the changes necessary to
become a cancer cell. This increased rate of
changes in DNA is called genomic instability,
which is proposed to be an early step in many          $1,074,355

The Gladstone CIRM Scholars Training Program
will train CIRM scholars in the postdoctoral and
clinical tracks. The J. David Gladstone Institutes
conducts basic research on three of the most
important medical problems of modern times:
cardiovascular disease, AIDS, and
neurodegenerative disorders. Each of these
research areas addresses promising targets for
regenerative medicine. Gladstone recently
consolidated its research activities in a new
200,000 sq. ft. facility, including laboratory space
constructed without federal funding. Its location      $2,397,240
This CIRM Scholars Training Program seeks
continued funding of a highly successful Type II
(Intermediate training) program that is currently
funded for postdoctoral and clinical scholars. The
host institution conducts basic research on three
of the most important medical problems of
modern times: cardiovascular disease, AIDS, and
neurodegenerative disorders. Each of these
research areas addresses promising targets for
regenerative medicine. The host institution is
located in a new 200,000 sq. ft. facility, including
CIRM-funded laboratory space constructed
without federal funding. Its
location—[REDACTED] —provides an ideal
environment for collaboration between scientists
at the host institution, neighboring [REDACTED]
laboratories, and other research institutions. The
host institution is an independent research
institute affiliated with [REDACTED], and we
combine some of our educational activities with
the robust training programs in stem cell biology
at [REDACTED], thus facilitating synergy and
eliminating duplication. The host institution
offers a unique training for CIRM scholars,
providing a commitment to educating the next
generation of biomedical scientists, highly            $5,111,047

Public school classrooms are often strapped for
resources, with ill-fitted lab equipment and a
lackluster science curriculum, and teachers often
struggle to provide interactive science
opportunities for their students. Our scientists
believe a highly skilled workforce benefits the
state of California and that underprivileged
students deserve to be part of the exciting field of
stem cell research. So, in 2008 we created a
summer internship experience for public high
school students in our laboratories in an effort to
increase the number of underrepresented
students who pursue undergraduate and
graduate science degrees and to expand the
diversity of biomedical researchers.
Each summer, six rising high school seniors are
selected to work with a mentor in our labs
spending 75% of their time conducting
biomedical research and 25% of their time in
supplementary educational activities. Their work
culminates in a final poster session in which
students describe their work, hypothesis and
findings to our scientific community.


CIRM funding will allow us to ensure that two of
our six interns specialize specifically in stem cell
biology. Our interns will be able to learn methods
for enhancing cell-fate commitment and analyses
to determine genetic variation on cellular
maturation and survival. Our institution has a
robust stem cell biology research program, and
our scientists are enthusiastic about sharing their
passion for this science with our high school
interns.                                                   $30,690
Just like cells in a human embryo, embryonic
stem cells have the potential to give rise to all cell
types and tissues in a human body. That is why it
is an exciting prospect to use these cells in tissue
repair. But in order to do so, we have to
understand how we can guide the differentiation
of stem cells. For example, if one wants to use
stem cells for replacing defective insulin-
producing cells in the pancreas, we have to learn
how we can convert stem cells into pancreas
cells, or at least precursors to pancreas cells. So
the question is then, how do cells in an embryo
become different from each other? Research
done in animals has shown that there are
signaling proteins that instruct cells to change
from one type into another. One important group
of these signaling proteins are the Wnts. Studied
in our lab for along time, Wnts are powerful
differentiation factors. To use Wnt proteins as
factors under controlled conditions, one has to be
able to isolate them. This has been a major
problem in the past, but we have solved this
recently. We are therefore now in a position to
test how Wnt proteins, when added to stem cells,         $2,354,820
Hair cells (HCs) convert sound and balance signals
into electrical impulses in the inner ear, including
the cochlea and the vestibular endorgans, with
remarkable precision and sensitivity. Our long-
term goal is to stimulate HC regeneration in
human inner ears and to enable the functional
innervations of HCs by neurons. Hair cells are
terminally-differentiated cells. Once HCs are lost
due to noise, ototoxic drugs or aging, there is no
effective way to stimulate HC regeneration in
mature inner ears. However, recent studies from
our group and others have demonstrated very
encouraging results: new HCs may be formed
from stem cells. We know very little about how to
induce HC regeneration in a mature sensory
epithelia in the auditory and vestibular organs.
Indeed, determination of the mechanisms of
induction of HCs and the assembly of the
functional machinery of HCs in the mature
cochlea has direct relevance to our
understanding of how a HC may be derived from
specific human embryonic stem cells (hESCs).
Strong evidence from data in developmental cell
biology and electrophysiology motivates our
hypothesis that the specific factors regulating HC
differentiation interact to confer their functions     $469,327 Hearing Loss
Like most tissues of the body, bone possesses a
natural regenerative system aimed at restoring
cells and tissues lost to natural cell aging, disease
or injury. These natural regenerative systems are
complex combinations of cell growth factors and
support structures that guide and control the
development of specialized bone stem cells.
However, the regeneration process may still fail,
for multiple reasons. For instance, the degree of
skeletal injury may be so great that it overwhelms
the natural regenerative capacity. Alternatively,
the natural regenerative capacity may be
defective; this is exemplified by osteoporosis, a
frequent condition affecting post-menopausal
females and elderly males and females.
Osteoporotic individuals have severe declines in
stem cell numbers (10-fold decrease from age 30
to 80) and stem cell function (tendency of stem
cells to turn into fat rather than bone cells with
age), leading to bone loss and "fragility fractures"
that typically would not occur in persons with
normal stem cell number and function. Thus,
there is a tremendous need for therapies to
increase the number and function of endogenous
adult stem cells with the potential to build new



One option is to introduce so called mesenchymal
stem cells (MSC) from the patient to bone repair
sites. However, significant hurdles to autologous
MSC use include the need for 2-3 week culture
times to isolate MSC before application.
Moreover culturing introduces infectious and
immunogenic risks from prolonged exposure to
animal products and cancerous risks from cellular
gene changes in culture. In addition, once
isolated, MSC require appropriate growth factor
stimulation to form bone. Finally, MSC isolated
from patient tissues such as fat or bone marrow
are heterogenous and of undetermined
composition - making growth factor dosing and
conformance with FDA regulations for defining
target product identity, purity, and potency more
difficult.
To circumvent these problems, we have identified
and purified the cells at the origin of human MSC.
We have termed these perivascular stem cells
(PSC) because they are natively localized around
all arteries and veins, forming the key cellular
component of the natural regenerative system. In
a significant breakthrough, we are able to isolate
these cells within hours from adipose tissues in
sufficient numbers for therapy without the need
for culture. This realizes the possibility of
harvesting and implanting stem cells during the
same operative period. In another breakthrough,
we have identified a potent growth factor NELL-1
that potently amplifies the ability of PSC to form
bone and vascular structures. This has led to the
development of our target PSC+NELL-1 product,
which effectively stimulates and augments the
body's natural bone regenerative system by
providing all the components (stem cells, growth
factor, and allograft bone support structure)
necessary to "jump start" as well as maintain the
function of bone stem cells.                           $5,391,560 Bone or Cartilage Disease
Human embryonic stem cells (hESC) hold great
promise as sources of tissue for regenerative
medicine and therapeutics. In addition, their
utility as tools to study the origins and biology of
human disease must not be underestimated.
hESC give rise to tissue-specific adult stem cells
and, ultimately, to all mature tissues in the body.
As such, disruptions to normal stem cell function
can have catastrophic consequences and result in
life-threatening or debilitating disease.
Understanding how such diseases arise will afford
novel insights into how we can better prevent
and treat them. Laboratory based studies with
hESC therefore stand to make extraordinary
contributions to human health. Human tumors,
and in particular the cancers that affect children,
often look like tissues that have not developed
normally and whose growth has gone unchecked.
In fact, recent studies have shown that, in many
cases, tumors arise because genetic mutations in
the DNA of normal stem cells lead to disordered
development, resulting in formation of malignant
rather than normal tissues. For example,
leukemia can arise when a mutation occurs in a
normal blood stem cell, thus inducing formation         $675,001 Solid Tumor, Pediatrics
Cervical spinal cord injuries result in a loss of
upper limb function because the cells within the
spinal cord that control upper limb muscles are
destroyed. The goal of this research program is to
create a renewable human source of these cells,
to restore upper limb function in both acute and
chronic spinal cord injuries. There are two
primary challenges to the realization of this goal:
1) a source of these human cells in high purity,
and 2) functional integration of these cells in the
body after transplantation. Human embryonic
stem cells (hESCs) can form any cell in the body,
and can reproduce themselves almost indefinitely
to generate large quantities of human tissue. One
of the greatest challenges of hESC research is to
find ways to restrict hESCs such that they
generate large amounts on only one cell type in
high purity such that they could be used to
replace lost cells in disease or trauma. Our
laboratory was the first laboratory in the world to
develop a method to restrict hESCs such that they
generate large amounts of only one cell type in
high purity. That cell type is called an                         Amyotrophic Lateral Sclerosis, Spinal Muscular
oligodendrocyte, which insulates connections in                  Atrophy, Spinal Cord Injury, Neurological
the spinal cord to allow them to conduct              $2,396,932 Disorders


We proposes to use human embryonic stem cells
(hESCs) differentiated into neural
progenitor/stem cells (NPCs), but modified by
transiently programming the cells with the
transcription factor MEF2C to drive them more
specifically towards dopaminergic (DA) neurons,
representing the cells lost in Parkinson's disease.
We will select Parkinson's patients that no longer
respond to L-DOPA and related therapy for our
study, because no alternative treatment is
currently available. The transplantation of cells
that become DA neurons in the brain will create a
population of cells that secrete dopamine, which
may stop or slow the progression of the disease.
In this way, moderate to severely affected
Parkinson's patients will benefit.
The impact of development of a successful cell-
based therapy for late-stage Parkinson's patients
would be very significant. There are
approximately one million people in the United
States with Parkinson's disease (PD) and about
ten million worldwide. Though L-DOPA therapy
controls symptoms in many patients for a period
of time, most reach a point where they fail to
respond to this treatment. This is a very
devastating time for sufferers and their families
as the symptoms then become much worse. A
cell-based therapy that restores production of
dopamine and/or the ability to effectively use L-
DOPA would greatly improve the lives of these
patients. Because of our extensive preclinical
experience and the clinical acumen of our Disease
Team, we will be able to quickly adapt our
procedures to human patients and be able to
seek an IND from the FDA within four years.             $96,448 Parkinson's disease

Mobility is critical for human social interactions
and quality of life. In the aged mobility is
progressively impaired due to painful joints. The
articular cartilage in the joints is damaged. The
long-term goal of our research is the utilization of
human embryonic stem cells (hESCs) for cartilage
formation and therefore, regeneration of
articular cartilage. Stem cells have enormous
potential. Their potential can be directed by
morphogens governing chondrogenesis. Bone
and cartilage morphogenetic proteins induce
stem cells to form cartilage cells. This research
will contribute directly to the development of
therapy for osteoarthritis for the aging
Californians.                                          $367,650
An important class of neurological diseases
predominantly affects spinal motor neurons, the
neurons that control muscle movement. The
most well known of these motor neuronopathies
is Amyotrophic Lateral Sclerosis (ALS), commonly
referred to as Lou Gehrig’s disease for the famous
Yankee first baseman who died of the disease.
The first symptoms of ALS are usually increasing
difficulty walking or speaking clearly. People with
ALS progressively lose their ability to initate and
control movements, and may become totally
paralyzed during the late stages of the disease.
There are no cures or effective treatments for
these diseases. Riluzole (Rilutek), the only FDA
approved medication for ALS, only modestly
slows disease progression. Consequently, ALS is
usually fatal within one to five years from onset,
with half dying within eighteen months. Although
genetic studies have identified many mutations
that cause these diseases, it is not understood
why these mutations kill motor neurons. This lack
of understanding about the root causes of motor
neuron diseases currently hinders the
development of effective treatments. We seek to
study motor neurons carrying these mutations in                  Amyotrophic Lateral Sclerosis, Neuropathy, Spinal
cell culture dishes to understand how these           $2,259,092 Muscular Atrophy, Neurological Disorders
Since their discovery in 1998, human embryonic
stem cells (hESCs) have been considered to hold
great potential for the treatment of many
currently incurable diseases. Possibly the most
exciting application of hESC in the clinic is in the
arena of regenerative medicine where hESC-
derived cell populations are used to replace
diseased, damaged or dead tissues. A major
safety concern in developing hESC-based cell
replacement therapies has been the potential risk
of tumor growth, which is due to residual
primitive, or undifferentiated, hESCs within the
cell graft. Eliminating these undifferentiated and
tumor promoting cells has proven to be difficult.
In this grant application, we propose to develop a
technology to identify and enrich the cells of
interest while eliminating undesired and
contaminating cell populations. Using an elegant
method to introduce genes into hESCs, we will
engineer cell lines that will express a marker only
when a particular cell type has been produced.
                      will
Such "marker lines"• be used to develop and
optimize protocols to efficiently derive specific
mature and specialized cell types suitable for
transplantation. Cell purification methods will be      $1,993,586

RNA interference is a naturally occurring means
to block the function of genes in our body. We
propose that RNA interference can be used to
block HIV-1 infection and its reproduction within
the body. When RNA interference is introduced
into a stem cell, its blocking activity will be
present throughout the lifetime of the stem cell,
theoretically the lifespan of a human being. Thus,
in theory an effective stem cell RNA interference
therapy will require only a single treatment as
opposed to the current lifetime administration of
anti-HIV-1 drugs often accompanied by serious
side effects. In nature, some individuals carry a
genetic mutation that renders them resistant to
HIV-1 infection. This mutation prevents HIV-1
from attaching to the white blood cells. Our RNA
interference approach will be to mimic this
natural situation by blocking the activity of this
"co-receptor" within infected individuals by
creating a new blood system that carries the RNA
interference therapy. This therapy will be
developed as a combination with other gene
therapeutic reagents to protect the new blood
system from HIV infection.                             $19,999,580 HIV/AIDS, Immune Disease
For the millions of Americans who are born with
or develop heart disease, stem cell research
offers the first hope of reversing or repairing
heart muscle damage. Thus, early reports
suggesting heart regeneration after
transplantation of adult bone marrow-derived
stem cells were met with great excitement in
both the scientific and lay community. However,
although adult stem cell transplantation was
shown to be safe, results from over a dozen
clinical trials concluded that the benefits were
modest at best and whether any true
regeneration is occurring was questionable. The
basis for these disappointing results may be
related to poorly characterized cell types used
that have little capacity for true regeneration and
an inadequate understanding the factors
necessary for survival and differentiation of
transplanted stem cells. In this application, we
are proposing to study the growth and
differentiation properties of an authentic
endogenous human cardiac progenitor cell that
can differentiate into cardiac muscle cells,
smooth muscle cells and endothelial cells. We will
also determine the factors that support its            $1,378,076 Heart Disease
In addition to the important potential
applications for transplantation and treatment of
chronic diseases, human embryonic stem cells
(hESC) are also a valuable resource to study early
human development relevant to fertility and
healthy pregnancies. After fertilization, the
human zygote undergoes cell divisions and
ultimately becomes the blastocyst that has an
inner cell mass and a trophectoderm shell, the
precursor of the placenta and the tissue that
attaches to the surface of the lining of the uterus,
initiating the process of embryonic implantation.
After attachment, the placental cells invade into
the mother                                              $640,399 Fertility
AIDS is a disease that currently has no cure. It
arises when the human immunodeficiency virus
(HIV) infects certain types of blood cells. These
cells would normally be used to fight infection,
but instead are destroyed by the virus, leading to
immunodeficiency. We have recently been able
to induce the development of human embryonic
stem cells (hESC) into the types of cells that HIV
can infect. In addition, we were able to show that
a marker gene could be introduced into the hESC,
and this gene continued to produce its protein
throughout development of the cell into the
more mature blood cell types. This sets the stage
for testing the possibility of using gene-modified
hESC to treat HIV or other immune system
diseases. We have 3 different types of anti-HIV
genetic approaches that we will test in laboratory
models. These will be placed into hESC, and the
cells allowed to develop into blood cells. We will
then test whether our "therapeutic" genes can
inhibit HIV infection in culture. We will also
develop novel mouse models that allow
development of hESC into blood cells in the body
(in vivo). We will test the efficacy of certain of
these genetic approaches in these systems, as           $2,516,831 HIV/AIDS, Immune Disease

Patients with end-stage heart failure (ESHF) have
a 2-year survival rate of 50% with conventional
medical therapy. This dismal survival rate is
actually significantly worse than patients with
AIDS, liver cirrhosis, stroke, and other debilitating
diseases. Stem cell therapy may be a promising
strategy for inducing myocardial regeneration via
paracrine activation, prevention of cardiac
apoptosis, and other mechanisms. Several studies
have convincingly shown that human embryonic
stem cells can be differentiated into
cardiomyocytes (hESC-CMs) and that these cells
can be used to effectively improve cardiac
function following myocardial infarction (MI). The
objectives of this CIRM Disease Team Therapy
proposal are two-fold: (1) to perform IND
enabling studies involving hESC-CM for
subsequent FDA approval and (2) to complete a
Phase I trial with ESHF patients undergoing the
left ventricular assist device (LVAD) procedure
whereby hESC-CMs will be injected at the same
time.                                                    $108,895 Heart Disease
Multiple sclerosis (MS) is the most common
neurologic disease affecting young adults under
the age of 40 with the majority of MS patients
diagnosed in the second or third decade of life.
MS is characterized by the gradual loss of the
myelin sheath that surrounds and insulates axons
that allow for the conduction of nerve impulses –
a process known as demyelination. For unknown
reasons, the ability to remyelinate axons is
impaired in MS patients making recovery of
motor skills difficult. Therefore, developing novel
and effective approaches to remyelinate axons in
MS patients would dramatically improve the
quality of life of many MS patients. The
experiments described in this research proposal
utilize a well-accepted model of MS to further
characterize the potential clinical applicability of
human embryonic stem cells (hESCs) to
remyelinate axons. Such knowledge is crucial in
order to increase our understanding of stem cells
with regards to treatment of numerous human
diseases including MS.                                  $425,594 Multiple Sclerosis, Immune Disease
A major obstacle to stem cell based therapies is
the immune response of the patient to stem cell
derived tissue, which can be recognized as
foreign and attacked by the patient's immune
system. T cells orchestrate immune responses
and are "educated" about self versus foreign in
an organ called the thymus. It may be possible to
educate T cells in a patient to avoid attacking
stem cell derived grafts by "re-educating" them in
a thymus that contains the same material as the
graft. Humanized mouse models have
considerable potential as test beds for exploring
different therapeutic approaches, including
thymic re-education approaches because they
allow for human cells to be observed and
manipulated experimentally. This proposal aims
to refine humanized mouse models to allow for
different therapeutic strategies to promote the
acceptance of stem cell grafts by a patient's
immune system to be modeled and tested. This
proposal takes advantage of the most recent
innovations in microscopic imaging to probe the
interactions between developing T cells and their
support cells in living 3D tissues. In addition to
probing thymic development, in the future these
approaches could be further adapted to reveal          $1,079,393
There is much excitement over the possibility of
new and fundamentally-different therapeutic
applications for human embryonic stem cells and
the cells to which they differentiate. In addition,
there is equally great excitement in the scientific
community regarding the potential of human
embryonic stem cells for biological studies of how
different human cell types differentiate into
normal and diseased tissues. To date, there are
more than 400 human embryonic stem cell lines
that have been reported to have been derived
from human embryos that are donated for
research due to lack of suitability for transfer for
reproduction or being in excess of the needs for
reproductive purposes. The methodology to
derive new human embryonic stem cell lines was
largely derived from years of work in the clinic
that resulted in optimal conditions to grow
human embryos and from years of work in animal
species, mostly the mouse. In spite of this great
progress, we have not, however, yet derived
chromosomally-normal (genetically-normal)
human embryonic stem cell lines via
reprogramming techniques such as somatic cell
nuclear transfer. In part this is due to the
inaccessibility of human oocytes or eggs for
potential therapeutic and basic science                  $2,469,104 Fertility

The targeted disease is retinitis pigmentosa (RP),
is a severe form of blindness that runs in families.
This disease is not overly common, yet represents
an attainable near term target for stem cell
therapy for a number of reasons: 1) RP destroys
the light detecting cells of the retina but generally
leaves the rest of the visual system and body
unharmed, so the clinical goal is circumscribed; 2)
RP is prototypical of degenerations of the
nervous system, so a cure for this less common
disease would accelerate progress towards new
therapies for a range of more familiar conditions;
3) scientific research has shown that
degenerating rods and cones can be spared in
animals by transplanting particular types of stem
cells, so the scientific feasibility of treating RP in
this way has already been established in
principle.
The therapeutic approach is to save the light
sensing cells of the eye (rod and cone
photoreceptors) in people going blind using a
type of stem cell obtained from the immature
retina, but not from early embryos. These
particular stem cells from the retina, known as
progenitor cells, are capable of rescuing
photoreceptors from degeneration following
transplantation to the eye. These same cells are
also highly efficient at becoming rod
photoreceptors and this provides another more
sustained pathway by which they preserve the
crucial cone photoreceptors. In addition, there is
evidence that the stem cells themselves might
become functional photoreceptors and thereby
stabilize the retina by directly replacing the dying
cells in the patient's eye. Thus, transplanted stem
cells could treat the targeted disease of RP in
multiple ways simultaneously. Importantly, there
are a host of reasons why clinical trials in the eye
are easier and safer than most locations in the
body. The eye is an important proving ground for
stem cell-based therapies and provides a stepping
stone to many otherwise incurable diseases of
the brain and spinal cord.                             $3,855,277 Vision Loss
Alzheimer’s Disease (AD) is a major health
problem in the U.S. with 10% of people over the
age of 65 and 50% of people over the age of 85
afflicted with disease. In spite of the magnitude
of the problem, however, we lack a compelling
mechanistic understanding of AD. As a result, we
have no effective therapeutic agents for AD, with
few if any on the horizon. While cellular therapy
might some day be a viable therapy for AD,
current data do not strongly support such an
approach and the obstacles to implementing
cellular therapy for AD include the lack of a
compelling mechanism of neurodegeneration.
We propose to recruit a disease team that will
use human stem cells to accelerate the
development and prioritization of drug-like
therapeutic agents as well as developing targets
for therapeutic agent development based on the
mechanisms identified. Importantly, the resulting
cellular and animal models can also be used as
assays to screen chemical libraries to find novel
drugs that may protect against the degenerative
processes. These investigations will require
significant interdisciplinary activity as they will
need technologies, informatics, and computing            $55,000
Strokes that affect the nerves cells, i.e., "gray
matter", consistently receive the most attention.
However, the kind of strokes that affecting the
"wiring" of the brain, i.e., "white matter", cause
nearly as much disability. The most severe
disability is caused when the stroke is in the
wiring (axons) that connect the brain and spinal
cord; as many as 150,000 patients are disabled
per year in the US from this type of stroke.
Although oligodendrocytes ("oligos") are the
white matter cells that produce the lipid rich
axonal insulator called myelin) are preferentially
damaged during these events, stem cell-derived
oligos have not been tested for their efficacy in
preclinical (animal) trials. These same white
matter tracts (located underneath the gray
matter, called subcortical) are also the primary
sites of injury in MS, where multifocal
inflammatory attack is responsible for stripping
the insulating myelin sheaths from axons
resulting in axonal dysfunction and degeneration.
Attempts to treat MS-like lesions in animals using
undifferentiated stem cell transplants are
promising, but most evidence suggests that these
approaches work by changing the inflammation         $2,566,701 Multiple Sclerosis, Stroke, Immune Disease

UC Berkeley and the Children                         $2,529,810
Huntington’s disease (HD) is a devastating
degenerative brain disease with a 1 in 10,000 risk
of having a mutation that inevitably leads to
death. These numbers do not fully reflect the
large societal and familial cost of HD, which
requires extensive caregiving. HD has no effective
treatment or cure and symptoms progress
without stopping for 15-20 years, with onset
typically striking in midlife. Because HD is
genetically dominant, the disease has a 50%
chance of being inherited by the children of
patients. Symptoms of the disease include
uncontrolled movements, difficulties in carrying
out daily tasks or continuing employment, and
severe psychiatric manifestations including
depression. Specific regions of the brain are
severely affected, most notably the striatum.
Current treatments only treat some symptoms
and do not change the course of the disease,
therefore a completely unmet medical need
exists. Human embryonic stem cells (hESCs) offer
a possible long-term treatment that could relieve
the tremendous suffering experienced by
patients and their families. HD is the 3rd most
prevalent neurodegenerative disease, but             $54,618
Parkinson's disease (PD) is a neurodegenerative
movement disorder that affects 1 in 100 people
over the age of 60, one million people in the US
and six million worldwide. Patients show a resting
tremor, slowness of movement (bradykinesia),
postural instability and rigidity. Parkinson's
disease results primarily from the loss of neurons
deep in the middle part of the brain (the
midbrain), in particular neurons that produce
dopamine (referred to as "dopaminergic"). There
are actually two groups of midbrain dopaminergic
(DA) neurons, and only one, those in the
substantia nigra (SN) are highly susceptible to
degeneration in Parkinson's patients. There is a
relative sparing of the second group and these
are called ventral tegmental area (VTA)
dopaminergic neurons. These two groups of
neurons reside in different regions of the adult
ventral midbrain and importantly, they deliver
dopamine to their downstream neuronal targets
in different ways. SN neurons deliver dopamine in
small rapid squirts, like a sprinkler, whereas VTA
neurons have a tap that provides a continuous
stream of dopamine. A major therapeutic
strategy for Parkinsons' patients is to produce DA
neurons from human embryonic stem cells for          $1,407,076 Parkinson's disease
The tissue regenerative capacity deteriorates with
age in animals and in humans, leading to the loss
of organ function, which is well exemplified in
skeletal muscle, but is poorly understood in
molecular terms. Our recent work uncovered that
factors produced by human embryonic stem cells
have a unique ability to enhance the regenerative
responses of organ stem cells, dedicated for
tissue maintenance and repair, be they young or
old and located in young or old organism. This
proposal seeks to understand the molecular
mechanism of this novel phenomenon, which is
two-fold important: in expanding our knowledge
of the stem cell biology and in developing entirely
novel embryonic stem cell-based therapeutic
applications that do not have the side-effects
associated with immune rejection. Importantly,
this uncovered enhancement of tissue repair is
conserved between mice and humans , which
allows use of an animal model for identifying
these therapeutically-relevant human factors and
greatly facilitates the pre-clinical data collection,
interpretation and translation to clinic. The main
goals of this Proposal are to identify the
embryonic pro-regenerative factors, to
understand their mode of action and to validate         $2,246,020 Aging, Muscular Dystrophy, Pediatrics, Trauma



In this application, we propose to identify small
molecule compounds that can stimulate human
embryonic stem cells to become dopamine-
producing neurons. These neurons degenerate in
Parkinson's disease, and currently have very
limited availability, thus hindering the cell
replacement therapy for treating Parkinson's
disease. Our proposed research, if successful, will
lead to the identification of small molecule
compounds that can not only stimulate cultured
human embryonic stem cells to become DA
neurons, but may also stimulate endogenous
brain stem cells to regenerate, since the small
molecule compounds can be made readily
available to the brain due to their ability to cross
the blood-brain barrier. In addition, these small
molecule compounds may serve as important
research tools, which can tell us the fundamental
biology of the human embryonic stem cells.               $564,309 Parkinson's disease
Stem cell research offers new tools to help treat
and cure diseases that affect diverse cells types in
the body such as neurological diseases, heart
disease and diabetes by producing human cells
for transplantation or to enable drug discovery .
Recent advances have allowed researchers to
generate patient-matched cell types from the skin
or other tissues of patients. These patient-
matched cells are important because they are
unlikely to cause immune rejection upon
transplantation and they may help to model
diseases caused by gene variations found only in
rare individuals. Despite their promise, patient-
matched cells differ from traditional stem cells in
ways that may cause them to be less stable or
increase their potential to cause tumors. This is
because patient-matched cells are generated
from tissues taken from adult patients using
methods that dramatically alter the
chromosomes of these cells. These factors could
endow these reprogrammed cells with mutations
that would not be present in cells derived from
embryonic sources. To ensure the safety and
clinical utility of reprogrammed cells, it is critical
to establish methods to identify potentially             $1,755,864


One of the most difficult yet ultimately rewarding
goals in stem cell research is to repair damaged
neural systems with newly generated neurons.
Our work examining neuronal integration and
survival in the postnatal and adult brain shows
that incoming neurons are uniquely and
exquisitely sensitive to the immune response and
inflammation that is always present when cells
are transplanted into the injured or diseased
brain or spinal cord. Here we propose to: 1)
further refine our understanding of the molecular
mechanisms that promote or inhibit new neuron
integration; 2) evaluate pharmacological or
biological methods for enhancing transplant
efficiency and 3) test the developed techniques in
a model of stem cell therapy for treating children
who suffer neurological damage due to treatment
for brain cancer. Future studies anticipate the use
of these interventions to improve stem cell
therapies for a variety of neurological injuries and
diseases.                                                $2,501,125 Trauma
Human embryonic stem (hES) cells are
pluripotent stem cells that can theoretically give
rise to every cell type in the human body.
Consequently, hES cells have enormous promise
for the treatment of human disease. Specialized
cell types derived from hES cells could be used to
treat a wide variety of diseases and disorders
including spinal cord injury, Parkinson                $2,509,438

Hematopoietic stem cells (HSC) have been used
successfully to cure various life-threatening blood
diseases. Yet, matching HSCs are not available for
every patient. Human embryonic stem cells
(hESC) may provide an unlimited source of HSCs
for therapeutic use. However, hESC derived
hematopoietic cells do not develop properly in
those culture conditions that are currently used,
and thereby their function is impaired.
Hematopoietic cells that are derived from human
ES cells lack the ability to self-renew, which is a
prerequisite for the ability to generate blood cells
for the individual                                      $577,037 Blood Disorders
Infants with inherited blood diseases (such as
sickle cell anemia, thalassemia, bleeding
disorders) or other inherited metabolic disorders
can be identified early in development using
sophisticated diagnostic tests. Currently, the
treatment for many of these childhood illnesses
may include bone marrow transplantation which
is complicated by: (1) the toxicity associated with
chemotherapy or radiation-based regimens
necessary to ensure the transplanted cells persist;
(2) serious health complications associated with
rejection of the donor cells; (3) the fact that only
~20-25% of children will have a matched donor,
which is even less likely for ethnic populations
and underrepresented minorities; and (4) the
concern that significant damage, particularly to
the brain, has occurred by the time the child is
being considered for transplantation. Recent
studies suggest that very early treatment before
damage from the disease has occurred provides
the best survival outcomes, and that immature
cell sources may be most effective because they
have characteristic features that are more
compatible with the developmental stage of the
patient. Human umbilical cord blood has been
demonstrated to be a very effective source of          $4,214,592
Amyotrophic lateral sclerosis (ALS) is a rapidly
progressive, fatal neurological disease that leads
to the degeneration of motor neurons in the
brain and in the spinal cord. There are currently
20,000 ALS patients in the United States, and
5,000 new patients are diagnosed every year.
Unfortunately no cure has been found for ALS.
The only medication approved by the FDA to
treat ALS can only slow the disease's progression
and prolong life by a few months in some
patients. Thus it is critical to explore other
therapeutic strategies for the treatment of ALS
such as cell replacement strategy. Because of the
ability to generate many different cell types,
human embryonic stem cells (hESCs) may
potentially serve as a renewable source of cells
for replacing the damaged cells in diseases.
However, transplanting ESCs directly may cause
tumor growth in patients. To support cell
transplants, it is important to develop methods to
differentiate hESCs into the specific cell types
affected by the disease. In this application, we
propose to develop an effective method to
differentiate hESCs into corticospinal motor
neurons (CSMNs), the neurons in the cerebral
cortex that degenerate in ALS. We will test          $500,000 Amyotrophic Lateral Sclerosis
White blood cells are the main players of human
immunity in defense against infection. Defects in
CD4 T white blood cells, for example, can lead to
the devastating infections observed in AIDS
patients and patients with a genetic
immunodeficiency syndrome ("bubble boy"
syndrome). A normal immune system can
recognize and attack pathogens but not "self".
This is achieved by rigorous selection and
"education" during development of T or B white
blood cells and by regulatory T cells that suppress
occasional "run-away" white blood cells. Glitches
in these processes can also lead to equally
devastating problems as seen in many
autoimmune diseases like type I diabetes,
multiple sclerosis and rheumatoid arthritis. Thus,
the availability of T cells or regulatory cells could
lead to therapies for many human diseases. A
major limitation in using T cells in therapy is the
lack of available primary T cells generated in the
laboratory. Attempts thus far to generate T cell
precursors in a tissue culture dish from the
existing NIH approved embryonic stem (ES) cell
lines have had only limited success, perhaps due
to the partial white blood cell potential of these       $499,999
Embryonic stem (ES) cells are remarkable cells in
that they can replicate themselves indefinitely
and have the potential to turn into all possible
cell type of the body under appropriate
environmental conditions. These characteristics
make ES cells a unique tool to study development
in the culture dish and put them at center stage
for regenerative medicine. Two techniques, one
called somatic cell nuclear transfer (SCNT) and
the other in vitro reprogramming, have shown
that adult cells from the mouse can be reverted
to an ES like state. In SCNT, adult cell nuclei are
transferred into oocytes and allowed to develop
as early embryos from which ES cells can be
derived, while in the in vitro method four genes
are ectopically activated in the adult cell nucleus
to induce an embryonic state in the culture dish.
Key requirement for both processes is to erase
the memory of the adult cell that specifies it as an
adult cell and set up the ES cell program. How
this happens remains unclear, and if it can be
reproduced with human adult cells is an open
question. Therefore, we will attempt to use the in
vitro reprogramming method to generate human            $2,229,427
Stem cells hold great potential for treating a
variety of human diseases, but more information
is needed on how they will function once
administered to patients for regenerative
medicine purposes. If imaging techniques can be
developed that allow the monitoring of these
transplanted stem and progenitor cells over time
once injected into the body, this would provide a
very powerful tool to determine the fate of the
cells. This proposal specifically addresses new
ways to optimize the use of positron emission
tomography (PET), an imaging technology
currently used in the human clinical setting, for
this purpose. PET is an imaging technique that
produces a three-dimensional image by detection
of a tracer or label that has been introduced into
the body. In these studies we plan to optimize
these imaging techniques when a special tag or
label is attached to individual stem and
progenitor cells, and address the sensitivity of the
scanner for their detection. An important goal is
to improve the ability to detect the small
quantities of cells that may be used, and ensure
that the images obtained can accurately identify
the number of cells at any given location. Several     $842,149


Human embryonic stem cells (hESCs) are one of
the most fascinating subjects of interest in all of
biology and medicine these days. Under certain
physiologic conditions, they can be induced to
become specialized cells such as brain, cardiac,
liver, pancreatic, and bone marrow cells. This
opens up the exciting possibility that hESCs may
one day be used to treat patients with Parkinson       $658,123
Magnetic resonance imaging (MRI) has emerged
as one of the predominant modalities to evaluate
the effects of stem cells in restoring the injured
myocardium. However, MRI does not enable
assessment of a fundamental issue in cell
therapy, survival of the transplanted cells. The
transplanted human embryonic cells (hESC) must
at the very least survive to restore the injured
myocardium. This research proposal will address
this specific challenge to image non-invasively
both the survival of the transplanted hESC and
the resultant restoration of the myocardium
through sensitive detection of the molecular
events indicating hESC survival and rapid imaging
of myocardial function. In order to achieve this
dual capability, there are 2 primary
considerations: 1) amplification of molecular
signals and 2) high spatial and temporal
resolution imaging of the myocardium. No single
imaging modality will fulfill all needs of non-
invasive molecular imaging in the heart. Only an
imaging modality that optimizes the 2 technical
specifications will provide physiologically relevant
meaning of the molecular signal of the
transplanted hESC. The molecular signal will be
useful if some correlation between hESC survival       $658,125 Heart Disease
One of the great promises of stem cell research is
that it will one day be possible to prepare
replacement cells or organs from stem cells such
as embryonic stem cells, which can be
transplanted to patients to substitute for
diseased or defective patient tissues or organs.
Unfortunately, the immune system reacts against,
and rejects, transplanted tissues that are not
perfectly matched with the recipient. A promising
approach around this problem is a two step
procedure, in which a patient is first transplanted
with blood stem cells of a specific type, and later
with replacement tissues or cells derived from the
same embryonic stem cells as the blood stem
cells. If the blood cell transplant is successful, the
patient's blood cells will forever after be
composed of a mixture of their own blood cells
and the donor blood cells ("chimerism"). It is
known that blood cell chimerism induces the
recipient to be accept diverse types of grafts of
the same source as the blood cells. Thus, the
blood cell graft prepares the recipient to accept
other types of grafts derived from the same stem
cells. Unfortunately, blood stem cell grafts are
themselves subject to a specific type of immune          $958,808
Although most individuals are aware that
osteoporosis is disease of increased bone fragility
that results from estrogen deficiency and aging,
most are unaware of the high risk and cost of the
disorder. It is estimated that close to 30% of the
fractures that occur in the United States each
year are due to osteoporosis (Schwartz & Kagan
(2002). California, with one of the largest over-
age-65 populations, is expected to double the
fracture rate from 1995 to 2015 (Schwartz &
Kagan 2002). One study places the cost per year
in osteoporotic fractures at 2.4 billion dollars
(Schwartz & Kagan 2002), establishing it as one of
the highest health care costs for older individuals.
The prevalence of osteoporosis is projected to
increase with increasing lifespan globally both
from age related bone loss and from secondary
causes of bone loss including inflammatory
diseases and cancer. In additional, medications
used for the treatment of cancer and
inflammatory diseases can also induce bone loss.
Current treatment of osteoporosis is focused on
agents that prevent further bone loss such as the
bisphosphonates or selective estrogen
modulators. The only bone growing agent that is
We have developed a small molecule, LLP2A-
Alendronate that augments the homing of
endogenous mesenchymal stem cells (MSCs), the
cells that have the potential to grow bone tissue,
to the bone surface and form new bone.
Therefore, we plan to file IND in the next sin
months and we will perform two clinical trials to
test its safety and efficacy in two clinical trials in
the next fours years.


Yrs. 1-2: Phase I clinical trial. To determine if
LLP2A-Ale is safe when used in patients with
osteoporosis. After this phase I study, our
research group will decide on two or three doses
of LLP2A-Ale and two dosing regimens and will
perform a phase II clinical trial.




Yrs. 3-4: Our phase II clinical trials will evaluate
the efficacy of LLP2A-Ale in patients with
osteoporosis The primary endpoint will be bone
mineral density measured by DEXA of the lumbar
spine and hip and biochemical markers of bone
turnover, also calciotrophic hormones of bone
metabolism (Vitamin D, FGF23, Sclerostin, IGF-
1,and sclerostin,etc). Secondary clinical study
endpoints will include a detailed assessment of
the quantity of new bone formed and its
distribution throughout the skeleton with
XtremeCT, a new high-resolution 3 dimensional
bone scan that allows regular follow-up
measurements with software that automatically
matches cortical and trabecular bone regions
(SCANCO Medical microCT Systems) at 3 month
intervals and bone biopsies performed at the iliac
crest after treatment is completed. All the
patients in the trials will be followed at 3 month
intervals for 2 years.                                   $110,000 Bone or Cartilage Disease
Our objective is to use induced pluripotent stem
(iPS) cell technology to produce a cell-based test
for long QT syndrome (LQTS), a major form of
sudden cardiac death. Nearly 500,000 people in
the US die of sudden cardiac death each year.
LQTS can be triggered by drug exposure or
stresses. Drug-induced LQTS is the single most
common reason for drugs to be withdrawn from
clinical trials, causing major setbacks to drug
discovery efforts and exposing people to
dangerous drugs. In most cases, the mechanism
of drug-induced LQTS is unknown. However,
there are genetic forms of LQTS that should allow
us to make iPS cell–derived heart cells that have
the key features of LQTS. Despite the critical
need, current tests for drug-induced LQTS are far
from perfect. As a result, potentially unsafe drugs
enter clinical trials, endangering people and
wasting millions of dollars in research funds.
When drugs causing LQTS such as terfenadine
(Seldane) enter the market, millions of people are
put at serious risk. Unfortunately it is very
difficult to know when a drug will cause LQTS,
since most people who develop LQTS have no
known genetic risk factors. The standard tests for    $1,708,560 Heart Disease, Toxicity
Induced pluripotent stem cells (iPSCs) have
tremendous potential for patient-specific cell
therapies, which bypasses immune rejection
issues and ethical concerns for embryonic stem
cells (ESCs). However, to fully harness the
therapeutic potential of iPSCs, many fundamental
issues of cell transplantation remain to be
addressed, e.g., how iPSC-derived cells participate
in tissue regeneration, which type of cells should
be derived for specific therapy, and what kind of
matrix is more effective for cell therapies. The
goal of this project is to use iPSC-derived neural
crest stem cells (NCSCs) and nerve regeneration
as a model to address these fundamental issues
of stem cell therapies. NCSCs are multipotent and
can differentiate into cell types in all three germ
layers (including neural, vascular, osteogenic and
chondrogenic cells), which makes NCSC a valuable
model to study stem cell differentiation and
tissue regeneration. Peripheral nerve injuries and
demyelinating diseases (e.g., multiple sclerosis,
familial dysautonomia) affect millions of people.
Stem cell therapy is a promising approach to cure
these diseases, which will have broad impact on
healthcare.
This project will advance our understanding of
how extracellular microenvironment (native or
engineered) regulates stem cell fate and behavior
during tissue regeneration, and whether stem
cells such as iPSC-NCSCs and differentiated cells
such as iPSC-Schwann cells have different
therapeutic effects. The results from this project
will provide insights that will facilitate the
translation of stem cell technologies into
therapies for nerve injuries, demyelinating
diseases and many other disorders that may be
treated with iPSC-NCSCs.                               $1,341,064


Heart disease is one of the biggest killers in the
civilized world, and as populations age, this trend
will increase dramatically. Currently the only way
to treat failing hearts is with expensive and
relatively ineffective drugs, or by heart
transplantation. Ideally, we would like to be able
to regenerate sick or dead heart tissue. The best
strategy would be to make new heart cells that
match the patients' cells (to avoid rejection), and
inject them into diseased heart so that they could
regenerate the sick heart.Unfortunately, current
strategies that are planned to do so are
ineffectual. We wish to attempt to generate heart
cells from human embryonic stem cells, or skin-
derived "induced pluripotent cells" by
"reprogramming" the stem cells into heart cells.
This would be accomplished by turning on heart
genes that normally are off in stem cells and
seeing if this turns stem cells into heart cells. If
this approach is successful, these newly
generated stem cells could be used for
regenerative therapies in the future.                  $2,847,600
Previous clinical studies have shown that grafting
of human fetal brain tissue into the CNS of adult
recipients can be associated with long-term
(more then 10 years) graft survival even after
immunosuppression is terminated. These clinical
data represent in part the scientific base for the
CNS to be designated as an immune privilege site,
i.e., immune response toward grafted cells is
much less pronounced. With rapidly advancing
cell sorting technologies which permit effective
isolation and expansion of neuronal precursors
from human embryonic stem cells, these cells are
becoming an attractive source for cell
replacement therapies. Accordingly, there is great
need to develop drug therapies or other
therapeutic manipulations which would permit
an effective engraftment of such derived cells
with only transient or no immunosuppression.
Accordingly, the primary goal in our studies is to
test engraftment of 3 different neuronal
precursors cell lines of human origin once grafted
into spinal cord in transiently immunosuppressed
minipigs. In addition, because the degree of cell
engraftment can differ if cells are grafted into
injured CNS tissue, the survival of cells once
grafted into previously injured spinal cord will     $1,387,800 Spinal Cord Injury
Human embryonic stem cells (hESCs) can undergo
unlimited reproduction and retain the capability
to differentiate into all cell types in the body.
Therefore, as a renewable source of various cell
types, hESCs hold great promise for human cell
replacement therapy. Significant progress has
been made in establishing the conditions to
differentiate hESCs into cells of therapeutic value.
However, a major obstacle to the clinical
application of these promising hESC-based
therapies is the immune-mediated rejection of
hESC-derived cells by the recipient because these
cells express antigens that differ from those of
the recipient patients. While rejection of grafts
expressing different antigens can be delayed for a
period of time if the recipient's immune system is
persistently suppressed, most grafts are rejected
eventually. In addition, persistent immune
suppression also increases the risk for cancer and
infection. Therefore, to develop hESC-based
therapy, it is critical to develop effective
approaches to induce immune tolerance to hESC-
derived cells. Extensive studies indicate that
transplantation of donor's hematopoietic stem
cells (HSCs) into the recipient prior to graft         $1,193,292
Embryonic stem cells are pluripotent which
means they can in principle be instructed to
become every cell type in the body. Moreover,
they can produce an infinite number of daughter
cells. Therefore, human embryonic stem cells
have great potential as a cell source for
regenerative therapies of a wide range of
diseases, some of which require the replacement
of hundreds of millions of cells. A major obstacle
towards the realization of regenerative therapies
using for example neurons or liver cells derived
from human embryonic stem cells is the immune
reaction they provoke after transplantation. This
is caused by markers all differentiated cells
display on their surface which enable the body's
immune system to distinguish potentially harmful
foreign structures from its own cells. These so
called histocompatibility markers are encoded in
the genome and differ significantly between most
humans which necessitates suppression of the
immune system before incompletely matched
cells or organs can be transplanted. Drugs
effective at long-term immune suppression can
cause severe side effects. Therefore, the creation
of pluripotent stem cells that are matched to the       $342,962
Embryonic stem cells have great potential in
therapeutic use to replace diseased or damaged
tissues because they have the unique capability
of giving rise to any cell type of the body while
perpetuating their own identity, even after
repeated cell divisions. Recent advances in this
area have resulted in a new way to generate stem
cells from specialized adult cells by introducing 3
to 4 genes encoding proteins called stem cell
factors, which are highly active in natural stem
cells, into these adult cells using viruses as the
carrier. These derivatives are called induced
pluripotent stem (iPS) cells and have properties
that are very similar to those of embryonic stem
cells. Because iPS cells can be generated from the
patient’s own tissues, problems associated with
immune rejection are avoided. Furthermore, this
process does not use embryos, so there are no
ethical concerns. Unfortunately, the use of
viruses to generate these cells is problematic
because the virus may also activate harmful
genes in the cells, such as those that cause
cancer. We recently developed a way to switch
on inactive genes in human cells using small RNA
molecules instead of viruses, and coined the          $1,375,144
Many neurological disorders are characterized by
an imbalance between excitation and inhibition.
Our ultimate goal: to develop a cell-based
therapy to modulate aberrant brain activity in the
treatment of these disorders. Our initial focus is
on epilepsy. In 20-30% of these patients, seizures
are unresponsive to drugs, requiring invasive
surgical resection of brain regions with aberrant
activity. The candidate cells we propose to
develop can inhibit hyperactive neural circuits
after implantation into the damaged brain. As
such, these cells could provide an effective
treatment not just for epilepsy, but also for a
variety of other neurological conditions like
Parkinson's, traumatic brain injury, and spasticity
after spinal cord injury. We propose to bring a
development candidate, a neuronal cell therapy,
to the point of preclinical development. The
neurons that normally inhibit brain circuits
originate from a region of the developing brain
called the medial ganglionic eminence (MGE).
When MGE cells are grafted into the postnatal or
adult brain, they disperse seamlessly and form
inhibitory neurons that modulate local circuits.
This property of MGE cells has not been shown         $1,752,058 Neurological Disorders
This proposal describes a Type I stem cell training
program at UCSD including the UCSD School of
Medicine, the UCSD Division of Biology, UCSD
Skaggs School of Pharmaceutical Sciences, and
UCSD Jacobs School of Engineering. This program
is designed to provide interdisciplinary training in
stem cell biology and medicine by taking
advantage of the unique interdisciplinary and
inter-institutional environment at UCSD and in La
Jolla. A major goal is to train a cadre of young
basic and clinical scientists and engineers in the
use of quantitative and engineering approaches
from the physical sciences such as chemistry,
computation, and materials science to make
novel discoveries in basic and clinical
biomedicine. Basic and clinical science and
engineering trainees who complete our program
will be ideally suited for future careers as
academic or industrial scientists investigating
stem cell biology and medicine, or using stem cell
based methods to develop new therapeutic
approaches to human diseases. Our approach will
be to build on each trainee                            $3,683,349
This proposal describes a Type I stem cell training
program including a School of Medicine, a
Division of Biological Sciences, a School of
Pharmacy and Pharmaceutical Sciences, and a
School of Engineering. This program is designed
to provide interdisciplinary training in stem cell
biology and medicine by taking advantage of the
unique interdisciplinary and inter-institutional
environment. A major goal is to train a cadre of
young basic and clinical scientists and engineers
in the use of quantitative and engineering
approaches from the physical sciences such as
chemistry, computation, and materials science to
make novel discoveries in basic and clinical
biomedicine. Basic and clinical science and
engineering trainees who complete our program
will be ideally suited for future careers as
academic or industrial scientists investigating
stem cell biology and medicine, or using stem cell
based methods to develop new therapeutic
approaches to human diseases. Our approach will
be to build on each trainee’s specialized
foundation of basic or clinical knowledge and
provide: •Rigorous education in the principles
and applications of embryonic and adult stem cell
biology from humans and model organisms               $7,890,588
This proposed Comprehensive Training Program
will include 16 CIRM Scholars, three clinical
fellows, eight postdoctoral fellows, and five pre-
doctoral fellows. Our multidisciplinary program
will provide training opportunities in stem cell
biology, engineering, and medicine, with a focus
on applying stem cell research toward the goal of
treating human disease. Coursework offered as a
part of this program will cover basic stem cell
biology and current and potential uses of stem
cells in regenerative medicine, as well as ethical,
legal and social issues in stem cell research. CIRM
Scholars' research projects may investigate
fundamental biomedical problems such as the
molecular basis of stem cell pluripotency, stem
cell differentiation into mature tissues such as
blood, nerve and muscle, or the reduction of
stem cell regenerative capacity with ageing. CIRM
Scholars whose expertise is in engineering may
work to develop controlled environments for
expansion and tissue-specific differentiation of
human embryonic stem cells, or devices to enable
or evaluate the results of stem cell
transplantation. Clinical Fellows will integrate
basic and translational research, with particular
emphasis on cord blood transplantation for            $6,902,189
The CIRM Creativity Program is a novel internship
program for high school students in cutting edge
stem cell research facilities. It is a motivating,
stimulating and successful program encouraging
young people from California to enter the field of
stem cell biology and research. We conducted a
previous successful summer internship program
where motivated and talented students from
[REDACTED] CA high schools were selected from
the winners of our University's well-established
high school student award program in the field of
biotechnology and regenerative medicine. This
program was highly rewarding for both students
and mentors. We now propose to expand this
program to include more students. They will
participate in a lab project guided by a mentor,
and can choose to intern in one of 29 laboratories
involved in developing cutting edge stem cell
therapies for injury and diseases that currently
have few other options for treatment. Students
will participate in a formal theoretical and
practical class in stem cell biology and stem cell
manufacturing practices, earn a certificate of
training in how stem cell treatments are
produced, and will prepare and present, in front
of their peers and CIRM officers, a poster about     $264,000
Autism spectrum disorders (ASD) are a group of
neurodevelopmental diseases that occur in as
many as 1 in 150 children in the United States.
Three hallmarks of autism are dysfunctional
communication, impaired social interaction, and
restricted and repetitive interests and activities.
Even though no single genetic defect has been
ascribed to having a causative role in the majority
of ASD cases, twin concordance studies and rare
familial forms of the disease strongly support a
genetic malfunction and a combinatorial effect of
genetic risk factors may contribute to the
variability in the symptoms. One major obstacle
to ASD research is the difficulty in obtaining
human neural tissue to model the disease in
vitro. Mouse models of ASD are limited since only
rare genetic mutations have been identified so
far, and single mutations in those genes cannot
fully reproduce the range of critical behaviors
characteristic of ASD. Direct reprogramming of
patient tissues to induced pluripotent stem (iPS)
cells and derivation of forebrain neurons from
them will provide much needed insight into the
molecular mechanism of neuronal dysfunction in
diverse individuals on the autism spectrum. The       $1,391,400 Autism
Genetic skin diseases constitute a diverse group
of several hundred diseases that affect up to 2%
of the population and include common disease
such as psoriasis, atopic dermatitis, and wound
healing. Patients with one genetic disease,
dystrophic Epidermolysis bullosa (EB), lack a
normal collagen VII (COL7A1) gene and suffer
from debilitating blistering and scarring that can
be lethal by young adulthood. The disease is
devastating and despite all efforts, current
therapy for DEB is limited to wound care. For
recessive dystrophic EB (RDEB) where there is no
COL7A1 protein, our EB Disease team has shown
that retroviral delivery of the COL7A1 provides a
powerful disease modifying activity as
autologous, cell-based therapy. While successful,
our initial approach cannot treat many
dominantly inherited diseases such as dominant
dystrophic EB (DDEB) where a poison subunit
inhibits the function of the normal protein.
Recent development of induced pluripotent stem
(iPS) cells that are generated from the somatic
cells of individual patients could provide an ideal
source of therapy. Because of recent advances by
our team and others in stem cell technology, our
hypothesis is that we can create genetically-         $11,709,574 Skin Disease
Like embryonic stem (ES) cells, induced
pluripotent stem (iPS) cells can differentiate into
every cell type in the body, providing enormous
potential for regenerative medicine. Unlike ES
cells, the derivation of iPS cells is more
straightforward technically, and can be
performed on human adult cells. This potentially
obviates the need for donated eggs or embryos,
and permits the ability to generate patient-
specific stem cells for disease research, drug
development, and new cell-based therapies -
generating great excitement in the scientific
community as well as with the public. iPS cells
hold great promise for regenerative medicine, but
the cellular signaling that controls their derivation
and function remains poorly understood. We are
developing methods to measure protein
phosphorylation (the most common mechanism
of cellular signaling) in iPS cells, and we will use
the key signaling events we identify to improve
the speed and efficiency of iPS derivation, as well
as the safety and utility of iPS cells for
regenerative medicine. In addition to improved
iPS cell protocols that will benefit basic science
and clinical therapy, the methods we develop to
measure protein phosphorylation in will make a          $1,447,956


Non-invasive imaging techniques for an in vivo
tracking of transplanted stem cells offer real-time
insight into the underlying biological processes of
new stem cell based therapies, with the aim to
depict stem cell migration, homing and
engraftment at organ, tissue and cellular levels.
We showed in previous experiments, that stem
cells can be labeled effectively with contrast
agents and that the labeled cells can be tracked
non-invasively and repetitively with magnetic
resonance imaging (MRI) and Optical imaging
(OI). The purpose of this study is to apply and
optimize these labeling techniques for a sensitive
depiction of human embryonic stem cells (hESC)
with OI and MRI. Experimental Design: hESC will
be labeled with various contrast agents for MRI
and OI, using a variety of labeling techniques,
different contrast agent concentrations and
different labeling intervals (1h                         $251,088
To fix a broken car, the mechanic either repairs or
replaces the defective part. Similarly, one of the
most promising approaches physicians foresee
for treating human disease and ameliorating the
aging process is regenerative medicine. A major
aim of this field is to restore function by repairing
or replacing damaged organs. Scientists envision
a day when people with heart failure can be
cured with hearts grown from their own cells, and
a future in which dialysis machines are not
needed because patients with damaged kidneys
can be furnished with new ones. However, organ
engineering is highly complex, and the field of
regenerative biology is still in its early stages.
Therefore, it is important to provide proof of
principle and lay the foundation for creation of
new organs by first using as simple a system as
possible, and teeth provide an excellent model
system for organ replacement. Their physiology is
less complex than many other organs, but their
development has much in common with that of
other organs. This means that much of the
information obtained from studying tooth
regeneration will be generally applicable for
building other organs. Teeth are a relatively safe      $3,250,251
Because there is still considerable morbidity and
mortality associated with the process of whole
liver transplantation, and because more than a
thousand people die each year while on the liver
transplantation list, and tens of thousands more
never get on the list because of the lack of
available livers, it is evident that improved and
safer liver transplantation would be valuable, as
would approaches that provide for an increased
number of transplantations in a timely manner. A
technology that might address these issues is the
development of a human liver cell line that can
be employed in liver cell transplantation or in a
bioartificial liver. Developing such a cell line from
human embryonic stem cells (hESC) would
provide a valuable tool for pharmacology studies,
as well as for use in cell-based therapeutics. The
objective of this proposal is to focus a team effort
to determine which differentiated hESC will be
the most effective liver-like cells in cell culture
and in animal studies, and to then use the best
cells in clinical trials of cell transplantation in
patients with advanced liver disease. In the
proposed studies, the team will differentiate
hESC so that they act like liver cells in culture.      $5,199,767 Liver Disease
We aim to develop, test and validate a new,
sensitive and affordable scanner for tracking the
location of injected cells in humans and animals.
This new scanning method, called Magnetic
Particle Imaging, will ultimately be used to track
the location and viability of stem cells within the
human body. It could solve one of the greatest
obstacles to human hESC therapy---the ability to
track stem cells and see if the cells are thriving
and becoming a fully differentiated cell that can
improve function of damaged organs. All of the
current imaging methods used to track stem cells
have significant problems when tracking stem
cells through a living mouse or human. MRI is too
insensitive and expensive. Optical imaging
methods (fluorescence and luminescence) are
useful for cell studies under a microscope, but
they cannot produce high resolution images
when the labeled cells are deeper than about 1
cm. Nuclear imaging methods involve radiation
and offer poor spatial resolution. Ultrasound has
many obstructions and the gas bubble stem cell
tags do not persist very long. Hence, we wish to
develop a new imaging method tailored for
tracking stem cells in the human body---Magnetic      $882,430
We aim to develop, test and validate a new,
sensitive and affordable scanner for tracking the
location of injected cells in humans and animals.
This new scanning method, called Magnetic
Particle Imaging, will ultimately be used to track
the location and viability of stem cells within the
human body. It could solve one of the greatest
obstacles to human hESC therapy---the ability to
track stem cells and see if the cells are thriving
and becoming a cell that can improve function of
damaged organs.
None of the current methods to track stem cells
will be useful for tracking stem cells through a
living human. MRI is too insensitive and
expensive. While optical imaging methods
(fluorescence and luminescence) are useful for
cell studies under a microscope, they all cannot
produce high resolution images deeper than a
few mm. Nuclear imaging methods involve
radiation and offer poor resolution. Ultrasound
has many obstructions and the gas bubble stem
cell tags do not persist very long. Hence, we wish
to develop a new imaging method tailored for
tracking stem cells in the human body---Magnetic
Particle Imaging. Magnetic Particle Imaging has
200x better sensitivity compared to MRI, it will be
significantly more affordable, and will require no
expert operator. Only developed in the last year,
Magnetic Particle Imaging scanners are not
available commercially. Our expected resolution
is 200 um with scan times of seconds per imaging
slice. Initial in-vitro tests show promise that 200
cell detection is feasible. In fact, with industrial
efforts on electronics and contrast agents, single
cell detection may be feasible. The method
employs FDA approved superparamagnetic
nanoparticles (e.g., Resovist or Ferumoxtran) for


Our specific aims are to (1) construct a Magnetic
Particle Scanner for mice; (2) Optimize the MPI
nanoparticle contrast agent for spatial resolution
and sensitivity; (3) Validate the MPI scanner
against histology with [REDACTED]; and (4)
disseminate our designs to the stem cell
community.


An affordable high-resolution, and quantitative
stem cell scanner is absolutely critical for the field
of stem cell therapy to progress to humans.
Research on mESC is funded heavily by the NIH,
but our research is motivated principally to track
hESCs in humans and, hence, is very unlikely to
be funded by the Federal Government.                     $1,452,360
The human embryonic stem cells (hESC) have the
remarkable potential to replicate themselves
indefinitely and differentiate into virtually any cell
type under appropriate environmental
conditions. They accomplish this through
regulating the production of a unique set of
proteins in the cells, a process known as gene
regulation. While the genes encoding these stem
cell proteins have been largely identified over the
years, the mechanisms of gene regulation are not
yet understood. This gap in our knowledge has
seriously limited our ability to manipulate hESC
for therapeutic purposes. In Eukaryotic cells, gene
regulation depends on specific sequences in the
DNA known as transcriptional regulatory
elements. These regulatory DNA consists of
promoters, enhancers, insulators and other
regulatory sequences. As a key step towards
understanding the gene regulatory mechanisms
in hESC, we will produce a comprehensive map of
promoters, enhancers and insulators in the hESC
genome. We will use a newly developed, high
throughput experimental strategy to identify
these sequences that are engaged in gene
activation in hESC. Our strategy involves
identifying the DNA sequences that are                   $691,489
The proposed Master's of Science degree
specialization in stem cell research will benefit
the state of California and its citizens in several
ways. First, establishing the training program will
provide our state's citizens with a previously
unavailable opportunity to gain practical training
in stem cell research and advance their careers.
This benefit will become increasingly important as
additional commercial ventures are established
to support the effective use in stem cells for
treating disease. In a related fashion, this
program will provide California with an increased
number of highly-trained employees to manage
and participate in the research and development
of stem-cell based therapeutics. Success of these
stem-cell based therapeutics will in turn support
effective health-care for California's citizens by
providing us with the latest in disease treatments.
Furthermore, this program will support the
growth of the California economy by training of
highly-skilled stem cell researchers to assist in the
development of medically efficacious and
financially lucrative stem-cell based therapeutics.
Through these aspects and more, our proposed
Master's of Science degree specialization in stem
cell research will be of substantial benefit to the     $3,020,182
The immune system is the body's defense system
against disease and can recognize foreign cells.
Because of this, stem cells and organs that are
transplanted from one person to another are
usually "rejected" by the immune system, forcing
doctors to use powerful immune suppressive
drugs with severe side effects. This natural
defense system will therefore limit our ability to
use stem cell therapies until we develop better
solutions to prevent rejection ("induce
tolerance"). We are developing a unique solution
to this problem: if we transplant cells in utero,
before the immune system is fully developed, we
can educate the fetus to tolerate the foreign cells
and avoid rejection without using any drugs. This
strategy could be useful for many inherited stem
cell disorders such as sickle cell disease,
thalassemias, and muscular dystrophy. In
addition, if tolerance to a particular donor is
established, it may be used to transplant an
organ (eg. kidney) from the same donor for other
congenital anomalies. Many of these diseases can
be diagnosed early in pregnancy and the surgical
expertise for performing the transplants safely
already exists. Although this strategy has been       $1,324,229
A major issue for tissue and cell therapy in
regenerative medicine is the immune rejection of
grafts originated from a non-compatible
individual. Mature eggs contain factors essential
for the re-programming of cell nuclei from
patients to allow the establishment of patient-
compatible pluripotent stem cells for the
treatment of diverse degenerative diseases.
Although up to half a million dormant small
follicles are present in young women reaching
puberty, only 400 of them developed to the large
follicle stage and release mature eggs during a
women's reproductive life. The present
application proposes to overcome the major
obstacle dealing with the shortage of human
mature oocytes for the generation of patient-
compatible pluripotent stem cells. The
{REDACTED} preserved ovarian tissues from
cancer patients before chemo- and radiation
therapy to avoid damages. We have obtained
patients' consent and propose to promote the
growth of arrested small follicles from ovaries of
cancer patients with specific activators to allow
the development of hundreds of large follicles
containing mature eggs. The surplus eggs can be
used to re-program cell nuclei from patients, thus   $1,432,197 Fertility

The ability to convert human skin cells to induced
pluripotent stem cells (IPSCs) represents a
seminal break-through in stem cell biology. This
advance effectively circumvents the problem of
immune rejection because the patient                 $1,327,973
Short Bowel Syndrome is an expensive, morbid
condition with an increasing incidence.
Fundamental congenital and perinatal conditions
such as gastroschisis, malrotation, atresia, and
necrotizing enterocolitis (NEC) may lead to short
bowel syndrome (SBS). NEC is the most common
gastrointestinal emergency in neonates and
primarily occurs in premature infants As rates of
prematurity are increasing, so are the numbers of
children with SBS and NEC. In addition,
prevalence is increased for other diagnoses such
as gastroschisis, which has nearly doubled.
Medical and surgical treatment options carry high
dollar and human costs and morbidities including
multiple infections and hospitalizations for
vascular access, liver failure in conjunction with
parenteral nutrition-associated cholestasis, and
death. Small bowel transplant has a reported 5
year graft survival of 48%, but is attended by
rejection, the morbidity of major surgery, and a
lifelong need for anti-rejection medication. A
report on 989 grafts in 923 patients by the
Intestine Transplant Registry reveals improving
outcomes, but one year graft/ patient survival
rates are 65%/77%. Tissue engineered small
intestine (TESI) offers a potential alternative      $3,415,000 Intestinal Disease
Buried deep inside the brain are cells known as
choroid plexus epithelial (CPe) cells. Although not
as famous as other cells in the nervous system,
CPe cells perform a large number of important
jobs that keep the brain and spinal cord healthy.
They produce the fluid (known as cerebrospinal
fluid, or CSF) that bathes the brain and spinal
cord with many nourishing chemicals, which
promote normal nervous system health and
function, learning and memory, and neural repair
following injury. In addition, CPe cells protect the
brain and spinal cord from toxins – such as heavy
metals and the amyloid-beta peptide associated
with Alzheimer’s disease – by absorbing them or
preventing them from entering the nervous
system altogether by forming the so-called blood-
CSF barrier. Accordingly, as CPe functions
diminish during normal aging or in accelerated
fashion in certain diseases, memory loss,
Alzheimer’s disease, and a number of other
neurologic and neuropsychiatric disorders may
ensue or become worse. The ability to grow and
make CPe cells should therefore enable many
clinical applications, such as CPe cell
replacements, transplants, and pharmaceutical
studies to identify beneficial drugs that can pass     $3,169,328
The human ES cells are euploid cells that can
proliferate without limit and maintain the
potential to differentiate into all cell types.
Differentiation of human ES cells involves
selective activation or silencing of genes, a
process that involves not only combinatorial
interactions between the cis-regulatory
sequences and DNA binding transcription factors,
but also post-translational histone modifications
and other epigenetic mechanisms such as DNA
methylation and non-coding RNAs. A number of
transcription factors have been found to be
essential for the ES cells to maintain their identity
or differentiate along specific lineages. These
regulators exert their effects through interacting
with the promoters, enhancers or silencer
elements to modulate the expression of target
genes. Currently, the molecular details of how
transcription factors modulate target gene
expression upon binding to DNA and how they
mediate ES cell differentiation are still unclear.
The proposed project is aimed to determine the
role that histone modifications play in this
process. We will conduct experiments to identify
the DNA binding proteins, chromatin modifying
enzymes and chromatin binding proteins that are         $1,726,564

Heart disease is a leading cause of adult and
childhood mortality. The underlying pathology is
typically loss of heart muscle cells that leads to
heart failure, or improper development of
specialized cardiac muscle cells called
cardiomyocytes during embryonic development
that leads to congenital heart malformations.
Because cardiomyocytes have little or no
regenerative capacity after birth, current
therapeutic approaches are limited for the over 5
million Americans who suffer from heart failure.
Embryonic stem cells possess clear potential for
regenerating heart tissue, but efficiency of
cardiac differentiation, risk of tumor formation,
and issues of cellular rejection must be overcome.
Our recent findings regarding direct
reprogramming of a type of structural cell of the
heart or skin called fibroblasts into
cardiomyocyte-like cells using just three genes
offer a potential alternative approach to
achieving cardiac regeneration. The human heart
is composed of muscle cells, blood vessel cells,
and fibroblasts, with the fibroblasts comprising
over 50% of all cardiac cells. The large population
of cardiac fibroblasts that exists within the heart
is a potential source of new heart muscle cells for
regenerative therapy if it were possible to directly
reprogram the resident fibroblasts into muscle
cells. We simulated a heart attack in mice by
blocking the coronary artery, and have been able
to reprogram existing mouse cardiac fibroblasts
after this simulated heart attack by delivering
three genes into the heart. We found a significant
reduction in scar size and an improvement in
cardiac function that persists after injury. The
reprogramming process starts quickly but is
progressive over several weeks; however, how
this actually occurs is unknown. Because this
finding represents a new approach that could
have clinical benefit, we propose to reveal the        $1,708,560
During an individual’s lifetime, blood-forming
cells in the bone marrow called hematopoietic
stem cells (HSCs) supply all the red and white
blood cells needed to sustain life. These blood
stem cells are unique because they can make an
identical copy of themselves (self-renew).
Disorders of the blood system can be terminal,
but such diseases may be cured when patients
are treated with a bone marrow transplant.
Unfortunately, bone marrow is in short supply
due to limited availability of donors, and it is not
yet possible to expand HSCs outside of the
human body; HSCs that are removed from their
native environment, or niche, rapidly lose their
ability to self-renew and thus cannot sustain
hematopoiesis in a transplant recipient.
Furthermore, attempts to make blood stem cells
from embryonic stem cells (ESCs) have also
proved unsuccessful to date because these
“tailored HSCs” are defective in self-renewal as
well. These problems suggest that our
understanding of the biology of HSCs is not
sufficient to foster their maintenance or
generation. To address this issue, we propose to
study hematopoietic stem cells in the context of       $2,286,900
The promise of embryonic stem cells in
regenerative medicine is based on their potential
to make every cell in the body, a property coined
pluripotency. With rapid recent advances in
technology, it is becoming relative
straightforward to make embryonic stem cell-like
lines from adult tissues. In the near future, the
generation of these lines will become increasingly
common practice including the production of
patient-specific lines that can be used to evaluate
the disease and even replace damaged tissue in
these patients. However, we still do not fully
understand the molecules that underlie
pluripotency. It is essential for us to do so, in
order to improve on the generation and quality
control testing of the embryonic stem cells.
Exciting recent work has shown that
modifications to the genome that do not change
the actual DNA sequence, but do change how
that sequence is presented, is a central
component of pluripotency. These modifications
have been coined epigenetic modifications
because they are not altering the underlying
genetic code. Specifically, it was recently shown
that these epigenetic modifications maintain the         $3,204,897
Stem cells can mature into a diverse range of
specialized cell types, providing exciting
possibilities for regeneration of different tissue
types. Many disorders can conceivably be treated
by transplanting stem cells to replace the
defective cells. However, several disorders affect
a specific cell type, while other cells and tissues in
the same patient are functioning normally.
Examples of such cell type-specific cases are
Parkinson’s disease, diabetes and anemia. A
fundamental challenge in using stem cells to treat
disease is to be able to steer their maturation
into the specific cell type needed. Maturation
into the wrong cell type may cause problems due
to uncontrolled growth or immune rejection. For
example, a blood stem cell transplant intended to
treat anemia would be optimally efficient and
safe if the transplanted cells could be directed to
generate red blood cells without also producing T
cells. Another major limitation of transplantation
therapy is the shortage of cells for clinical use.
This too could be alleviated by efficient
generation of the desired cell type. This proposal
investigates the regulation of stem cell
maturation into specific functional cell types. We       $2,330,111
Human embryonic stem cells (hESCs) are capable
of unlimited self-renewal, a process to reproduce
self, and retain the ability to differentiate into all
cell types in the body. Therefore, hESCs hold
great promise for human cell and tissue
replacement therapy. Because DNA damage
occurs during normal cellular proliferation and
can cause DNA mutations leading to genetic
instability, it is critical to elucidate the
mechanisms that maintain genetic stability during
self-renewal. This is the overall goal of this
proposal. Based on our recent findings, I propose
to investigate two major mechanisms that might
be important to maintain genetic stability in
hESCs. First, I propose to elucidate pathways that
promote efficient DNA repair in hESCs. Second,
based on our recent findings, I hypothesize that
another primary mechanism to maintain genetic
stability in self-renewing hESCs is to eliminate
DNA-damaged hESCs by inducing their
differentiation. Therefore, I propose to identify
the pathways that regulate the self-renewing
capability of hESCs in the presence and absence
of DNA damage. In summary, the proposed
research will contribute significantly to our
understanding of the pathways important to               $2,570,000 Cancer, Genetic Disorder
Embryonic stem cells (ESCs) are derived from very
early stage embryos. ESCs can be maintained in
culture indefinitely while retain the ability to
make any type of cell in the body. These
properties make ESCs a very powerful tool to
address basic biology questions. ESCs also offer
an important renewable resource for future cell
replacement therapies for many diseases such as
Parkinson’s disease, spinal cord injury, etc.
However, before the full potential of ESCs can be
exploited in the clinic, we need to understand
more about their biological properties so that we
can control their fate towards either self-renewal
or differentiation into a specific cell type required
for cell replacement therapy. STAT3 is a major
player in controlling the fates of a variety of cell
types including ESCs. Recently we demonstrated
that STAT3 has diverse and distinct roles in
regulating cell fate in both mouse and human
ESCs. In mouse ESCs, STAT3 is involved in cell
adhesion, cell growth/survival and maintenance
of self-renewal. Interestingly, STAT3 seems to
have opposite roles in human ESCs. It induces
growth arrest and differentiation of human ESCs.
Why does the same factor play such diverse and
contradictory roles between these very similar          $2,413,650
Adult stem cells play an essential role in the
maintenance of tissue homeostasis.
Environmental and therapeutic insults leading to
DNA damage dramatically impact stem cell
functions and can lead to organ failure or cancer
development. Yet little is known about the
mechanisms by which adult stem cells respond to
such insults by repairing their damaged DNA and
resuming normal cellular functions. The blood
(hematopoietic) system provides a unique
experimental model to investigate the behaviors
of specific cell populations. Our objective is to use
defined subsets of mouse hematopoietic stem
cells (HSCs) and myeloid progenitor cells to
investigate how they respond to environmental
and therapeutic insults by either repairing
damaged DNA and restoring normal functions;
accumulating DNA damage and developing
cancer; or undergoing programmed cell death
(apoptosis) and leading to organ failure. These
findings will provide new insights into the
fundamental mechanisms that regulate stem cell
functions in normal tissues, and a better
understanding of their deregulation during
cancer development. Such information will
identify molecular targets to prevent therapy-          $2,274,368 Blood, Trauma
Understanding differentiation of human
embryonic stem cells (hESCs) provides insight into
early human development and will help directing
hESC differentiation for future cell-based                         Parkinson's disease, Stroke, Neurological
therapies of Parkinson                                  $3,035,996 Disorders
Human embryonic stem cells (hESC), and other
related pluripotent stem cells, have great
potential as starting material for the manufacture
of curative cell therapies. This is primarily for two
reasons. First, by manipulating cues in their cell
culture conditions, these cells can be directed to
become essentially any desired human cell type
(a property known as pluripotency). Second, hESC
have the remarkable capacity to expand rapidly
with essentially no change in their identity. At a
practical level, this means enough cells to
manufacture thousands, and even millions, of
therapeutic cell doses can be generated in a
matter of weeks. Thus, the biomedical potential is
tremendous, but several practical matters remain
to be resolved. One of the biggest concerns is
that manufacturing processes, i.e., methods to
direct                                                  $5,405,397 Diabetes
There are now viable experimental approaches to
elucidate the genetic and molecular mechanisms
that underlie severe brain disorders through the
generation of stem cells, called iPS cells, from the
skin of patients. Scientists are now challenged to
develop methods to program iPS cells to become
the specific types of brain cells that are most
relevant to each specific brain disease. For
instance, there is evidence that defects in cortical
interneurons contribute to epilepsy, autism and
schizophrenia. The experiments proposed in this
grant application aim to understand basic
mechanisms that underlie the development of
cortical interneurons. We are discovering
regulatory elements (called enhancers) in the
human genome that control gene expression in
developing interneurons. We have three
experimental Aims. In Aim 1, we will study when
and where these enhancers are expressed during
mouse brain development. We will concentrate
on identifying enhancers that control gene
expression during development of specific types
of cortical interneurons, although we hope to use
this approach for additional cell types. Once we
identify and characterize where and when these
enhancers are active, in Aim 2 we will use the          $1,387,800
Human pluripotent stem cells (hPSCs) hold a
great potential to treat many devastating injuries
and diseases. However, current hPSC cloning still
faces challenges in creating animal product-free
culture conditions for performing genetic
manipulation and induced differentiation of
hPSCs for cell-based therapy. In order to obtain
the ideal culture conditions for hPSC cloning,
microfluidic technology can be applied as a
powerful tool. Microfluidic systems handle and
manipulate tiny amounts of fluids at volumes a
thousand times smaller than a tear drop. The
goals of our proposal are to develop and validate
a robotic microfluidic platform, composed of a
robotic liquid dispensing system, a fluorescence
microscope, cell culture chips and an operation
interface. We will apply such a robotic platform
to (i) perform chemical screening in search of
culture conditions and small molecules that
facilitate single-cell expansion of hPSCs and (ii)
achieve a better understanding on how chip-
based culture environments and the molecules
identified in the screens affect the hPSC fate.
Compared to the macroscopic setting employed
for the conventional hPSC research, the
advantages of the robotic microfluidic technology    $914,096
Regenerative therapies could be particularly
beneficial for heart disease, which is the leading
killer of adults in the U.S, and is responsible for
the 5 million Americans with insufficient cardiac
function. At the other end of the age spectrum,
malformations of the heart involving abnormal
cell lineage or morphogenetic decisions are the
leading noninfectious cause of death in children.
Unfortunately, since adult heart cells cannot
multiply after birth, the heart has almost no
regenerative capacity after injury or in response
to malformations. Deciphering the secrets of
heart formation might lead to novel approaches
to repair or regenerate damaged heart muscle
using embryonic stem cells (ESCs) and progenitor
cells. Our research is focused on determining
what causes ESCs to specialize into cells that
belong to the mesodermal, or middle, layer of an
embryo, which develops into blood, muscle, and
bone, among other cells, with a specific focus on
cues that stimulate cardiac and skeletal muscle
formation. Small RNA molecules called
microRNAs have emerged as an elegant and novel
mechanism nature uses to titrate dosage of
critical proteins by regulating the flow of genetic
information as it is translated into proteins.        $3,164,000
A major hurdle for regenerative medicine is the
safe transplantation of human embryonic stem
(ES) cells or their derivatives into patients. While
the unlimited growth potential of ES cells is a
major asset for their potential in tissue
replacement, it is also a major risk for
tumorigenesis. Therefore, it is critical to
determine what molecules are responsible for
silencing the tumorigenic risk of embryonic stem
cell derivatives as occurs during the process of
normal development. Identification of such
molecules should provide both markers for
tumorigenic risk as well as potential targets for
therapeutic intervention when tumors do
develop from transplanted tissue. We now know
that most, if not all adult cells can revert to an
early stem cell phenotype. This has been proven
by a technique called somatic cell nuclear
transfer, where adult cell nuclei are transferred
into oocytes and allowed to develop as early
embryos. These embryos reactivate the
embryonic stem cell program within the adult
nuclei. Cells derived from these embryos, the
embryonic stem cells, have regained the ability to
proliferate indefinitely, a property termed self-      $631,831
Many mental disorders are closely associated
with problems that occur during brain
development in early life. For instance, by 2 years
of age, autistic children have larger brains than
normal kids, likely due to, at least in part, excess
production of neurons and support cells, the
building blocks of the nervous system. In autistic
brains, how neurons grow various thread-like
processes also shows some abnormalities. The
cause of autism is complex and likely involves
many genetic factors. These developmental
defects are also associated with mental disorders
caused by single-gene mutations, such as Rett
syndrome and fragile X syndrome, the most
common form of inherited mental retardation,
whose clinical features overlap with autism.
However, what causes the developmental defects
in brains of children with different mental
disorders is largely unknown. In recent years, an
exciting new regulatory pathway was discovered
that may well contribute to the etiology of
mental disorders. The major player in this novel
pathway is a class of tiny molecules 21                $791,000 Autism, Developmental Disorders

Congestive heart failure, the inability of the heart
to continue to pump effectively due to damage of
its muscle cells, affects approximately 4.8 million
Americans and is a leading cause of mortality.
Causes of the irreversible damage to the
cardiomyocytes that results in congestive heart
failure include hypertension, heart attacks, and
coronary disease. Because the cadiomyocytes in
the adult heart tissue are terminally
differentiated and thus cannot regenerate
themselves, once they are damaged, they are
irreversibly damaged. As a consequence, despite
the advances in medical devices and
pharmaceuticals, still more than 50% of
congestive heart failure patients die within 5
years of initial diagnosis. The goal therefore must
be to restore the heart cells                          $363,707 Heart Disease
Mitochondrial Dysfunction in Embryonic Stem
Cells {REDACTED} A major concern for the
utilization of human Embryonic Stem Cells
(hESCs) for cell replacement therapy is that with
prolonged culture, the capacity of the cells to
generate the desired cell types for therapy
declines. While the reason for this is currently
unknown, our research suggests that an
important factor is damage to the genetic
blueprints that are necessary to sustain the
cellular power plants of the cell, the
mitochondria. The human cell is the product of a
symbiotic merger that occurred two billion years
ago of two different cell types: one generating
the host cell and the other generating an intra-
cellular colony of bacteria, the mitochondria. In
the modern human cell, the host cell constitutes
the nucleus and the cytosol and the genetic
information (DNA) for this nucleus-cytosol
organism resides in the nucleus and is responsible
to building and maintaining the structural
elements of the cell: analogous to the carpenters
blueprints for building a house. The mitochondria
have their own DNA blueprints, the mitochondrial       $632,500
Stem cell quality and safety in developing
regenerative medicine therapies is of utmost
importance. Poor outcomes include inadequate
functionality, exhaustion, immune rejection,
cancer development, and others. Recent studies
strongly support our core hypothesis that
mitochondrial function determines stem cell
quality and safety. Dysfunctional mitochondria
foster cancer, diabetes, obesity,
neurodegeneration, immunodeficiency, and
cardiomyopathy. Unlike whole genome
approaches, methodological hurdles for
evaluating mitochondria in human embryonic
stem cells (hESCs) and in reprogrammed human
induced pluripotent stem cells (hiPSCs) are
significant and techniques developed or adapted
for stem cells are almost non-existent. With a 2-
year CIRM Seed Grant, we developed new
approaches for analyzing respiration (oxygen
consumption that drives energy production) in
hESCs in a series of 4 invited publications for the
stem cell scientific community (www.JoVE.com;
2008). A manuscript describing the function of
hESC mitochondria in low oxygen (hypoxia), in
normoxia (room air), and during differentiation is
in final preparation. We also collaboratively         $1,323,029
Stem cells have entered the public consciousness
as "cells that can do anything" and have been
hailed as a panacea in the fight against disease,
aging and cancer. Unfortunately, we have only
scratched the surface in understanding these
cells. Some of the things we think we know are
that: embryonic stem cells hold great promise
because they do seem to be "cells that can do
anything", but still cannot be isolated from
consenting adults, and that adult stem cells, while
isolatable, are much more limited in their ability
to replenish tissue beyond their organ of origin.
In addition, we know very little about human
embryonic development for the simple fact that
experiments on human embryos has proven to be
nearly impossible due to ethical and technical
obstacles. Clearly, if we gained a deep
understanding about human embryos and human
embryonic stem cells, we could not only develop
useful clinical opportunities, but also potentially
detect and treat errors made during human
development. This proposal suggests that in fact
we could learn a great deal about not only the
therapeutic potential of hESCs, but also human
development by exploiting cell culture. We               $571,575


Five million people in the U.S. suffer with heart
failure, at a cost of $30 billion/year. Heart failure
occurs when the heart is damaged and becomes
unable to meet the demands placed on it. Unlike
some tissues, heart muscle does not regenerate.
Human embryonic stem cells grow and divide
indefinitely while maintaining the potential to
develop into many tissues of the body, including
heart muscle. They provide an unprecedented
opportunity to both study human heart muscle in
culture in the laboratory, and advance cell-based
therapy for damaged heart muscle. We have
developed methods for identifying and isolating
specific types of human embryonic stem cells,
stimulating them to become human heart muscle
cells, and delivering these into the hearts of mice
that have had a heart attack. This research will
identify those human embryonic stem cells that
are best at repairing damaged heart muscle,
thereby treating or avoiding heart failure.             $2,229,140 Heart Disease

Parkinson                                                $758,999 Parkinson's disease
Human embryonic stem cells (hESCs) are
pluripotent entities, capable of generating a
whole-body spectrum of distinct cell types. We
have developmental procedures for inducing
hESCs to develop into pure populations of human
neural stem cells (hNS), a step required for
generating authentic mature human neurons.
Several protocols have currently been developed
to differentiate hESCs to what appear to be
differentiated dopaminergic neurons (important                  Amyotrophic Lateral Sclerosis, Parkinson's
in Parkinson                                         $2,879,210 disease, Genetic Disorder, Neurological Disorders
During human development, autonomic neurons
align with and pattern alongside blood vessels.
This patterning allows the autonomic nervous
system to control the vascular function a
phenomenon that is very useful during situations
such as "fight or flight" responses where the
blood vessels need to respond rapidly and
involuntarily to stimuli. Since the alignment of
blood vessels with autonomic neurons occurs
during embryogenesis, human embryonic stem
cells provide a system in which we can observe
and understand how neurons and blood vessels
differentiate and co-align to form a neurovascular
unit. We have developed a human embryonic
stem cell differentiation model where we are able
to visualize the early stages of human blood
vessel and neuronal development and their co-
alignment and patterning in real time over a
period of three weeks. Using this model, we have
identified a cell-adhesion protein T-Cadherin,
present on both the blood vessels and neurons,
which may act as the "molecular velcro" in
attaching neuronal cells to the blood vessel
networks. We have also identified small RNA
molecules termed microRNAs that may regulate T-
Cadherin protein expression during this process.     $1,361,448
Hematopoietic cells are responsible for
generating all cell types present in the blood and
therefore critical for the provision of oxygen and
nutrients to all the tissues in the body. Blood cells
are also required for defense against
microorganisms and even for the recognition and
elimination of tumor cells. Because blood cells
have a relatively short life-span, our bone marrow
is constantly producing new cells from
hematopoietic progenitors and responding to the
relative needs to our tissues and organs. Blood
cancers (leukemias), as well as other disorders or
treatments that affect the production of blood
cells (such as chemotherapy or radiation therapy)
can significantly jeopardized health. Transfusions
are done to aid the replacement of blood cell
loss, but pathogens and immunological
compatibility are significant and frequent
roadblocks. In this grant application, we present
experiments to further understand how another
cell in the body, the endothelium, located in the
inside wall of all our vessels, can be coax to
produce large numbers of hematopoietic cells
with indistinguishable immunological properties
from those in the bone marrow of each
individual. Endothelial cells are easily obtained
from skin biopsies or from umbilical cord and           $1,371,477 Blood Disorders
Our lab is known for its discovery of the family of
nuclear hormone receptors (NHRs) that use
vitamins/hormones to control genes and thereby
regulate embryonic development, cell growth,
physiology and metabolism. Of 48 known NHRs,
we discovered that a unique subset of 38
receptors are expressed in adipose-derived
human induced pluripotent stem cells (hiPSCs).
The process of converting adult cell types like skin
or fat into stem cells literally occurs in the nucleus
by a process known as epigenetic
reprogramming. A unique property of NHRs that
distinguishes them from other classes of
receptors is their ability to directly interact with
and control the expression of genomic DNA.
Consequently, NHRs play key roles in both the
etiology and the treatment of disease by
controlling genes. Drugs targeting NHRs are
among the most widely prescribed in the world.
While adipose-derived iPSCs express 38 NHRs,
virtually nothing is known about their function in
controlling stem cell renewal and differentiation
into specific cell types (cell fate). How the
extensive family of hormonal ligands can be used
to control iPSC generation, maintenance and cell         $1,712,880
One of the main objectives of stem cell biology is
to create physiologically relevant cell types that
can be used to either facilitate the study of or
directly treat human disease. Tremendous
progress towards these goals has been made in
the area of motor neuron disease and spinal cord
injury through the findings that motor neurons
can be generated from human embryonic stem
cells and induced pluripotent stem cells. These
advances have made possible the creation of
motor neurons from patients afflicted with
neurodegenerative diseases such as amyotrophic
lateral sclerosis and spinal muscular atrophy that
can be studied in the laboratory to determine the
root causes of these diseases. In addition, stem
cell-derived motor neurons could potentially
serve as replacement cells that could be
introduced into the spinal cord to recover motor
functions in these patients, as well as those
suffering from spinal cord injuries. A major
assumption, however, is that human embryonic
and induced pluripotent cell-derived motor
neurons are identical to their normal
counterparts. Despite its relevance, few studies of
human motor neuron development have been                         Amyotrophic Lateral Sclerosis, Spinal Muscular
carried out, and little information on the genetic    $1,363,262 Atrophy, Spinal Cord Injury, Genetic Disorder
The use of human pluripotent stem cells for cell-
based therapeutics is predicated on the ability to
convert these cells into functional equivalents of
those lost in disease or injury. However, there is
only scant evidence that either human embryonic
stem cells or human induced pluripotent stem
cells make differentiated progeny that are
functionally equivalent to those found in tissues.
Our preliminary results, gathered over several
years suggest that in fact human pluripotent stem
cells may make authentic tissue derived cells, but
they appear to be most similar to cells found only
during very early fetal development. As a result, it
is unclear if these cells will suitably replace tissue
derived cells in postnatal therapies. We have also
uncovered several genes whose expression
appears to distinguish mature tissue derived cells
and those generated from human pluripotent
stem cells. We have designed this project to
determine whether manipulating expression of
those genes in pluripotent derivatives can bring
them closer to postnatal tissue derived cells. We
also propose to discover small molecule
compounds that can have the same effect. Upon
successful completion of these aims, we will bring       $1,354,230
The liver is a promising target for cell therapy
since it supports and functionally integrates
transplanted cells. Human liver contains more
than 50 billion cells and more than 10%
replacement will be required for most liver
diseases. Hence, embryonic stem cells (ESC),
which have unlimited growth capacities,
represent one of the few cell types with potential
for liver cell therapy. However, to be functionally
effective and safe, ESC have to be differentiated
into hepatocytes, the cells of the liver that
provide its typical functions, before
transplantation. Unfortunately, current ESC
differentiation protocols generate cells that are
not fully differentiated or functional. To achieve
levels of differentiation that would be therapeutic
we propose to identify the mechanisms that
establish hepatocyte function in progenitor cells
in the adult liver. Adult liver progenitors are
typically absent from the normal liver but
become apparent in liver disease when
hepatocytes are damaged. Remarkably, adult
liver progenitors can differentiate into fully
functional hepatocytes within a few days. We
hope to identify the genes that enable this rapid
maturation process in order to apply it to            $3,207,510
A major problem in regenerative medicine today
is that stem cells have the ability to cause tumors
and in most cases we currently lack methods to
make them safe. For example, two of the most
promising stem cells for regenerative medicine,
human embryonic stem cells (hESC) and induced
pluripotent stem cells (iPS), both readily cause
tumors in mice and there is every reason to
believe they will do so in humans. The reality is
that if we cannot prove that stem cells are safe
and do not cause tumors, they will never be used
in patients. However surprisingly there is
inadequate research into this fundamental
problem and it is not funded to a significant
degree by the NIH presenting a major gap in the
field. In the proposed research we will address
this problem by studying why hESC and iPS cells
cause tumors and searching for new stem
regulators that are safer. Our overall goal is
produce safe hESC and iPS cell regenerative
medicine therapies. One likely key culprit in the
tumor forming capacity of these stem cells is a
gene called Myc. Myc is a unique factor in the
universe of stem cell regulators because it not
only has key roles in the normal, positive            $2,158,161
The adult brain contains a pool of stem cells,
termed adult neural stem cells, that could be
used for regenerative purposes in diseases that
affect the nervous system. The goal of this
proposal is to understand the mechanisms that
promote the maintenance of adult neural stem
cells as an organism ages. Understanding the
factors that maintain the pool of adult neural
stem cells should open new avenues to prevent
age-dependent decline in brain functions and to
use these cells for therapeutic purposes in
neurological and neurodegenerative diseases,
such as Alzheimer’s or Parkinson’s diseases. Our
general strategy is to use genes that play a
central role in organismal aging as we have
recently discovered that two of these genes, Foxo
and Sirt1, have profound effects on the
maintenance and self-renewal of adult neural
stem cells. We propose to use these genes as a
molecular handle to understand the mechanisms
of maintenance of neural stem cells. Harnessing
the regenerative power of stem cells by acting on
genes that govern aging will provide a novel angle
to identify stem cell therapeutics for neurological
and neurodegenerative diseases, most of which         $2,348,520 Aging, Neurological Disorders
One of the most exciting possibilities in stem cell
biology is the potential to replace damaged or
diseased neural tissues affected by
neurodegenerative disorders. Stem-cell-derived
neurons provide a potentially limitless supply of
replacement cells to repair damaged or diseased
neurons. Typically, only one or a very few types
of neurons are affected in most
neurodegenerative diseases, and simply
transplanting stem cells directly into a
degenerating or damaged brain will not
guarantee that the stem cells will differentiate
into the specific neurons types needed. In fact,
they may instead cause tumor formation. Thus,
we must learn how to guide stem cells, cultured
in a laboratory, toward a specific differentiation
pathway that will produce neurons of the
specified type. These cells would then provide a
safe, effective way to treat neurodegenerative
diseases and central nervous system injuries.
Since there are hundreds or thousands of types of
neurons in the cerebral cortex, functionally
repairing damaged neurons in the cortex will
require a detailed understanding of the
mechanisms controlling differentiation, survival,
and connectivity of specific neuronal subtypes. In    $2,200,715 Amyotrophic Lateral Sclerosis
Stem cell biology and its applications to cell-
based therapies, since its inception 30 years ago,
has been hindered by the immunological
considerations of rejection of non-autologous
cells in patients, as well as by ethical concerns.
The generation of pluripotent cells from a
patient's own somatic cells has therefore been
the holy grail of regenerative medicine. A variety
of techniques have been used to attempt nuclear
'reprogramming' including transfer of somatic
nuclei into oocytes (SCNT) that led to cloning of
the sheep 'Dolly'. A recent breakthrough was the
demonstration by Yamanaka and colleagues that
the introduction of only four molecular factors
into skin fibroblasts could generate induced
pluripotent cells (iPS cells), with potential similar
to ES cells in their ability to generate all of the
germ layers. iPS cells have an unparalled potential
for cell based therapies as they overcome the
immunological and ethical concerns as well as
provide a means to obtain cellular disease models
from patients as invaluable tools for disease
characterization and drug screening. However,
before their clinical applications can be realized,
it is of utmost importance (a) to characterize          $1,414,841
Prematurity/preterm birth is the leading cause of
neonatal death in the U.S. and in California.
During an average day in California, 149 babies
are born preterm. These babies are at increased
risk for long-term disabilities, including cerebral
palsy, gastrointestinal problems, and vision and
hearing loss. Many premature babies also suffer
from low birth weight, which not only increases
complications in the perinatal period, but also
leads to increased cardiovascular disease and
diabetes in adulthood. Finally, prematurity and
fetal growth restriction are many times the result
of obstetric diseases, such as pregnancy-induced
hypertension and seizures, which carry high rates
of maternal morbidity and mortality. All the
above-mentioned diseases result from abnormal
development and function of the placenta, which
is a transient organ that forms the interface
between mother and baby. Trophoblasts are the
primary cell type which carries out major
placental functions such as establishing blood
supply from the mother to the fetus. This
application proposes the placenta as a novel
target for stem cell therapy and seeks generation
of trophoblast stem (TS) cells, which give rise to      $3,253,580 Fertility
Heart disease is the number one cause of death
and disability in California and in the United
States. Especially devastating is Arrhythmogenic
Right Ventricular Cardiomyopathy (ARVC), an
inherited form of heart disease associated with a
high frequency of arrhythmias and sudden
cardiac death in young people, including young
athletes, who despite their appearance of health
are struck down by this type of heart disease.
Even though it is inherited, early detection is
hindered because people carrying the genetic
code have highly variable clinical symptoms,
making ARVC and catastrophic cardiac events
very hard to predict and avoid. Evidence suggests
that this heart disease is caused by mistakes in
the genetic code essential for holding the
mechanical integrity of heart muscle cells
together or cell junctions. What is missing is an
understanding of the basic biology of these heart
muscle cell junctions in humans and appropriate
human model systems to study their dynamics in
heart disease, which is important since other
heart diseases also share some of these same
heart cell defects. Our goal is to understand the
basic biology of how human heart muscle cell
junctions mature and what happens in disease,       $1,341,955 Heart Disease
Spinal Muscular Atrophy (SMA) and Amyotrophic
Lateral Sclerosis (ALS) are motor neuron diseases.
Motor neurons control the voluntary muscles
that are used for activities such as crawling,
walking, head and neck control, and swallowing;
and sadly there are no known cures for motor
neuron diseases at this time. SMA is a genetically
inherited disorder and about 1 in 40 people are
carriers. SMA symptoms typically become are
apparent soon after birth and is a devastating
childhood disorder that is relatively common and
affects approximately 1 in 6000 babies. A
mutation in the SMN1 gene has been identified
as being responsible for SMA and researchers
have developed excellent animals models to
investigate the cellular and molecular features of
the disorder. Although ALS is distinct from SMA
and does not typically begin to manifest itself
until 30-40 years of age, it too is a motor neuron
disorder which affects an estimated 100,000
Americans. 3% of ALS cases are due to mutations
in the SOD1 gene, and like SMA excellent animal
models have been created by researchers to
study the disease and test ideas for treatment.
The potential to use stem cells to help
characterize drugs and test cell replacement         $54,798
Stem cells have tremendous potential for treating
human diseases, as they have the unique capacity
to develop into any cell type in the body and to
proliferate indefinitely. The development of new
therapies based on the transplantation of human
stem cells (HuSC) into patients is a major focus of
California researchers. A critical step prior to
making new HuSC-based therapies available for
use in humans is to test their safety and
treatment efficacy in research animals that have
the relevant disease. The laboratory mouse,
widely recognized as the premier mammalian
model for studying human disease, is the optimal
organism for these preclinical studies. Mice
naturally develop many important human
diseases, and certain other diseases that afflict
humans but normally do not occur in mice can be
experimentally induced. While numerous
valuable mouse models are currently available,
these models must be further developed so that
they can accept HuSC transplantation, through
suppression of their immune systems. The lack of
proven mouse models in which the immune
system has been suppressed is a major bottleneck
in research to translate discoveries in basic stem
cell research to use in the clinic. An additional     $3,841,240

One in every ten thousand people in the USA has
Huntington's disease, and it impacts many more.
Multiple generations within a family can inherit
the disease, resulting in escalating health care
costs and draining family resources. This highly
devastating and fatal disease touches all races
and socioeconomic levels, and there are currently
no cures. Screening for the mutant HD gene is
available, but the at-risk children of an affected
parent often do not wish to be tested since there
are currently no early prevention strategies or
effective treatments.
We propose a novel therapy to treat HD;
implantation of cells engineered to secrete Brain-
Derived Neurotrophic factor (BDNF), a factor
needed by neurons to remain alive and healthy,
but which plummets to very low levels in HD
patients due to interference by the mutant
Huntingtin (htt) protein that is the hallmark of
the disease. Intrastriatal implantation of
mesenchymal stem cells (MSC) has significant
neurorestorative effects and is safe in animal
models. We have discovered that MSC are
remarkably effective delivery vehicles, moving
robustly through the tissue and infusing
therapeutic molecules into each damaged cell
that they contact. Thus we are utilizing nature's
own paramedic system, but we are arming them
with enhanced neurotrophic factor secretion to
enhance the health of at-risk neurons. Our novel
animal models will allow the therapy to be
carefully tested in preparation for a phase 1
clinical trial of MSC/BDNF infusion into the brain
tissue of HD patients, with the goal of restoring
the health of neurons that have been damaged
by the mutant htt protein.

Delivery of BDNF by MSC into the brains of HD
mice is safe and has resulted in a significant
reduction in their behavioral deficits, nearly back
to normal levels. We are doing further work to
ensure that the proposed therapy will be safe and
effective, in preparation for the phase 1 clinical
trial.




                                                      $99,248 Huntington's Disease
The significance of our studies is very high
because there are currently no treatments to
diminish the unrelenting decline in the numbers
of medium spiny neurons in the striata of
patients affected by HD. However this biological
delivery system for BDNF could also be modified
for other neurodegenerative disorders such as
amyotrophic lateral sclerosis (ALS),
spinocerebellar ataxia (SCA1), Alzheimer's
Disease, and some forms of Parkinson's Disease,
where neuroregeneration is needed.
Development of novel stem cell therapies is
extremely important for the community of HD
and neurodegenerative disease researchers,
patients, and families. Since HD patients
unfortunately have few other options, the benefit
to risk ratio for the planned trial is very high.     $99,248 Huntington's Disease

Human embryonic and patient-specific induced
pluripotent stem cells have the remarkable
capacity to differentiate into many cell-types,
including neurons, thus enabling the modeling of
human neurological diseases in vitro, and permit
the screening of molecules to correct diseases.
Maintaining the pluripotent state of the stem cell,
directing the stem cell towards a neuronal
lineage, keeping the neuronal progenitor and
stem cells alive - these are all maintained by
thousands of different proteins in the cell at
these different "stages". Thus the levels and types
of proteins are highly controlled by gene
regulatory mechanisms.
Genes produce pre-messenger RNA (mRNA)
transcripts in the nucleus, which undergo a
process of refinement called splicing, whereby
long (1,000-100,000 bases) stretches of
nucleotides are excised, and much shorter pieces
(150 bases) are ligated together to form mature
messenger RNA to eventually make proteins in
the cytoplasm. Strikingly, some pieces of RNA are
used in a particular cell-type, but not another, in
a process called "alternative splicing". This is the
most prevalent form of generating transcriptome
diversity in the human genome, and is important
for pushing cells from one state to another i.e.
stem cells to neurons, maintaining a cell state i.e.
keeping a stem cell pluripotent, or a neuron alive
and functioning. Alternative splicing is highly
controlled by the recognition of even smaller
stretches (6-10 bases) of RNA binding sites) by
proteins that bind directly to RNA called splicing
factors.


The goal of the proposed research is to produce a
regulatory map of where these splicing factors
bind within pre-mRNAs across the entire human
genome with unprecedented resolution using a
high-throughput biochemical strategy.
Furthermore, using advanced genomic
technologies, we will deduce what happens to
splicing when these factors do not bind to their
binding sites. Finally, using molecular and imaging
methods, we will analyze what happens to
survival of stem and neuronal cells when these
factors are depleted or over-expressed, and if
stem cells are induced to make neurons if the
levels of these factors are altered. Completion of
the proposed research is expected to transform
our understanding of the regulatory mechanisms
underlying transcriptome complexity important
for neurological disease modeling, especially
human neurodegeneration, and stem cell biology.
In turn, this will facilitate more accurate
comparisons of diseased states of neurons from
stem-cell models of Amyotrophic Lateral Sclerosis
(ALS), Myotonic Dystropy, Spinal Muscular
Atrophy (SMA), Parkinson's and Alzheimer's to
identify mis-spliced genes and the splicing factors
responsible for therapeutic intervention.              $1,372,660
Traumatic brain injury (TBI) affects 1.4 million
Americans a year; 175,000 in California. When
the brain is injured, nerve cells near the site of
injury die due to the initial trauma and
interruption of blood flow. Secondary damage
occurs as neighboring tissue is injured by the
inflammatory response to the initial injury,
leading to a larger area of damage. This damage
happens to both neurons, the electrically active
cells, and oligodendrocytes, the cell which makes
the myelin insulation. A TBI patient typically loses
cognitive function in one or more domains
associated with the damage (e.g. attention
deficits with frontal damage, or learning and
memory deficits associated with temporal
lobe/hippocampal damage); post-traumatic
seizures are also common. Currently, no
treatments have been shown to be beneficial in
alleviating the cognitive problems following even
a mild TBI. Neural stem cells (NSCs) provide a cell
population that is promising as a therapeutic for
neurotrauma. One idea is that transplanting NSCs
into an injury would provide "cell replacement";
the stem cells would differentiate into new
neurons and new oligodendrocytes and fill in for
lost host cells. We have successfully used "sorted"    $1,708,549 Neurological Disorders, Trauma
Ongoing degeneration of dopaminergic (DA)
neurons in the midbrain is the hallmark of
Parkinson's disease (PD), a movement disorder
that manifests with tremor, bradykinesia and
rigidity. One million Americans live with PD and
60,000 are diagnosed with this disease each year.
Although the cost is $25 billion per year in the
United States alone, existing therapies for PD are
only palliative and treat the symptoms but do not
address the underlying cause. Levodopa, the gold
standard pharmacological treatment to restore
dopamine, is compromised over time by
decreased efficacy and particularly increased side
effects over time. Neural transplantation is a
promising strategy for improving dopaminergic
dysfunction in PD. The rationale behind neural
transplantation is that grafting cells that produce
DA into the denervated striatum will reestablish
regulated neurotransmission and restore
function. Indeed, over 20 years of research using
fetal mesencephalic tissue as a source of DA
neurons has demonstrated the therapeutic
potential of cell transplantation therapy in animal
model of PD and in human patients. However,
there are limitations associated with primary
human fetal tissue transplantation, including high


Human neural stem cells are currently the only
potential reliable and continuous source of
homogenous and qualified populations of DA
neurons for cell therapy for PD. Such cell source is
ideal for developing a consistently safe and
efficacious cellular product for treating large
number of PD patients in California and
throughout the world



We have developed a human neural stem cell line
with midbrain dopaminergic properties and the
technology to make 75% of the neuronal
population express dopamine. We have also
shown that these cells are efficacious in the most
authentic animal model of PD. We now propose
to conduct the manufacturing of these cells in
conjunction with the safety and efficacy testing to
bring this much needed cellular product to PD
patients and treat this devastating disease.           $99,976 Parkinson's disease
Alzheimer disease (AD), the most common cause
of dementia among the elderly and the third
leading cause of death, presently afflicts over 5
million people in the USA, including over 500,000
in California. Age is the major risk factor, with 5%
of the population over age 65 affected, with the
incidence doubling every 5 years thereafter, such
that 40-50% of those over age 85 are afflicted.
Being told that one suffers from AD is one of the
most devastating diagnoses a patient (and their
family/caregivers) can ever receive, dooming the
patient to a decade or more of progressive
cognitive decline and eventual loss of all memory.
At the terminal stages, the patients have lost all
reasoning ability and are usually bed-ridden and
unable to care for themselves. As the elderly
represent the fastest growing segment of our
society, there is an urgent need to develop
therapies to delay, prevent or treat AD. If the
present trend continues and no therapy is
developed, over 16 million Americans will suffer
from AD by 2050, placing staggering demands on
our healthcare and economic systems. Thus,
supporting AD research is a wise and prudent
investment, particularly focusing on the power         $3,599,997 Aging, Alzheimer's disease


Alzheimer's disease (AD) is an incurable disorder
that affects memory, social interaction and the
ability to perform everyday activities. In the USA
alone, the number of AD patients aged 65 and
older has surpassed 5 million and that number
may triple by 2050. Annual health care costs have
been estimated to exceed 172 billion dollars, but
do not reflect loss of income and stress caused to
caregivers. Therefore, there is great hope for new
therapies that will both improve symptoms and
alleviate suffering.
There are few FDA-approved medications to treat
AD and none is capable of preventing, delaying
onset or curing AD. Current medications mostly
tend to temporarily slow the worsening of AD-
associated symptoms such as sleep disturbances,
depression and memory loss/disorientation.
Pharmaceutical companies continue to develop
new types of drugs or combination therapies that
can better treat the symptoms or improve the
quality of life of AD patients. There is also an
ongoing effort to discover novel drugs that may
prevent, reverse, or even cure AD. Unfortunately,
the number of clinical studies addressing the
possible benefit of such drugs is low, and agents
that have shown initial promise have failed at
later stage clinical testing, despite convincing
preclinical data. There are ongoing studies in AD
patients using vaccines and other biological
compounds but it is unclear when data from
these new trials will be available and more
importantly, whether they will be successful. The
need for divergent and innovative approaches to
AD is clearly suggested by the failure of
experimental drugs.



Our proposal is to use brain stem cells to treat
AD. This is a completely different approach to the
more standard therapies described above such as
drugs, vaccines, etc., and one that we hope will
be beneficial for AD patients as a one-time
intervention. AD is characterized by a dysfunction
and eventual loss of neurons, the specialized cells
that convey information in the brain. Death or
dysfunction of neurons results in the
characteristic memory loss, confusion and
inability to solve new problems that AD patients
experience. It is our hope that stem cells
transplanted into the patient's brain may provide
factors that will protect neurons and preserve
their function. Even a small improvement in
memory and cognitive function could significantly
alter quality of life in a patient with AD.           $98,050 Alzheimer's disease
Huntington’s disease (HD) is a devastating
neurodegenerative disease with a 1/10,000
disease risk that always leads to death. These
numbers do not fully reflect the large societal and
familial cost of HD, which requires extensive
caregiving and has a 50% chance of passing the
mutation to the next generation. Current
treatments treat some symptoms but do not
change the course of disease. Symptoms of the
disease include movement abnormalities,
inability to perform daily tasks and and
psychiatric problems. A loss os specific regions of
the brain are observed. The mutation for HD is an
expansion of a region of repeated DNA in the HD
gene and the longer the repeat, in general the
earlier the onset of disease. While the length of
this polyglutamine repeat largely determines the
age-of-onset, there is variance in onset age that is
not accounted for by repeat length but is
determined by genetic and environmental
factors. In addition, the symptoms can vary
significantly among patients in a non-repeat
dependent manner. To assist in preventing onset
of HD, there is a great need to identify genes that
are involved in why one individual with 45             $1,369,800 Huntington's Disease
This proposal describes a sharply-focused, timely,
and rigorous effort to develop new therapies for
the treatment of injuries of the Central Nervous
System (CNS). The underlying hypothesis for this
proposal is that chemokines and their receptors
(particularly those involved in inflammatory
cascades) actually play important roles in
mediating the directed migration of human
neural stem cells (hNSCs) to, as well as
engagement and interaction with, sites of CNS
injury, and that understanding and manipulating
the molecular mechanism of chemokine-
mediated stem cell homing and engagement will
lead to new, better targeted, more specific, and
more efficacious chemokine-mediated stem cell-
based repair strategies for CNS injury. In recent
preliminary studies, we have discovered and
demonstrated the important role of chemokine
SDF-1-alpha and its receptor CXCR4 in mediating
the directed migration of hNSCs to sites of CNS
injury. To manipulate this SDF-1-alpha/CXCR4
pathway in stem cell migration, we have
developed Synthetically and Modularly Modified
Chemokines (SMM-chemokines) as highly potent
and specific therapeutic leads. Here in this
renewal application we propose to extend our
research into a new area of stem cell biology and    $759,000 Spinal Cord Injury, Stroke, Trauma
Spinal muscular atrophy (SMA) is the leading
genetic cause of infant death in the U.S. This
devastating disease affects 1 child in every 6,000-
10,000 live births, with a North American
prevalence of approximately 14,000 individuals.
The disease is characterized by the death of
spinal cord cells called motor neurons that
connect the brain to muscle. Death of these cells
causes muscle weakness and atrophy, which
progresses to paralysis, respiratory failure and
frequently death. The three different types of
SMA differ in severity and prognosis, with Type I
being the most severe. SMA is caused by a
genetic defect that leads to reduced levels of a
single protein called SMN. There are currently no
approved therapies for the disease. The existing
treatments for SMA consist of supportive care for
the respiratory and nutritional deficits, for
example ventilation and feeding tubes. Previous
attempts to develop drugs using conventional
technologies, such as cultured cancer cells or cells
derived from animals have been unsuccessful.
These failures are likely due the fact that previous
attempts used cell types that don't reflect the
disease or aren't affected by low levels of the
SMN protein. Our approach uses patient-derived         $5,665,887 Spinal Muscular Atrophy
Since their discovery almost ten years ago, there
has been steady progress towards the application
of human embryonic stem (ES) cells in medicine.
Now, the field is on the threshold of a new era.
Recent results from several laboratories show
that human skin cells can be converted to cells
resembling ES cells through simple genetic
manipulations in the laboratory. There is
currently much excitement about these induced
pluripotent stem (iPS) cells, which might have
advantages over ES cells in studying and treating
disease. However, we do not yet sufficiently
understand their nature and potential to be
certain that they can replace (ES) cells in research
and therapy. Because of this, it is important to
continue to develop new ES cell lines, and to
compare their properties with those of iPS cells.
Technological advances in ES cell research now
enable us to grow stem cells under conditions
that are much more suitable for future patient
use than those used to develop the first ES cell
lines. However, these new methodologies have
for the most part been developed with, and
tested on, a handful of the long-established ES
cell lines on the NIH Registry. In this proposal, we   $1,387,508

Stem cells are multipotent, meaning that they can
develop into any cell type of the human body.
Biomedical applications propose that, after
introduction into humans, stem cells could
replenish damaged or lost cells in human bodies
and thereby cure human diseases such as
Parkinson, Alzheimer                                    $595,469
The human body is composed of thousands of cell
types, which all came originally from embryonic
stem cells. Although all these cell types have the
same genetic blueprint, different genes are active
in different cells in order to give each its
distinctiveness. The process by which the genes
remember whether they are in liver, brain, or skin
cells is called “epigenetics.” A central problem in
regenerative medicine is to understand the
epigenetic program so that human embryonic
stem cells can be efficiently turned into the cell
types required for each specific patient.
Conversely, by manipulating the epigenetic
program, adult cells may be reprogrammed into
primitive cells that can turn into other cell types
to repair diseased or damaged tissues. The goal of
the proposed research is to better understand
the epigenetic program in human embryonic
stem cells and adult cells. We want to tap into the
natural mechanisms by which the body normally
“remembers” what kinds of cells reside in each
tissue and apply them to regenerative therapies.
Specifically, the research will study the roles of a
newly discovered type of genes, termed
“noncoding RNAs”, in stem cell epigenetics. A          $3,203,926
Age-related diseases of the nervous system are
major challenges for biomedicine in the 21st
century. These disorders, which include
Alzheimer                                              $5,883,026
The most prominent feature of the stem cell is its
pluripotent capacity to differentiate into various
types of cells. The importance of the orchestrated
interplay between molecular regulators has been
demonstrated in the maintenance of self-
renewing pluripotent property or the initiation of
differentiation. Advance in the generation of the
induced pluripotent stem cells (iPSCs) have been
benefitted by our knowledge on the molecular
regulation in stem cell renewal/differentiation.
Furthermore, the practical use of stem cells for
regenerative medicine will be possible through
our understanding on the mechanism underlying
distinct differentiation process. Recent progress
in stem cell biology has unveiled some important
features of molecular and cellular regulations in
stem cell pluripotency and differentiation, but it
remains largely elusive. The proposed study is
based on our recent published findings that
demonstrate the significance of the cell cycle
regulatory molecule in embryonic stem cell self-
renewal and differentiation. Our published data
strongly supports that CDK2AP1 (CDK2
associating protein 1) is a competency factor in
mouse embryonic stem cell (mESC)
differentiation. Even though the difference in       $1,259,371
The inability to separate stem cells and their
differentiated progeny accurately, easily, and
rapidly undermines progress in the stem cell field.
Traditional separation of living cells into
subpopulations relies on techniques that utilize
characteristic cell surface markers, but specific
markers are severely limited or lacking altogether
for many stem cell populations. Without ways to
discriminate and isolate subpopulations of stem
cells and their derivatives, controlling the purity
of cells for in vitro studies or transplantation is
impossible. A different method termed
“dielectrophoresis” (DEP) may provide a label-
free and unbiased method to address these stem
cell sorting issues. DEP employs a non-toxic
electric field to attract or repel cells in a
frequency-dependent manner independent of
marker expression. DEP detects intrinsic cell
components such as presence and distribution of
charges in the membrane and cytoplasm. A
variety of cells have been separated using DEP,
including subpopulations of human white blood
cells. However, this approach was only recently
applied to stem cells when it was shown that DEP
distinguishes mouse neural stem/precursor cells         $871,627
One of the great promises of stem cell research is
that doctors will find a way to isolate and modify
patient’s stem cells so that they be reinjected into
patients to treat their disease. Current examples
include islet cell transplantation to treat diabetes,
stem cells for treating heart failure, or engineered
immune cells for treating cancer. However, a key
challenge is to be able to monitor the cells after
they have been administered. Scientists need to
be able to follow the transplanted cells, to see if
they survive and engraft, home to areas of
disease, and whether they are able to reestablish
the activity needed to counteract disease. We are
developing novel tools to follow the fate and
function of transplanted stem cells, based on a
powerful medical camera called the PET scanner.
PET imaging, or positron emission tomography,
allows doctors to visualize the biology of cells in
living organisms, including patients. Three ways
to follow transplanted cells are being developed.
In one, distinctive changes of functions inside
cells will be probed using radioactive small
molecules. In a second approach, antibodies will
be used to detect cells based on distinctive
markers on the surface of the transplanted cells.       $914,096
Human embryonic stem cells have a great
potential for medical therapeutics. However, the
genes required for altering the fate of these cells
to differentiate into a particular tissue or cell type
is not well understood. The ability to efficiently
transfer genes or silence genes in ES cells would
be of great benefit for two reasons: 1) A
combination of gene therapy and ES stem cells
will likely broaden the therapeutic potential of
these cells, and 2) the ability to alter gene
expression will provide important tools for
unraveling the genetic programs required for
targeted differentiation into a specific tissue or
cell-type. Viral gene transfer vectors are derived
from viruses. The viral genes are removed and
replaced with a therapeutic gene or a gene under
biological study. Thus, the viral shell is used to
transfer the desired gene into cells. Although
there has been some success, current gene
transfer vectors do not work efficiently in ES cells.
To make this new gene transfer vector, we will
use the adenoassociated virus (AAV). This virus is
not associated with any known disease and has
been used in a number of human clinical trials.
Another advantage of vectors based on these              $640,642
Cardiovascular diseases remain the major cause
of death in the western world. Stem and
progenitor cell-derived cardiomyocytes (SPC-
CMs) hold great promise for the myocardial
repair. However, most of SPC-CMs displayed
heterogeneous and immature
electrophysiological phenotypes with substantial
automaticity. Implanting these electrically
immature and inhomogeneous CMs to the hearts
would be arrhythmogenic and deleterious.
Further optimization in identification, selection
and inducing maturation of subtypes of CMs from
primitive SPC-CMs are paramount for developing
a safe and effective cell-based therapy.
Commonly used CM isolation techniques are
microdissection, density sedimentation or
promoter-driven, fluorescence-activated cell
sorting (FACS). Microdissection and density
sedimentation are labor intensive and lack of
purity. Promoter-driven FACS may compromise
cell viability and which promoter is proficient for
selection remains unclear. We have established
several antibiotics (Abx)-resistant human
embryonic stem cell (hESC) lines conferred by
lentiviral vectors under the control of various
cardiac-specific promoters. With simple Abx           $906,629 Heart Disease
A promising approach to alleviating the
symptoms of Parkinson's disease is to transplant
healthy dopaminergic neurons into the brains of
these patients. Due to the large number of
transplant neurons required for each patient and
the difficulty in obtaining these neurons from
human tissue, the most viable transplantation
strategy will utilize not fetal dopaminergic
neurons but dopaminergic neurons derived from
human stem cell lines. While transplantation has
been promising, it has had limited success, in part
due to the ability of the new neurons to find their
correct targets in the brain. This incorrect
targeting may be due to the lack of appropriate
growth and guidance cues as well as to
inflammation in the brain that occurs in response
to transplantation, or to a combination of the
two. Cytokines released upon inflammation can
affect the ability of the new neurons to connect,
and thus ultimately will affect their biological
function. In out laboratory we have had ongoing
efforts to determine the which guidance
molecules are required for proper targeting of
dopaminergic neurons during normal
development and we have identified necessary
cues. We now plan to extend these studies to          $633,170 Parkinson's disease
The government has strict rules for producing
cells that will be transplanted into patients. For
example, these regulations discourage the use of
animal products that could transmit diseases to
humans. In this context, the high-quality and
tightly regulated procedures that govern other
cell-based therapies, e.g., bone marrow
transplants, will be applied to regenerative-type
clinical applications that employ human
embryonic stem cells (hESCs). We need to
produce these cells now so that they will be ready
to use when research findings are translated into
patient therapies. Our goal is to supply
researchers in California and outside the state
with the highest-quality hESCs. To achieve this
goal, we will build on our previous work,
published in the scientific literature, which
includes deriving hESCs from intact embryos and
their single-cell components. We also study the
basic properties of embryos and hESCs so that we
can formulate theories about how to improve the
derivation process, which we then test in our
laboratory. For example, adult humans need very
precise levels of oxygen. Our work shows that the
same is true for embryos and hESCs. We have
also developed novel culture conditions that use     $1,383,419
The overall goal of this proposal is to explore a
new stem cell-based treatment for major defects
in the orofacial regions resulted from burns,
physical injuries, genetic diseases, cancers,
infectious diseases, and recently, bisphosphonate-
associated osteonecrosis of the jaw (BONJ), using
the patient’s own stem cells obtained from the
oral cavity known as orofacial mesenchymal stem
cells (OMSCs). The standard surgical
reconstruction of orofacial defects relies on
different sources of bone grafts harvested from
distant anatomical site of the same patient or
other donors. However, those approaches are
associated with higher morbidity and
unpredictable clinical outcomes. Evidences have
shown that bone marrow mesenchymal stem
cells (BMMSCs) could be a promising alternative
for bone reconstruction but not in the orofacial
region. These clinical results may be due, in part,
to the fact that orofacial and long bones are
derived from different cell origins, termed as
neural crest cells and mesoderm, respectively. In
addition, OMSCs are readily accessible from the
oral cavity and can be easily expanded for cell-
based therapies due to their inherently high
proliferative capability. These evidences suggest     $3,428,464 Bone or Cartilage Disease
Somatic cell nuclear transfer (NT) is a powerful
research tool with the potential for creating
unique cell and tissue sources for studies of
disease pathogenesis and regenerative medicine.
Creation of pluripotent mouse embryonic stem
(ES) cells using NT has been achieved and the
prospects for generating human ES cells by NT
are promising. However, there are only a handful
of researchers who have reported their
experience with NT and development of this
approach in California would benefit from
increasing dedicated efforts toward this goal. We
have assembled a team focused on NT that has
achieved several experimental milestones that
motivate these proposed studies of NT in human
oocytes. These prior achievements include NT in
mouse oocytes, efficient production of novel ES
cells from mouse embryos, and controlled
enucleation of recipient human oocytes. With
CIRM SEED funds, we will use systematic
approaches to identify conditions that generate
multipotent human cells from NT into human
oocytes, with the goal of eventually producing
new patient-specific human ES cell (hESC) lines
for studies of disease pathogenesis,
transplantation and tissue regeneration.              $656,074


We study human muscle development, and are
actively investigating potential cell-based
therapies for the treatment of degenerative
muscle diseases, such as muscle dystrophy. This
project will define the pathway that muscle stem
cells follow as they form new muscle, and identify
which muscle stem cells are most useful for
therapy. Our approach will be to examine human
embryonic stem cells as they become muscle
stem cells and mature muscle in culture, to define
the stages of normal muscle development. We
will then transplant these stem cells at various
stages of development into the leg muscles of
mice with muscular dystrophy, and study how
these cells become new muscle tissue, how this
impacts the animals’ ability to exercise, and
the strength of the treated muscles. Our goal for
this research is to fully understand the normal
process of human muscle stem cell development,
and to identify specific stem cells that provide
therapeutic benefit when transplanted into
dystrophic muscle.                                   $1,381,296
Our research group at [REDACTED] has had a long-
standing interest in understanding the cause of
several disorders that result in severe, and often
times fatal forms of diarrhea in children. These
diarrheal disorders are inherited, and somehow
lead to poor absorption of nearly all forms of
nutrients, including protein, sugars and fats. Why
children with these disorders have impaired
absorption of nutrients is one of the main
unsolved mysteries, but they generally require
life-long the daily infusion of intravenous
nutrients or an intestinal transplantation to
sustain proper growth and nutrition.




The goal of this grant application is to develop
personalized disease-in-a-dish models that can be
used to solve these and other gastrointestinal
disorders that are poorly understood. Specifically,
we propose to develop custom-made "diarrhea-in-
a-dish" models that will use pluripotent stem (iPS)
cells derived from skin biopsies of individuals with
various forms of diarrhea. These iPS cells will be
induced to form gut epithelium that we believe
will resemble various characteristics of the
subjects native intestine. We will also develop
methods that are already established in mice, to
isolate and expand human intestinal (somatic)
stem cells in cell incubators and in fat
compartments of immunodeficient mice. We
believe that the resulting intestinal units can be
manipulated using various commonly used tools
to introduce and/or suppress genes that might
control the histology and function of the gut.
We are also using newly developed genetic tools
where the entire important (coding) region of the
human genome is sequenced to identify genes
that are defective, and thereby may account for
the diarrheal disorder under investigation. This
new approach generally identifies several genes
that are defective, and we propose to introduce
the normal forms of these various genes into the
stem cell derived gut tissue to see which gene
might reverse the abnormality. We believe that
the combination of these various approaches will
likely assist us in defining the cause of various
forms of diarrhea.




While short-term bouts (acute) of diarrhea are
very common, approximately 5% individuals
experience chronic (>2 weeks) diarrheal
symptoms, and some may be life-long.
Unfortunately, Physicians and Scientist alike have
a very poor understanding of why so many
patients experience chronic diarrhea. While the
congenital diarrheal disorders under investigation
in this grant are rare conditions, improving our
understanding of these types of genetic disorders
will undoubtedly provide new insight into how
nutrients are absorbed, and may enhance our
understanding of several common but poorly
understood disorders, including IBD, IBS, drug-
induced and other idiopathic forms of chronic
diarrhea. Developing, refining and expanding the
tools described here may also set the foundation
to study other common disorders, and to screen
for novel drug discovery.                            $1,783,250
Five million people in the U.S. suffer with heart
failure, resulting in ~60,000 deaths/year at a cost
of $30 billion/year. Heart failure occurs when the
heart is damaged and becomes unable to meet
the demands placed on it. Unlike other organs,
the heart is unable to fully repair itself after
injury. One of the common causes for the
development of heart damage is a heart attack.
After a myocardial infarction (heart attack),
irreversible loss of contracting heart muscle cells
occurs, resulting in scar formation and
subsequently heart failure. Current therapies
designed to treat heart attack patients in the
acute setting include medical therapies and
catheter-based technologies that aim to open the
blocked coronary arteries with the hope of
salvaging as much of the jeopardized heart
muscle cells as possible. Unfortunately, despite
advances over the past 2 decades, it is rarely
possible to rescue the at-risk heart muscle cells
from some degree of irreversible injury and
death. Attention has turned to new methods of
treating heart attack and heart failure patients in
both the acute and chronic settings after their
event. Heart transplantation remains the ultimate     $53,972
This application seeks to bring to the clinic a new
treatment for myocardial disease based on
human embryonic stem cell (hESC) derived
cardiomyocytes. hESC-cardiomyocytes have the
unique potential to address the underlying cause
of heart disease by repopulating areas of
damaged myocardium (heart tissue) with viable
cardiac cells. This therapeutic approach
represents a potential breakthrough in heart
disease treatment, serving one of the most
intractable, largest, and most costly unmet
clinical needs in the U.S.
Currently available heart disease treatments have
demonstrated ability to slow progression of the
disease, but to date none can restore the key
underlying defect in heart failure, a loss of
contractile function. Cell therapy approaches
have generated excitement for their unique
potential to play a curative role in myocardial
disease through the restoration of lost contractile
and/or circulatory function. hESC-cardiomyocytes
are unique amongst the cell therapy approaches
in that they are a human cardiomyocyte (heart
muscle cell) product; replacing damaged
myocardium with viable heart cells which can
integrate and form fully functional cardiac tissue.
This approach has the potential to significantly
halt or reverse cardiac functional decline. These
benefits can significantly impact patient
medication requirements and hospitalizations
associated with ongoing cardiac decline, key
drivers of the enormous health care costs
associated with heart failure.




The proposed scope of this project includes
activities leading up to and including a regulatory
filing with the FDA to initiate clinical testing of
hESC-cardiomyocytes for the treatment of heart
failure, as well as the enrollment and initial follow-
up of a small cohort of patients in a first-in-
human trial. The proposed product has
completed extensive process development,
product characterization, and preclinical (animal
model studies) proof-of-concept studies to date.
The scope of the proposed research includes: (i)
performance of key preclinical safety and efficacy
studies to enable entry to clinical testing (ii)
manufacture of material for use in preclinical
studies, development work, and clinical testing
(iii) development and qualification of assays for
product characterization, and (iv) preparation for
and execution of initial clinical studies.               $0 Heart Disease
Cancer is the leading cause of death for
individuals under 85. Relapse and metastatic
disease are the leading causes of cancer related
mortality. Anti-apoptotic BCL2 family member
overexpression has been shown to promote
disease progression in both chronic myeloid
leukemia (CML) and prostate cancer. Andr., the
emergence of cancer stem cells (CSC) promotes
apoptosis resistance in the bone marrow
metastatic microenvironment. While targeted
therapy with BCR-ABL inhibitors has improved
survival of patients with chronic phase CML, the
prevalence has doubled since 2001 with over
22,000 people living with CML in the US in 2009.
Unfortunately, a growing proportion of patients
become intolerant or simply cannot afford full
dose BCR-ABL inhibitor therapy and thus,
progress to advanced phase disease with a 5 year
survival rate of less than 30%. Although prostate
cancer prevalence was high at 2.26 million in
2007, distant disease was relatively rare at 5%.
However, like blast crisis CML, metastatic
prostate cancer survival was only 30% over 5
years. Overexpression of B-cell
lymphoma/leukemia-2 (BCL2) family genes has
been observed in human blast crisis CML and         $3,341,758 Blood
The derivation and culture of human embryonic
stem cells has provided new possibilities for
treatment of a wide variety of human diseases
because these cells have the potential to help
regenerate and repair many types of damaged
tissue. Diseases for which such cell-based
treatments may be helpful include obstructive
renal disease, a disorder for which there has been
little progress made in terms of treatment.
Infants with this and other inherited kidney
disease may be severely compromised before
birth and treatments necessary to prolong their
life may be accompanied by severe side effects.
This raises many difficulties not only for these
young patients but also for their families. If new
ways to treat these infants prior to birth can be
developed, this could lead to the delivery of
healthy babies at full term. The use of cells
obtained from human embryonic stem cells to
repair and treat damaged kidneys prior to birth
offers promise to improve survival and quality of
life for these babies. Since it is clear that
embryonic stem cells have vast potential to form
a variety of cell types, it is possible that the kinds
of cells needed to provide repair could be               $2,257,040 Kidney Disease
A critical bottleneck to translate the promise of
regenerative medicine to the clinic is the ability to
efficiently harvest, expand, and deliver sufficient
numbers of viable stem cells. While relatively
large numbers of patient-specific, multipotent
human adipocyte stem cells (hASC) can be
harvested from adults, these cells must be re-
delivered to the patient (either with or without
intervening culture steps) in sufficient quantity
for functional regeneration. We propose
development of a clinically translatable
biomaterial that is used both to improve the
efficiency of stem cell expansion and to enhance
the effectiveness of stem cell delivery. Current in
vitro stem cell expansion protocols are time-,
space-, energy-, and cost-intensive and often
result in the spontaneous loss of self-renewal in
addition to a heterogeneous population of
differentiated cells. Furthermore, the most non-
invasive method of stem cell delivery to the
patient, direct cell injection, commonly results in
less than 5% cell viability. Our specific aims
demonstrate the flexibility of a single biomaterial
to address these bottlenecks in three different
clinical paradigms: 1) direct re-injection of hASC       $1,415,981
The ability of human embryonic stem (hES) cells
to form a wide variety of adult human cell types
offers hope for development of novel therapies
to treat human degenerative diseases such as
Alzheimer's, diabetes, and muscular dystrophy.
However, to prevent rejection of the transplanted
cells by a patient's immune system it will be
important to use hES cell derived tissues that are
immunologically matched to the patient. One
way to do this involves somatic cell nuclear
transplantation (SCNT) where the nucleus
containing the genetic information is transferred
from a patient's cell into a human oocyte (egg)
from which the nucleus has been removed. The
oocyte is then stimulated to divide into a small
group of cells from which new hES cells are
derived. As cells derived from these hES cells
contain the patient's DNA they will be immune-
matched to the patient, thereby preventing tissue-
rejection. While SCNT has been performed using
cells and eggs from mice, it is not yet possible to
do this on a routine basis using human cells and
eggs. One reason for lack of progress concerns
the scarce supply of human oocytes available for
research. Oocytes are usually obtained from           $623,781

Human embryonic stem cells can be changed into
virtually any cell type in the adult body. Because
of this unique capability, these cells have the
potential to cure a vast majority of existing
human disorders. Several hurdles exist, however,
which need to be overcome before results from
the exciting field of stem cell research can be
used in the clinic. For example, the factors which
govern conversion of stem cells into a variety of
tissue types that may find uses in regenerative
medicine such as in liver, heart, brain, are not
well understood. Our research employs a unique
multidisciplinary and collaborative approach to
harness the expertise of several leading scientific
laboratories to bridge this information gap. In
particular, our area of specialization is in
understanding how the sugars which coat the
surfaces of cells impact processes such as the
malignant transformation of cancer cells. The
CIRM grant will enable us to apply this same
accumulated expertise to study the roles of cell
surface sugars in the transformation of human
embryonic stem cells into cell types useful for the
treatment of human diseases.                          $498,409
The therapeutic potential of human embryonic
stem cells is extraordinary. Without a doubt,
regenerative medicines will save thousands of
lives in the years to come. Before that day arrives,
much needs to be learned from the cells
themselves. The reasons that these cells hold so
much promise are two-fold: (1) embryonic stem
cells can renew themselves indefinitely (divide
and divide and...) and (2) embryonic stem cells
can be trained to become any cell type of the
body (neurons, heart muscle, skin, liver,
kidney...). However, it should be emphasized that
these two points are only valid if the growth
conditions are properly established. While we
have made great strides in developing culture
conditions that can support self-renewal of
embryonic stem cells, we are a long way from
mastering the conditions necessary for
differentiating embryonic stem cells into every
cell type of the body (of which there are about
200). Ultimately, if therapies based on stem cells
are to be realized, these cells will have to be
grown in massive quantities, with an
unprecedented level of quality control to ensure
that only one cell type can be found in the lot.       $734,202
The therapeutic promise of stem cell biology lies
in its potential for cell replacement therapies in
diseases where an essential cell type of the
patient malfunctions or degenerates. This is
particularly evident in diseases of the nervous
system where cells largely lose their ability to
proliferate and thus regenerate after embryonic
differentiation. Devastating neurodegenerative
disorders, such as amyotrophic lateral sclerosis
(ALS) and spinal muscular atrophy (SMA), are
characterized by a progressive paralysis caused
by motor neuron death and currently have no
cure. Strategies for replacing specific neuronal
cell types with cells derived from human
embryonic stem (hES) cells will require
understanding the genetic programs that control
hES cell differentiation. These rapidly dividing
pluripotent cells undergo a major transition in
gene expression to become neuronal progenitor
cells (NPC), while maintaining their proliferative
ability. Another drastic change in gene expression
program occurs as NP cells differentiate into
neurons, where cell division has stopped. A great
deal of important work is describing the DNA
level changes that control gene expression in ES
cells and during their transition to NPC and         $1,350,994
The capacity of human embryonic stem cells
(hESCs) to perpetuate themselves indefinitely in
culture and to differentiate to all cell types of the
body has lead to numerous studies that aim to
isolate therapeutically relevant cells for the
benefit of patients, and also to study how genetic
diseases develop. However, hESCs can cause
tumors called teratomas when placed in the body
and therefore, we need to separate potentially
beneficial cells from hazardous hESCs. Thus,
potential therapeutics cannot advance until the
development of methodologies that eliminate
undifferentiated cells and enrich tissue stem cells.
In our proposal we hope to define the cell surface
markers that are differentially expressed by
committed hESC-derived stem cells and others
that are expressed by teratogenic hESCs. To do
this we will carry out a large screen of cell subsets
that form during differentiation using a collection
of unique reagents called monoclonal antibodies,
many already obtained or made by us, to define
the cell-surface markers that are expressed by
teratogenic cells and others that detect valuable
tissue stem cells. This collection, after filing for IP
protection, would be available for CIRM
investigators in California. We were the first to         $2,636,900 Blood Disorders, Heart Disease, Immune Disease
More than 100,000 patients await for organ
transplants nationwide this year. The ground-
breaking discovery of new pluripotent human
stem cell lines (iPS) derived from skin fibroblasts
using a core of 3-5 transcription factors opens the
door to patient-derived pluripotent stem cells
and new approaches to organ and tissue
replacement. Patient-derived stem cells could
have an immediate impact on hundreds of other
medical applications and discoveries. A major
bottleneck in translating these breakthroughs
into the clinic is that pre-existing mutations in
patients and mutations acquired from viral and
DNA vectors pose a potential risk for cancer. To
overcome this obstacle, we propose an
alternative approach to generating patient-
derived stem cell lines using cell-permeable,
pluripotent-inducing transcription factors.
Introducing active proteins into cells avoids the
long-term risk of genetic mutations. Over the past
10 years, our labs have pioneered this technology
to introduce over 50 functional proteins in a wide
spectrum of human and animal cell types. First,
we will use this technology to determine the
optimal number of cell-permeable proteins
necessary to induce pluripotency in human cells.      $1,387,800
Blood and immune cells originate and mature in
the bone marrow. Bone marrow cells are
mixtures of blood cells at different stages of
development, and include rare populations of
blood-forming stem cells. These stem cells are the
only cells capable of generating the blood system
for the life of an individual. Bone marrow
transplants (BMT) have been performed > 50
years, to replace a diseased patient's blood
system with that of a donor. Unfortunately, BMT
have associated dangers which make the
procedure high risk. Major risks include a
syndrome called graft-versus-host disease (GvHD)
which results when the donor's mature blood
cells attack the organs of the host, and toxicity
from the treatments (radiation and
chemotherapy) required to permit the donor cells
to take in the recipient. These risk factor limit the
use of BMT to only immediate life-threatening
diseases. If made safer, BMT could cure many
other debilitating diseases. In addition to being
curative of blood cancers and non-malignant
blood diseases (such as sickle-cell anemia), these
transplants can cure autoimmune diseases, such
as juvenile (type I) diabetes and multiple              $1,403,557


Glioblastoma multiforme is the most prevalent
and aggressive type of brain tumor, and
devastating to any patient unfortunate enough to
receive its diagnosis. As the most populous state
in the nation, more Californians are diagnosed
with glioblastoma multiforme than any other
state. Over the past 20 years, surgery, radiation
therapy and chemotherapy have been utilized
with frustrating results. Today, even with the
most advanced treatments available, survival
rates average only 14-15 months.
Our proposed research focuses on a new theory
that brain tumor cells are initiated and
maintained by a small fraction of cells with stem
cell-like properties. This "cancer stem cell"
hypothesis states that if this small subset of
cancer stem cells could be eliminated then the
tumor would cease to grow. Cancer stem cells in
glioblastoma have been identified using CD133, a
well known marker for isolating normal neural
stem cells. The fact that CD133 is present on
normal stem cells means that only targeting this
molecule would be potentially dangerous. To
enhance targeting, we reasoned that a cancer-
specific alteration found in glioblastoma could be
used as a potential marker for cancer stem cells.
EGFRvIII is a specific variant of the normal EGF
receptor and is widely found in glioblastoma but
is rarely present in normal tissues. We have now
shown that tumor cells that express both CD133
and EGFRvIII have the most cancer stem cell
properties-more so than cells that have CD133 or
EGFRvIII alone. We then developed a "bispecific"
antibody that simultaneously recognizes both of
these markers and we have shown that this
bispecific selectively kills the cancer cells in




To move this into patients, we will produce large
quantities of the bispecific and perform rigorous
tests to ensure that it is uniform and has the
required properties. We will also determine that
it is safe through a combination of cell based and
animal studies. Extensive planning will be made
for the correct format for the clinical trial to test
this molecule. Once the properties of the
bispecific are certified and plans for the clinical
trial are finalized, we will submit the drug to the
FDA for an Investigational New Drug application.
Once approved by the FDA, we can then move
forward with testing this compound in
glioblastoma patients. We are particularly excited
about the bispecific as it could serve as the
paradigm for a new class of drugs that specifically
target cancer stem cells.                               $109,750 Brain
Over 3.2 million people worldwide are bilateral
blind from corneal diseases. Limbal stem cell
deficiency (LSCD) has been recognized as a major
cause, either primary or secondary, of significant
visual loss and blindness in many common
corneal disorders. A healthy, transparent ocular
surface is made up of non-keratinized, stratified
squamous epithelium that is highly differentiated.
The corneal epithelium is constantly renewed and
maintained by the corneal epithelial stem cells, or
limbal stem cells (LSCs) that are presumed to
reside at the limbus, the junction between the
cornea and conjunctiva. When the LSCs are
deficient and unable to repopulate the corneal
surface, the cornea surface will become opaque.
Corneal transplant can't survive and is
contraindicated in LSCD. LSC transplantation, in
the form of keratolimbal allograft to restore a
transparent corneal surface, has been the main
therapy in the United States. The 5-year survival
of these allografts is about 30%, largely due to
immune rejection. Transplantation of autologous
limbal epithelial stem cells that have been
expanded on tissue culture has successfully
restored vision and revolutionized the patient
specific stem-cell based therapy as recently          $1,654,058 Vision Loss
The clinical potential of human embryonic stem
cells (hESC) for transplantation will be realized
only when we can develop methods to control
the process of tissue differentiation far more
efficiently than is currently the case. From over
40 years of experience with adult stem cells, it is
recognized that the growth of transplanted bone
marrow is generated from the hematopoietic
("blood-forming") stem and progenitor cells
present in the graft. Mature, differentiated cells
that accompany the stem cells disappear rapidly
after transplantation as they lack the ability to
self renew. It is thus essential when designing
clinical approaches that use tissue derived from
hESC, to specifically target the production of stem
and progenitors that will survive, proliferate and
differentiate after transplantation. This proposal
addresses three fundamental questions for the
entire hESC field 1.Do hESC differentiate through
the same pathways that exist in adult tissues,
2.How do the conditions in which hESC are
initially derived from blastocysts affect their
subsequent potential for generating tissue
specific stem and progenitor cells, and 3.How can
hESC differentiation be regulated to provide large
numbers of tissue specific stem and progenitor        $2,551,088
Our research focuses on developing new tools
and models for the next generation of doctors
and scientists in all specialties of regenerative
medicine. The major obstacles in regenerative
medicine are the limited number of pre-existing
stem cells and the inability to regulate their
proliferation. Our aim is to identify the
mechanisms that regulate adult stem cell
proliferation. We propose to use this knowledge
to produce cell-permeable proteins to reactivate
proliferation in these dormant stem cells. These
engineered proteins could be used to stimulate
regeneration in a variety of organs without the
use of genetic vectors. As a model to study adult
stem cell quiescence and activation, we study the
hair follicle. The hair follicle is an organ that can
regenerate itself many times during a lifetime.
The mechanisms that regulate the cell cycle of
the hair stem cells are likely to function in other
adult stem cells. The products of this research will
be cell-permeable proteins that mimic the
activation of hair stem cells and could be applied
to other organ systems to induce regeneration.
These tools will be made available to the broader
stem cell community to determine the efficacy of        $3,231,649
Human ES cells can be used to make healthy
neurons to replace the cells that are lost in
neurological diseases such as Alzheimer                  $668,987
The genetic information contained in all human
cells is arranged into distinct territories or
"neighborhoods" with barriers or "fences" that
protect the action in one neighborhood from
spilling over into an adjacent region. In this way,
one gene (A) can be working while its neighboring
genes (B and C) are resting. As physiological
conditions change in the body, appropriate
signals are transmitted to cells that instruct genes
to alter their genetic "programming" by opening
or closing the fences. This allows gene A to be
turned off and genes B and C to start working.
Importantly, these "fences" can control large
numbers of genes that regulate critical cellular
processes. For example, a well-known fence
borders a chromosomal region containing genes
that encode oxygen-carrying hemoglobin. By
opening or closing this fence, hemoglobin
synthesis, and our oxygen carrying ability, can be
turned on or off. Many, as yet, unidentified
fences are likely to exist in our genetic material.
This proposal is designed to find the fence(s) that
border certain genes (Nanog-Stellar-GDF3) that
are important to maintain stem cells in their most
plastic state that is, having the ability to become     $678,788
Stem cell biology, since its inception 30 years ago,
has been hindered by our limited ability to
observe and direct the decisions of individual
stem cells. In the case of adult tissue-specific
stem cells, such as those from blood, muscle or
pancreas, the numbers available for clinical use
are extremely limited, as in tissue culture the cells
either have limited viability, do not divide, or
rapidly specialize and lose their stem cell
properties and potential to contribute to tissue
regeneration. To overcome this hurdle, over the
past three years we have been developing and
optimizing a novel technology that employs
arrays of bioengineered hydrogel microwells to
study the fate of single stem cells dynamically by
timelapse microscopy. This technology has
several distinct advantages: (1) The hydrogel
material is hydrated and substantially softer than
standard tissue culture plastic, which
substantially increases stem cell viability; (2) The
arrays consist of wells containing hundreds of
microwells so that single stem cells can be
monitored simultaneously, which is critical since
the stem population is inherently diverse; (3)
Finally, the hydrogels we developed can be              $949,608 Aging, Skeletal Muscle, Trauma
The goals of this proposal are to utilize cell
populations known to control immune reactions
termed regulatory T cells and study their ability
to protect embryonic stem cells (ESC) from
immune rejection. Much has been learned about
the control of immune reactions where it has
been found that a variety of different factors
control excessive and at times harmful immune
reactions. Clearly the localization of immune
responses, blood flow and both pro-inflammatory
and anti-inflammatory cytokines or proteins play
a major role in the control of immune reactions.
More recently has been the discovery that there
are specific populations of T cells, termed
regulatory T cells, that have the capability of
suppressing immune reactions which have
enormous potential in clinical medicine. In this
grant proposal, two distinct research groups with
complementary expertise will come together to
study this important problem. The laboratory of
[REDACTED] has studied regulatory T cell biology
in the setting of bone marrow transplantation
and translated key findings to the clinic. The
laboratory of [REDACTED] has studied ESC biology
and has demonstrated that ESCs will be rejected
in animal models. The goals of this research are    $1,427,980
Injuries to the spinal cord commonly result from
motor vehicle accidents, traumatic falls, diving,
surfing, skiing, and snowboarding accidents,
other forms of sports injuries, as well as from
gunshot injuries in victims of violent crimes.
Injuries to the anatomically lowest part of the
spinal cord, the lumbosacral portion and its
associated nerve roots commonly cause paralysis,
loss of sensation, severe pain, as well as loss of
bladder, bowel, and sexual function. Lumbosacral
injuries represent approximately one-fifth of all
traumatic lesions to the human spinal cord. As a
result of the direct injury to the lumbosacral
portion of the spinal cord, there is degeneration
and death of spinal cord nerve cells, which
control muscles in the legs as well as bladder,
bowel, and sexual function. No treatments are
presently available in clinical practice to reverse
the effects of these devastating injuries. In order
to reverse the loss of function after lumbosacral
spinal cord injury, replacement of the lost nerve
cells is required. Recent research studies have
identified some properties that are shared by
spinal cord neurons responsible for muscle and
bladder control. Human embryonic stem cells can       $1,614,441 Spinal Cord Injury
If the therapeutic potential of human embryonic
stem (ES) cells is to be realized, the ability to
produce pluripotent stem cells with defined
genetic backgrounds is essential. Pluripotent
cells, through differentiation, have the ability to
become any cell type. For basic and applied
research, access to human ES cells derived from
patients with specific diseases would be very
valuable. In a more therapeutic setting, the ability
to isolate differentiated cells from an individual
patient and reprogram these cells to a
pluripotent, stem-like state may ultimately lead
to truly personalized medicine. Thus, an
understanding of the genes that establish and
maintain the pluripotent state of human ES cells
is critical to future medical applications. The
overall goal of this research program is to
establish an experimental protocol to efficiently
reprogram differentiated human cells into a
pluripotent state. It has recently been shown that
the expression of only four genes in mouse
fibroblasts reprograms these cells to a pluripotent
state. We will pursue a similar strategy using
differentiated human cells. Importantly, we have
recently developed a new technology for
regulating protein expression in human cells, and      $647,681
The ability to dedifferentiate or reverse lineage-
committed cells to pluripotent/multipotent cells
might overcome many of the obstacles (e.g. cell
sources, immunocompatibility and bioethical
concerns) associated with using other ES and
adult stem cells in clinical applications. With an
efficient dedifferentiation process, it is
conceivable that healthy, abundant and easily
accessible somatic cells could be reprogrammed
to generate different types of functional cells for
the repair of damaged tissues and organs.
However, the cellular processes involved in
dedifferentiation remain poorly understood, and
methods for the control and study of
dedifferentiation to pluripotency in human
somatic cells are lacking. Reprogramming of
murine somatic cells in embryonic and adult
fibroblast cultures to pluripotent ESC-like cells
has recently been achieved by simultaneous viral
transduction of four transcription factors
together. With such proof-of-principle
demonstration, next critical steps would be to
“translate” such reprogramming methods into
human somatic cells and identify small molecules
that would allow temporal reversible treatment
to induce/enhance reprogramming without risks
of genetic manipulations. Here we propose to          $2,943,375
Our institution's long-standing Research
Mentorship Program is a hands-on program for
highly motivated high school students interested
in participating in academic research in a variety
of disciplines. During their six intensive weeks on
campus, participants learn to analyze papers and
write their own, evaluate research presentations
and present their own research in a culminating
symposium, and engage in aspects of on-going
research with [REDACTED] faculty or one of their
research team members as a mentor. Depending
on the nature of the project, lab hours may range
from 30 to 40 hours a week. In summer 2011,
CIRM funded a pilot program in stem cell
research within our Research Mentorship
Program and we would like to increase the
number of CIRM students from 6 to 10 and invite
more researchers from our 30 research faculty
who work in our Stem Cell Research Center to
mentor these interested students. The future of
stem cell research in the state depends on
successful recruitment of top people at all levels.
Active populations of aware and highly
knowledgeable pre-exposed bright thinkers can
predictably lead to a blossom of a generation of
workers and leaders who can be ready to push          $223,080
Retinoic acid is a metabolic derivative of vitamin
A that has recently been shown to stimulate
differentiation of human embryonic stem cells
into motor neurons. However, almost nothing is
known about how retinoic acid may perform this
function. The recent discovery that retinoic acid
antagonizes the action of fibroblast growth factor
suggests a possible mechanism for retinoic acid
function during motor neuron differentiation. We
plan to use our knowledge of retinoic acid-
fibroblast growth factor interaction to
understand how retinoic acid stimulates human
embryonic stem cells to go down the motor
neuron lineage. Such knowledge will allow us to
devise rational strategies for optimal use of
retinoic with other reagents to reliably
differentiate human embryonic stem cells into
motor neurons. Our studies will contribute to the
development of cell-replacement therapies for
motor neuron loss in patients with amyotrophic
lateral sclerosis or spinal cord injury. We plan to
study the effect of retinoic acid on differentiation
of human embryonic stem cell lines that are
ineligible for federal funding. Because all of the
human embryonic stem cell lines approved for
federal funding were generated using methods           $759,000
Advancing our understanding of stem cell biology
often relies on answers to the following types of
questions: What are the differences in gene
expression between a stem cell and the “mature”
cell (for example, a neuron or heart cell) made by
the stem cell? Answers to such questions can lead
to methods for directing stem cells to make
specific types of progeny. How similar are the
patterns of gene expression between a “normal”
cell and a stem cell-derived cell (for example, a
healthy neuron in the brain versus a neuron
made from an embryonic stem cell)? Answers to
these types of questions can determine exactly
how closely a stem cell-derived cell matches the
cell it is meant to replace. This information is
essential for developing safe and effective
therapies. To best answer these questions, it is
necessary to study gene expression in specific
cells within their normal setting. This presents a
technical hurdle, since the normal setting of a cell
is typically within a complex tissue, surrounded
by other cell types. To perform these types of
experiments using currently available tools, it is
necessary to first physically remove cells of
interest from all other cells. This type of            $483,803
Human embryonic stem cells (hESC) have the
remarkable capacity to replicate indefinitely and
differentiate into virtually any cell type in the
human body. Maintaining this pluripotent cell
state requires the precise control of hundreds, if
not thousands of proteins in the cells, a process
known as gene regulation. Recently it has been
shown that adult human cells can be induced to
revert back to earlier stages of development and
exhibit properties similar to hESCs. The exact
method for "reprogramming" is still being
optimized but currently requires inserting
multiple genes into adult cells and then exposing
them to the appropriate environment suitable for
hESC growth, to produce these "induced
pluripotent stem (iPS) cells". Generation of
patient-specific iPS cells will be of tremendous
benefit to disease-related biomedical research
and therapy. It is of interest that many of these
genes are hESC enriched or specific to pluripotent
stem cells, thus understanding the regulation of
genes important for pluripotency is of strong
benefit to reprogramming as well. Genes are
regulated at many different levels, beginning with
the production of RNAs in the nucleus
(transcription), and ending with the generation of   $1,376,802
The recent discovery of iPSC (induced Pluripotent
Stem Cell) technology marks a promising
breakthrough in regenerative medicine. The
beauty of the technology is its ability to convert
adult mature cells into embryonic stem cells
through the expression of a cocktail of essential
factor genes. Thus, iPSCs bypass the ethical
dilemma of using embryonic materials and eggs.
In addition, the creation of iPSCs for individual
patients using their own cells can avoid immune
rejection and achieve successful therapeutic
effects. Since its initial discovery, the method has
been used to generate patient-specific stem cells
for regenerative therapy and drug screening,
including Parkinson disease, sickle cell anemia,
Huntington disease and many other genetic
diseases. It is predicted that patients may
someday be treated with their own healthy
versions of stem cells. The technology of iPSC
induction, however, is in its infancy. Generation
of iPS cells depends on the synthesis of factor
proteins that regulate the developmental clock of
adult cells in order to return them to the
embryonic state. Viruses are a common approach
to deliver factor genes into the cell but they incur     $1,452,693
The life of every human starts with a fertilized
egg. This single cell starts to divide and, in a truly
amazing process, gives rise to a developed human
being. Although each cell of a developed
organism is a progeny of this single zygote, and
shares the same genetic information with every
other cell, cells differentiate to specialized forms
such as skin, muscle or nervous cells. Thus, new
information emerges during development, and is
inherited in a fashion that does not involve
changes in DNA sequence. This fascinating
process is called epigenesis. Epigenetic changes
underlie not only normal, but also pathological
development. Abnormal epigenesis contributes
to human pathology, such as aging, cancer,
degenerative diseases, developmental defects
and mental retardation. Embryonic stem cells
(ESCs) share with the early embryo the potential
to produce every type of cell in the human body.
This rare biological property is known as
pluripotency. Pluripotency is a unique epigenetic
state, in that ESCs can self-renew, while retaining
the potential for multilineage differentiation. The
research proposed here aims at elucidation of the
precise molecular nature of pluripotency. In the          $658,126
Like a thick frosting on a cake, complex sugar
chains decorate every surface of every cell. Try to
approach a cell, as friend or foe, and the canopy
of sugars is the first gate-keeper. Each cell makes
and organizes these sugar chains, called glycans,
on its surface. They are very complicated
molecules, and different cells choose to decorate
themselves with different glycans-- for reasons
best known to the cells themselves. Because
glycans have such complicated structures, it is
hard to work with them and understand their
function. They are much more diverse than DNA
and proteins, and so the technology for dissecting
their structures and functions has lagged behind
the others in the molecular revolution in biology
and medicine. Glycans are complicated
molecules, hard to work with, difficult to
understand, but they are absolutely
indispensable to life. Human genetic disorders
where just one step in their assembly is missing
causes mental retardation, seizures, blindness
and poor motor skills. Glycans are used for
communication both within and between cells,
and this is especially true when cells signal each
other about their past and future journeys within
the developing body and exactly where they will       $759,000

Stem cells are able to develop into most of the
specialized cells and tissues of the body and
therefore have the potential to replace diseased
cells with healthy functioning ones. It is the hope
of the scientific and medical communities that
the use of stem cell based therapies to treat
diseases such as Alzheimer                            $790,999
One of the key issues in stem cell transplant
biology is solving the problem of transplant
rejection. Despite over three decades of research
in human embryonic stem cells, little is known
about the factors governing immune system
tolerance to grafts derived from these cells. In
order for the promise of embryonic stem cell
transplantation for treatment of diseases to be
realized, focused efforts must be made to
overcome this formidable hurdle. Our proposal
will directly address this critically important issue
by investigating the importance of matching
immune system components known as human
leukocyte antigens (HLA). Because mouse and
human immune systems are fundamentally
different, we will establish cutting-edge mouse
models that have human immune systems as
suitable hosts within which to conduct our stem
cell brain transplant experiments. Such models
rely on immunocompromised mice as recipients
for human blood-derived stem cells. These mice
go on to develop a human immune system,
complete with HLAs, and can subsequently be
used to engraft embryonic stem cell-derived brain
cells that are either HLA matched or mismatched.
Due to our collective expertise in the central          $1,472,634
The research proposed in this project has very
high potential to identify new medications to
boost the natural ability of stem cells to prevent
rejection of transplanted organs. This is a very
important goal, because patients that receive a
life-saving transplanted organ must take toxic
medications that increase their risk for cancer
and serious infections. Experimental clinical trials
have recently shown that stem cells given to
patients at the same time as they receive their
transplanted organ can engraft in the patient and
prevent rejection of the transplanted organ,
without the need to take immunosuppressive
medications. The problem though is that the
stem cells don't last forever; they are eventually
rejected by the patient's own immune system. A
promising target to prevent rejection of stem
cells in patients is a group of primitive molecules
that are receptors on stem cells, as well as many
other cells in the body. These primitive receptors
are called innate immune receptors and they
provide the trigger for activation of a cascade of
mechanisms that lead to rejection of the stem
cells. If the trigger is not pulled, then the stem
cells will not be rejected. Therefore, our proposal
focuses on how to block activation of the              $1,746,684
Human embryonic stem cells (hESCs) hold great
potential for treating multiple human dread
diseases, including but not limited to cancer,
diabetes, obesity, Alzheimer disease, and certain
types of heart failure. However, a growing
appreciation exists for the notion that not all
hESCs have identical capabilities in correcting or
ameliorating disease and not all hESCs will be
valuable as potential therapeutic cell sources.
Because hESCs contain genetic information like all
human cells, some hESCs will have genetic
mutations or alterations that will make them
more or less desirable for therapy. The heritable
information contained with hESCs comes from
DNA in the cell nucleus and also from DNA within
maternally inherited mitochondria. In fact, it is
the functional capabilities of mitochondria in
hESCs that this proposal addresses because over
400 mutations in mitochondrial DNA result in
disease and many more disorders associated with
mitochondrial dysfunction, often unidentified at
the molecular level, arise from mutations in
nuclear DNA. It is potentially dangerous that so
little is known about the functional capabilities
and role for mitochondria in hESCs and in the
major decisions that hESCs make, such as             $635,024
Multipotent Neural Stem Cells (NSC) can be
derived from adult central nervous system (CNS)
tissue, embryonic stem cells (ESC), or iPSC and
provide a partially committed cell population that
has not exhibited evidence of tumorigenesis after
long term CNS transplantation. Transplantation of
NSC from these different sources has been shown
by multiple investigators in different CNS injury
and disease paradigms to promote recovery or
ameliorate disease. Additionally, both
{REDACTED} groups have shown that human NSCs
transplanted in the subacute period after spinal
cord injury promote functional recovery. While
the role of the host immune response has been
considered in the context of immune-rejection,
predominantly regarding the T-cell response, the
consequence of an ongoing inflammatory
response within the context of the tissue
microenvironment for cell fate, migration, and
integration/efficacy has been largely overlooked.
Critically, the tumorigeneis, fate, migration, and
integration/repair potential of a stem cell is
driven by: 1) the intrinsic properties of cell
programming, e.g., the type and source of cell /
means used to derive the cell, and                    $1,358,405 Spinal Cord Injury
The roles of stem cells are to generate the organs
of the body during development and to stand
ready to repair those organs through
repopulation after injury. In some cases these
properties are not correctly regulated and cells
with stem cell properties expand in number.
Recent work is demonstrating that the genes that
control stem cell properties are sometimes the
same genes that are mutated in cancer. This
means that a cell can simultaneously acquire
stem cell properties and cancer properties. In
order to effectively use stem cells for therapeutic
purposes we need to understand the link
between these two programs and devise ways to
access one program without turning on the other.
In other words, we would like to expand stem cell
populations without them turning into cancer.
Recent work in our laboratory has found that the
reduction of a specific tumor suppressor gene,
p16, not only removes an important barrier to
cancer but also confers stem cell properties
within the cell. Cells that have reduced p16
activity can turn on a program that increases and
reduces expression of specific genes that control
differentiation. In this proposal we will test         $639,150
Recent technical advancements in human
embryonic stem cell (ESC) and induced
pluripotent stem cell (iPSC) production have
revolutionized their potential applications in
regenerative medicine. However, a remaining big
hurdle in this process is the need for efficient,
effective, and stable generation of specific cell
types from such stem cells for therapeutic usage.
The ultimate goal of the proposed study is to
identify approaches to increase the production of
therapeutically useful blood cells from human
ESCs and patient-specific iPSCs. Currently, bone
marrow transplantation is the best way to cure
many blood-related disorders, such as sickle cell
anemia, thalassemia, and blood cancers like
leukemia. Furthermore, blood transfusion is an
effective way to rapidly counteract blood cell loss
due to ablative treatments, such as
chemotherapy and radiation therapy.
Unfortunately, the limiting factor in
transplantation and transfusion treatments is the
lack of matched donors. The ability to producing
unlimited numbers of blood stem cells and/or
functioning differentiated blood cells from human
ESCs and patient-derived iPSCs will greatly
improve the opportunity of such treatments. In        $1,371,540
Embryonic stem cells open up exciting new
prospects for medicine, because they can
differentiate into any tissue in the body.
Therefore, they have the potential to be used to
repair faulty tissues in diseases like diabetes,
heart disease, and neural disorders. Furthermore,
stem cells can be corrected by gene therapy and
transplanted, in order to treat a wide variety of
genetic diseases, such as sickle cell anemia.
However, embryonic stem cell research has been
difficult because of the technical and ethical
problems involved in obtaining these cells from
human embryos, as well as the need to transplant
cells that are immune-matched to the recipient
patient. The solution to these challenging
biological and ethical problems may emerge from
recent findings that show that cells that behave
like embryonic stem cells can be derived from
ordinary cells easily obtained from a patient, such
as skin cells. This process is known as
reprogramming. This breakthrough means that
embryos may no longer be required to generate
the stem cells needed for exciting new therapies.
However, the methodology that is currently used
to create reprogrammed cells involves                 $1,406,875
A Consortium for Stem Cell Internships in
Laboratory-based Learning was formed by faculty
and administrators from five institutions who
made a commitment to educate and train 30
students at the graduate level for careers in stem
cell biology, and to increase awareness about
scientific and societal issues related to stem cell
biology and regenerative medicine among non-
science majors. These two goals will be achieved
by means of a three-year CIRM Bridges to Stem
Cell Research Award. The lead University has a
strong tradition of educating a diverse student
population, and the Program Director heads a
department that offers the extensive classroom
graduate laboratory training, and operates two
nationally acclaimed graduate programs. The
Consortium for Stem Cell Internship program is
designed to equip students with a broad-based
understanding of stem cell biology through
classroom instruction and seminars, and in-
depth, laboratory-based expertise in a specialty
area unique to each student’s professional
development plan through a year-long internship.
More than 60 stem cell research investigators
from our consortium partner institutions are
committed to educating and training graduate          $3,614,907
We are proposing to optimize and scale up a
highly advanced (microfluidic) cell culture system
into manufacturable form. This system will allow
researchers to: 1.) Identify stem cell culture and
differentiation conditions 2.) Identify genes and
small molecules effecting stem cell self-renewal
and differentiation, and 3.) Identify genes and
small molecules involving or effecting
reprogramming of differentiated cells. ...much
more rapidly and efficiently than they have been
able to in the past. Reprogramming a patient's
own differentiated cells (e.g. skin cells) into stem
cells overcomes the ethical and immunological
barriers to theraputic usage which are present
with the use of embryonic stem cells. These stem
cells can be used in cell based therapy, tissue or
organ repair, and potentially even organ
reconstruction. Understanding what controls
stem cells to differentiate into a desired type of
cell helps directly in the development of
theraputic applications. Thus, this tool will help
both to determine conditions to convert
differentiated cells into stem cells, and to develop
therapies using the resulting stem cells.              $749,520
Embryonic stem cell-based therapies hold great
promise for the treatment of many human
diseases. These therapeutic strategies involve the
culture and manipulation of embryonic stem cells
grown outside the human body. Culture
conditions outside the human body can
encourage the development of changes to the
cells that facilitate rapid and sustained cell
growth. Some of these changes can resemble
abnormal changes that occur in cancer cells.
These include "epigenetic" changes, which are
changes in the structure of the packaging of the
DNA, as opposed to "genetic" changes, which are
changes in the DNA sequence. Cancer cells
frequently have abnormalities in one type of
epigenetic change, called "DNA methylation". We
have found that cultured embryonic stem cells
may be particularly prone to develop the type of
DNA methylation abnormalities seen in cancer
cells. A single rogue cell with DNA methylation
abnormalities predisposing the cell to malignancy
can jeopardize the life of the recipient of stem
cell therapy. We have developed highly sensitive
and accurate technology to detect DNA
methylation abnormalities in a single cell hidden      $685,000
This program will provide advanced laboratory
training in stem cell techniques for a total of ten,
high-achieving undergraduate and master’s
graduate students each year. This training will
expand the pool of personnel with the state-of-
the-art training necessary to undertake careers in
stem cell and regenerative medicine research.
Trainees will be recruited from existing and highly
successful science research preparation programs
that draw from the university’s diverse student
population and include students that might not
otherwise have the opportunity to acquire the
skills to succeed in a stem cell research lab. A new
curriculum at the home institution includes an
advanced stem cell lecture course, research
methods preparation, research seminars, and a
general education curriculum, which together will
enhance understanding of stem cell science
amongst trainees and the general university
population. After trainees take the stem cell
lecture course and research methods
preparation, they will take a short-course at a
shared research lab, which will be followed
directly by the focus of the program, a 12-month
internship experience at one of four local stem
cell research facilities. During the internship,       $3,597,177
The discovery of induced pluripotent stem (iPS)
cell technology promises to revolutionize our
understanding of human disease and to allow the
development of new cellular therapies for
regenerative medicine applications. The ability to
reprogram a patient's fibroblasts to iPS cells
creates the opportunity to expand human cells
with a specific genetic defect and to study that
defect in a defined cell population, either to
understand the basic biology of the disease or to
study potential therapeutics. Furthermore, the
genetic defects in iPS cells can be repaired and
the iPS cells used as a source for cellular therapies
after differentiation to specific cell lineages.
Although tremendous strides have been made in
recent years in treating human disease, replacing
damaged tissue remains almost completely
beyond our grasp. Harnessing human iPS stem
cells for this purpose will open completely new
areas of regenerative medicine. However, a
limited understanding of iPS cell self-renewal and
differentiation is a major roadblock in realizing
this long-term goal. One shared characteristic of
iPS cells and adult stem cells that reside in many
of our tissues is the ability to self-renew. Self-
renewal is the ability of a stem cell to divide and     $1,430,908
Human embryonic stem (ES) cells are a
remarkable cell type that are derived from a
group of cells called the inner cell mass (ICM) of a
very early stage embryo (about 100 cells in total)
obtained from in vitro fertilization program.
Human ES cells can be expanded in culture in an
undifferentiated state (self-renewal) without limit
while retaining the capacity to differentiate into
nearly any type of cell. Human ES cells offer an
important renewable resource for future cell
replacement therapies for many diseases such as
Parkinson                                                $663,209
We are a large, urban university serving a highly
diverse student population. We propose a new
stem cell biology training program for master’s-
level students in partnership with three leading
stem cell research institutions. We propose to
offer two new master’s-level specializations in
our Biology department to prepare students to
enter the stem cell workforce: a Masters of
Science in Cell and Molecular Biology with an
emphasis in Stem Cell Biology (the “MS program”)
in preparation for careers as senior researchers or
doctoral studies leading to faculty and research
science positions in stem cell biology; and a
Professional Science Masters with a
concentration in Stem Cell and Regenerative
Medicine (the “PSM program”) in preparation for
careers as laboratory technicians and research
associates. We will recruit and train 10 students
each year. Both programs involve core lecture
and laboratory courses in developmental,
molecular, and cell biology as well as bioethics
and scientific writing taught by faculty at our
institution who are experts in their field. PSM
students will also take business and
biotechnology courses while MS students will
begin the first six months of their internship in     $3,594,705

Human embryonic stem (hES) cells offer the
opportunity to be converted into replacement
tissues for diseased organs and provide cures for
diseases like Parkinson                               $4,316,515
The proposed summer internship will strengthen
the future of stem cell research in California by
providing California high school students the
exciting opportunity to delve into hands-on
research in various areas within stem cell biology.
Using a one-on-one direct mentorship model,
California students will be mentored by graduate
students, post-doctoral fellows and Faculty within
various research labs. Students will be trained on
the basics of the stem cell field through the
opportunity to attend a lecture series course in
stem cell biology. The students will have ample
opportunities to present their research through
an oral presentation, presentation at lab
meetings, as well as at a poster session. During
the summer, our goal for the students is to be
well trained in laboratory techniques and to
motivate them to continue their excitement for
stem cell and regenerative medicine research.
Participating students will disseminate their
excitement for regenerative medicine to their
families, classmates in high school, and local
communities. The discoveries that they make will
almost certainly be published in the top journals
in the field, further promoting stem cell research      $288,750
The objective of this study is to develop a new,
optimized technology to obtain a homogenous
population of midbrain dopaminergic (mDA)
neurons in a culture dish through neuronal
differentiation. Dopaminergic neurons of the
midbrain are the main source of dopamine in the
mammalian central nervous system. Their loss is
associated with one of the most prominent
human neurological disorders, Parkinson's
disease (PD). There is no cure for PD, or good long-
term therapeutics without deleterious side
effects. Therefore, there is a great need for novel
drugs and therapies to halt or reverse the
disease. Recent groundbreaking discoveries allow
us to use adult human skin cells, transduce them
with specific genes, and generate cells that
exhibit virtually all characteristics of embryonic
stem cells, termed induced pluripotent stem cells
(iPSCs). These cell lines, when derived from PD
patient skin cells, can be used as an experimental
pre-clinical model to study disease mechanisms
unique to PD. These cells will not only serve as an
"authentic" model for PD when further
differentiated into the specific dopaminergic
neurons, but that these cells are actually             $1,619,627 Parkinson's disease
Embryonic stem cells (ESC) originating from early
stage embryos are able to differentiate into any
type of cells in the body. The generation of ESC
lines from human embryos (hESC) has attracted a
lot of dispute among researchers, but raised the
hope that one day hESCs can be used in cell
replacement therapy for the treatment of
degenerative diseases and cancer. Substantial
efforts are currently focused on unveiling the full
potential of hESCs by developing culture systems
supporting the selective differentiation into the
cell types of interest. We have reported the
specific culture conditions that allow hESC
differentiation in the originator cells
(mesenchymal precursors) that form the bones,
cartilage and muscles in our body. Furthermore,
we then defined the conditions for selective
generation of skeletal muscle cells from the hESC-
derived mesenchymal precursors.
Transplantation of these muscle cells into the
limb muscle of immunodeficient mice showed
their ability to survive and integrate in the host’s
tissue. Muscular dystrophies (MD) are a group of
diseases affecting the muscles in our body. MD is
characterized by progressive muscle weakness           $1,623,064 Muscular Dystrophy
The goal of this proposal is to develop cell-based
therapies that lead to the better healing of
traumatic head injuries. Our first strategy will be
to use genetics and embryology in zebrafish to
identify factors that can convert human
embryonic stem cells into replacement skeleton
for the head and face. Remarkably, the genes and
mechanisms that control the development of the
head are nearly identical between fish and man.
As zebrafish develop rapidly and can be grown in
large numbers, a growing number of researchers
are using zebrafish to study how and when cells
decide to make a specific type of tissue – such as
muscle, neurons, and skeleton - in the vertebrate
embryo. Recently, we have isolated two new
zebrafish mutants that completely lack the head
skeleton. By studying these mutants, we hope to
identify the cellular origins and genes that make
head skeletal precursors in the embryo. These
genes will then be tested for their ability to drive
human embryonic stem cells along a head
skeletal lineage. Our second strategy will be to
test whether a population of cells, similar to the
one that makes the head skeleton in the embryo,
exists in the adult face. We have found that adult     $2,396,871 Bone or Cartilage Disease, Trauma
Pluripotent stem cells can give rise to any cell
type of the body and hold enormous promise for
regenerative medicine. Pluripotent stem cells,
such as embryonic stem (ES) cells, are derived
from very young human embryos. It is of great
interest to derive pluripotent stem cells from
adult cells. In this way, one could potentially
model in vitro genetic diseases that afflict
patients. In addition, cells derived from patient-
specific stem cells would not be rejected upon
transplantation back into the patient. A
methodology for generating induced pluripotent
stem (iPS) cells from adult cells has recently been
reported. It involves the forced activation of
specific genes in the adult cells. This method is
very recent: it was first reported in 2006 and only
six groups, including our lab, have to date
published work describing it. The published
literature documents how remarkably similar to
ES cells iPS cells are. However, they are not
identical, and a major difference is that ES cells
are derived from young embryonic cells, whereas
iPS cells are derived from older differentiated
cells. Furthermore, the method remains very
inefficient, has been used with a limited number      $1,307,201
The constant exposure of cells to endogenous
and exogenous agents that inflict DNA damage
requires active repair processes to eliminate
potentially mutagenic events in stem cells leading
to cancer. The same agents menace early human
embryos with DNA damage that can ultimately
lead to mutations, cancer, and birth defects. In
vitro, human embryonic stem cells (HESCs)
spontaneously undergo events leading to genetic
instability and mutations. All these three types of
genetic problems can have similar links to
malfunctions in DNA repair systems, but little
information now exists for HESCs. Therefore, the
first step in understanding the causes of HESC
genetic instability is to understand which DNA
repair systems are defective. We will investigate
the basis for this phenomenon in HESCs by
evaluating their capacity to either repair DNA or
form mutations. First, we will culture two HESC
lines and compare HESC repair and mutation
formation to that of control cells. We will use a
new technique which simplifies the production
and use of the feeder cells that support the
growth of the HESCs. We will also test the genetic
stability of HESCs grown on conventional feeder
cells, as well as those grown in feeder free          $357,978
This Bridges to Stem Cell Proposal will prepare
community college students, particularly
members of racial and ethnic minorities
underrepresented in the health sciences, to
obtain positions in the field of stem cell research
by providing them with hands-on laboratory
experience as well as academic instruction. A
second purpose is to encourage students to
pursue careers as stem cell scientists and thus,
continue their education until they have obtained
the required advanced degree. Selected students
will serve an internship in a collaborating
laboratory and will have the opportunity to work
alongside scientists and technicians as they
proceed through their experiments. Along with
honing their laboratory skills, students will
develop critical thinking skills and confidence in
their ability to work in today’s world of biological
science, which can be daunting when viewed
from the outside. Students will earn a special
certificate that will require that they complete
advanced training in working with stem cells and
participate in a course devoted to the scientific,
ethical and legal aspects of stem cell research,
along with their internship. Students will have the    $2,450,257
Heart failure is a leading cause of mortality in
California and the United States. Currently, there
are no "cures" for heart failure.Other life
threatening forms of heart disease include
dysfunction of cardiac pacemaker cells,
necessitating implantation of mechanical
pacemakers. Although mechanical pacemakers
can be efficacious, there are potential associated
problems, including infection, limited battery half-
life, and lack of responsiveness to normal
biological cues. Our research with human
embryonic stem cells will be aimed at developing
therapies for heart failure, and cardiac
pacemaker dysfunction. In each of these disease
settings, one might effect a "cure" by replacing
worn out or dysfunctional cardiac cells with new
ones. In the case of heart failure, the cells that
need to be replaced are heart muscle cells, which
do the majority of the work in the heart. In the
case of pacemaker dysfunction, the cells that
need to be replaced are pacemaker cells, a highly
specialized type of heart muscle cell. To replace
these cells, we need to find cells that can become
heart muscle or cardiac pacemaker cells,
understand how to generate fairly large numbers         $609,999 Heart Disease
Ischemia-induced paraplegia often combined
with a qualitatively defined increase in muscle
tone (i.e. spasticity and rigidity) is a serious
complication associated with a temporary aortic
cross-clamping ( a surgical procedure to repair an
aortic aneurysm). In addition to spinal ischemic
injury-induced spasticity and rigidity a significant
population of patients with traumatic spinal
injury develop a comparable qualitative deficit
i.e. debilitating muscle spasticity. At present there
are no effective treatment which would lead to a
permanent amelioration of spasticity and rigidity
and corresponding improvement in ambulatory
function. In recent studies, by using rat model of
spinal ischemic injury we have demonstrated that
spinal transplantation of rat or human neurons
leads to a clinically relevant improvement in
motor function and correlates with a long term
survival and maturation of grafted cells. More
recently we have demonstrated a comparable
maturation of human spinal precursors grafted
spinally in immunosupressed minipig. In the
proposed set of experiments we wish to
characterize a therapeutical potential of human
blastocyst-derived neuronal precursors when
grafted into previously ischemia- injured rat or        $2,445,716 Spinal Cord Injury
Heart failure affects 5 million patients in the U.S.,
representing the most common cause of hospital
admission and resulting in 300,000 deaths
annually. Despite aggressive treatment with
advanced pharmacotherapies and implantable
devices, the 5-year survival is only 50%. Cardiac
transplantation is limited to 2,000 patients per
year due to the lack of suitable donors.
Therefore, a strong mandate exists for novel
strategies to treat patients with end-stage heart
failure. Recent investigations support cell therapy
as a rational strategy to restore and regenerate
the injured myocardium. However, clinical studies
suggest that adult stem cell therapy provides only
limited efficacy. The {REDACTED} Cardiovascular
program has a distinguished history that includes
several firsts in transplantation and implantation:
the first human heart and heart-lung transplants
in the US and first human endovascular stent-
graft for aortic aneurysm. The {REDACTED}
Cardiovascular Regenerative Team follows this
tradition of translational research to focus on
efficient, integrated collaboration across multiple
disciplines within {REDACTED} and to accelerate
clinical implementation of innovative ideas by
fostering partnership between academia and              $55,000
This application proposes to continue, and
expand, our CIRM-funded integrated training and
research program in the fundamental biology of
embryonic stem cells, nuclear reprogramming,
tissue- and organ-specific stem cells and cancer
stem cells. We aim to produce the next
generation of leaders positioned to understand
basic stem cell mechanisms, develop relevant
human stem cell lines for investigation into
pathogenesis and treatment of diseases, and
provide the basis for development of new
molecular and cellular therapies. During the
previous funding period, the CIRM Training
program has been highly-successful and vital to
our stem cell efforts, providing valuable resources
for both Scholars and the greater community in
which they are educated. Our Program offers
outstanding opportunities for training
predoctoral, postdoctoral and clinical Scholars, in
stem cell biology, regenerative medicine, and
human disease. Because the School of Medicine,
Hospitals, and the University are situated on one
campus, our Program brings a powerful
combination of assets to this mission. Our faculty
have extensive experience in basic research,
clinical translation, and training in stem cell       $7,974,291
Stanford University is applying for three years of
funding to establish an integrated CIRM Scholar
training program in the fundamental biology of
embryonic and adult stem cells. We aim to
produce leaders who are positioned to
understand basic stem cell mechanisms and to
provide the fundamental and practical basis for
the development of novel molecular and cellular
therapies. We plan a 3 level Type I
comprehensive training program with
predoctoral (n=6), post-doctoral (n=5), and
clinical fellows (n=5), for 16 concurrent CIRM
Scholar positions. Stanford offers outstanding
opportunities for training both MD and PhD
predoctoral students, Ph.D. postdoctoral fellows,
and clinical fellows in stem cell biology,
regenerative medicine, and human disease. With
the School of Medicine, Stanford Hospitals, and
the University on one campus, Stanford brings a
powerful combination of assets to this mission. In
addition, Stanford faculty have extensive
experience in basic research, clinical translation,
and training in stem cell biology and medicine,
including leading discoveries in tissue and organ
stem cells, embryonic stem cells and cancer stem
cells. We propose an integrated program of            $3,733,707
This application will describe the depth and
breadth of our Stem Cell Programs in the "CIRM
Institute" category. We are requesting funds to
help with the construction costs for our Institute
of Stem Cell Biology and Regenerative Medicine,
a free-standing new building dedicated to our
Stem Cell Programs. Currently, our stem cell
program and our faculty are spread across
laboratories both on and off campus. Our
Institute represents a unique university-wide
collaboration that brings life, physical, and
engineering sciences together with leaders in
business, law, and education. Our stem cell
programs include all three elements in the RFA:
basic and discovery research (Element X), pre-
clinical research (Element Y), and pre-clinical and
clinical research (Element Z). The new building
will house faculty who were present prior to
launching our Institute of Stem Cell Biology and
Regenerative Medicine, new faculty that have
been recruited since 2002, and faculty who we
anticipate recruiting in the next five to ten years.
Our stem cell programs in Element X focus on
areas including embryonic stem cell biology,
reprogramming of adult somatic cells, tissue and
organ adult stem and progenitor cells, and cancer      $43,578,000
Retinal degeneration represents a group of
blinding diseases that are increasingly impacting
the health and well being of Californians. It is
estimated that by 2020, over 450,000 Californians
will suffer from vision loss or blindness due to the
age-related macular degeneration (AMD), the
most common cause of retinal degeneration
diseases in the elderly. AMD is a progressive
ocular disease of the part of the retina, called the
macula, which enables people to read, visualize
faces, and drive. The disease initially causes
distortion in central vision, and eventually leads
to legal blindness. A layer of cells at the back of
the eye called the retinal pigment epithelium
(RPE), provide support, protection, and nutrition
to the retinal photoreceptors (PR’s), light
sensitive rods and cones. The dysfunction and/or
loss of these RPE cells play a critical role in the
loss of the PR’s and hence the blindness in AMD.
Effective treatment could be achieved by proper
replacement of damaged RPE and retinal cells
with healthy ones. More specifically, the
regenerated and restored RPE layer would
prevent the irreversible loss of the PR’s. However,
the lack of a feasible approach to restore the RPE         $50,001
Retinal degeneration represents a group of
blinding diseases that are increasingly impacting
the health and well being of Californians. It is
estimated that by 2020, over 450,000 Californians
will suffer from vision loss or blindness due to the
age-related macular degeneration (AMD), the
most common cause of retinal degeneration
diseases in the elderly. AMD is a progressive
ocular disease of the part of the retina, called the
macula, which enables people to read, visualize
faces, and drive. The disease initially causes
distortion in central vision, and eventually leads
to legal blindness. A layer of cells at the back of
the eye called the retinal pigment epithelium
(RPE), provide support, protection, and nutrition
to the light sensitive cells of the retina; the
photoreceptors which consist of rods and cones .
The dysfunction and/or loss of these RPE cells
play a critical role in the loss of the PR's and
hence the blindness in AMD. Effective treatment
could be achieved by proper replacement of
damaged RPE and retinal cells with healthy ones.
More specifically, the regenerated and restored
RPE layer would prevent the irreversible loss of
the PR's. However, the lack of a feasible approach     $15,904,916 Vision Loss
The thymus is an organ that plays a key role in
controlling immune responses and immune
tolerance. The thymus promotes immune
tolerance by deleting and removing self-reactive T
cells from the immune system. In addition, the
thymus also helps drive the production of
important suppressor T cell populations like
regulatory T cells that also control immune
tolerance. Thus, strategies that expand and
improve thymic function could be critical in
improving transplantation of tissues derived from
embryonic stem cells. The thymus consists of a
supporting network of thymic epithelial cells that
help bone marrow derived T cell precursors
mature and differentiate into fully functional T
lymphocytes. Despite their importance, there has
been little progress in methods to grow and
expand out the supportive thymic epithelial
network. This project will explore strategies to
grow and expand out functional thymic epithelial
cells from human embryonic stem cells using a
multi-step culturing technique. These expanded
thymic epithelial cells will be characterized and
tested for the ability to support T cell
development and differentiation. Finally, the
expanded thymic epithelial cells will be put into    $1,314,090
The Human Immunodeficiency Virus (HIV) is still a
major health problem. In both developed and
underdeveloped nations, millions of people are
infected with this virus. HIV infects cells of the
immune system, becomes part of the cell's
genetic information, stays there for the rest of
the life of these cells, and uses these cells as a
factory to make more HIV. In this process, the
immune cells get destroyed. Soon a condition
called AIDS, the Acquired Immunodeficiency
Syndrome sets in where the immune system
cannot fight common infections. If left untreated,
death from severe infections occurs within 8 to
10 years. Although advances in treatment using
small molecule drugs have extended the life span
of HIV infected individuals, neither a cure for HIV
infection nor a well working vaccine could be
developed. Drug treatment is currently the only
option to keep HIV infected individuals alive.
Patients have to take a combination of drugs
daily and reliably for the rest of their lives. If not
taken regularly, HIV becomes resistant to the
drugs and continues to destroy immune cells.
What makes this situation even more
complicated is the fact that many patients cannot




                                                         $74,195 Blood, HIV/AIDS
Stem cell gene therapy for HIV may offer an
alternative treatment. Blood forming stem cells,
also called bone marrow stem cells make all
blood cells of the body, including immune system
cells such as T cells and macrophages that HIV
destroys. If "anti-HIV genes" were inserted into
the genetic information of bone marrow stem
cells, these genes would be passed on to all new
immune cells and make them resistant to HIV.
Anti-HIV gene containing immune cells can now
multiply in the presence of HIV and fight the
virus. In previous and current stem cell gene
therapy clinical trials for HIV, only one anti-HIV
gene has been used. Our approach, however, will
use a combination of three anti-HIV genes which
are much more potent. They will not only prevent
HIV from entering an immune cell but will also
prevent HIV from mutating, since it would have to
escape the anti-HIV effect of three genes, similar
to triple combination anti-HIV drug therapy. To
demonstrate safety and effectiveness of our
treatment, we will perform a clinical trial in HIV
lymphoma patients. In such patients, the
destruction of the immune system by HIV led to
the development of a cancer of the lymph nodes        $74,195 Blood, HIV/AIDS
Sickle cell disease (SCD), which results from an
inherited mutation in the hemoglobin gene that
causes red blood cells to “sickle” under
conditions of low oxygen, occurs with a frequency
of 1/500 African-Americans, and is also common
in Hispanic-Americans, who comprise up to 5% of
SCD patients in California. The median survival
based on 1991 national data was 42 years for
males and 48 years for females. Recent data
indicate that the median survival for {REDACTED}
California patients is only 36 years, suggesting
that serious problems regarding access to care
exist in this community. By twenty years of age,
about 15% of children with SCD suffer major
strokes and by 40 years of age, almost half of the
patients have had central nervous system
damage leading to significant cognitive
dysfunction. These patients suffer significant
damage to lungs and kidneys as well as severe
chronic pain that impacts on quality of life. While
current medical therapies for SCD can make a
significant difference in short-term effects, the
progressive deterioration in organ function
results in increased mortality and decreased
quality of life. Bone marrow transplant (BMT)         $33,110
Sickle cell disease (SCD), which results from an
inherited mutation in the hemoglobin gene that
causes red blood cells to "sickle" under conditions
of low oxygen, occurs with a frequency of 1/500
African-Americans, and is also common in
Hispanic-Americans, who comprise up to 5% of
SCD patients in California. The median survival
based on 1991 national data was 42 years for
males and 48 years for females. More recent data
indicate that the median survival for Southern
California patients with SCD is only 36 years,
suggesting that serious problems exist regarding
access to optimal medical care in this community.
By twenty years of age, about 15% of children
with SCD suffer major strokes and by 40 years of
age, almost half of the patients have had central
nervous system damage leading to significant
cognitive dysfunction. These patients suffer
recurrent damage to lungs and kidneys as well as
severe chronic pain that impacts on quality of life.
While current medical therapies for SCD can
make an important difference in short-term
effects, the progressive deterioration in organ
function results in compromised quality of life
and early deaths in ethnic populations who are         $9,212,365 Blood Disorders
The UC Davis Type I Stem Cell Training Program
establishes a collaborative training experience
dedicated to meeting the goals of the California
Institute of Regenerative Medicine (CIRM). The
overarching objective is to provide CIRM Scholars
with state-of-the-art multidisciplinary team
training to position them to become technically
skilled, critically thinking, and collaborative
scientists with successful independent research
careers in stem cell biology and medicine. The
training program will enroll pre-doctoral and post-
doctoral students and clinical fellows (16
trainees/year). A talented pool of applicants will
be selected from established graduate and clinical
training programs. A formal application process
overseen by an Internal Executive Committee is
described, including standardized selection
criteria. Faculty committed to the stem cell
training program will be drawn from the UC Davis
medicine, veterinary medicine, engineering,
biological sciences, agriculture and environmental
sciences, law, and management programs (13
lead mentors; 46 total mentors identified). CIRM
Scholars will participate in 1. structured
mentored research experiences; 2. core
curriculum including courses in basic research        $2,682,900
We propose a Type I training program in Stem
Cell Biology for eight predoctoral, four
postdoctoral, and four clinical CIRM Scholars, to
be administered by the Stem Cell Research Center
at the University of California, Irvine. Predoctoral
Scholars will enter the program at the end of
their first year in the Molecular Biology, Genetics
and Biochemistry (MBGB) graduate program, the
Interdepartmental Neurosciences Program (INP)
or other relevant PhD program at UCI. CIRM pre-
and postdoctoral Scholars will participate in
research training in the labs of UCI stem cell
mentors. The CIRM clinical Scholars will enter a
new track in our existing residency and a
subspecialty fellowship training program: after
completing two years of clinical training in a
specialty residency program and one year of
clinical training in subspecialty fellowship
program, the trainee will spend two years in basic
or translational stem cell research. All CIRM
Scholars will participate, during their first year of
support, in a year-long sequence of three new
courses: Basic Biology of Stem Cells; Clinical
Applications of Stem Cells; and Social, Legal and
Ethical Implications of Stem cell Research.             $2,039,845
To compete in today's global, high-tech economy,
we are becoming more dependent on workers
and leaders prepared in STEM fields. Engaging
high school students in STEM disciplines and
biomedical research is critical for our future. This
proposal seeks funding to expand our high school
summer internship program to include ten
participants who have a specific interest in stem
cell research. The program creates a dynamic and
stimulating educational and research
environment and inspires its participants to
choose STEM careers. It consists of an enriched
summer research experience, a mentorship with
our faculty and scientists, and coursework to
establish a framework for understanding the
scientific and ethical complexities of stem cell and
biomedical research. The objectives of the
program parallel the CIRM goals articulated in the
RFA solicitation. We seek to: (1) increase the
scientific knowledge of interns; (2) increase
scientific communication skills of interns; (3)
teach them to think critically about the theory
and application of biomedical research; and (4)
encourage a diverse population of students to
pursue careers in STEM fields. By providing this         $206,250
This project will test the effects of chemical
compounds similar to conventional pills for their
abilities to keep human embryonic stem cells
growing and multiplying in the laboratory or to
help them become one of the specialized types of
cells, like spinal cord cells, found in the human
body. Many of the substances currently used to
accomplish these goals come from animals or
animal cells. They carry a risk of transmitting
diseases or making the human cells display some
animal traits, either of which would make cells
derived from human stem cells useless for
transplantation and regenerative medicine. These
animal-derived substances can also be very
costly. Replacing these expensive materials will
be essential to the eventual development of
therapies for patients. These will be basic studies
using one of the already-approved human
embryonic stem cell lines. However, the
molecules that are prepared in this work and
discovered to have desirable properties should be
applicable to human embryonic stem cell lines
derived in the future by any technically and
ethically appropriate method. The project
therefore aims to discover new tools for
embryonic stem cell research that will be useful      $543,987

RNA interference is a naturally occurring means
to block the function of genes in our body. We
propose that RNA interference can be used to
block HIV-1 infection and its reproduction within
the body. When RNA interference is introduced
into a stem cell, its blocking activity will be
present throughout the lifetime of the stem cell,
theoretically the lifespan of a human being. Thus,
in theory an effective stem cell RNA interference
therapy will require only a single treatment as
opposed to the current lifetime administration of
anti-HIV-1 drugs often accompanied by serious
side effects. In nature, some individuals carry a
genetic mutation that renders them resistant to
HIV-1 infection. This mutation prevents HIV-1
from attaching to the white blood cells. One RNA
interference approach will be to mimic this
natural situation by blocking the activity of this
“co-receptor” within infected individuals by
creating a new blood system that carries the RNA
interference therapy. Other RNA interference
therapies will be directed against genes of HIV-1
itself.                                                $52,500
Duchenne muscular dystrophy (DMD) is the most
common and serious form of muscular dystrophy.
One out of every 3500 boys is born with the
disorder, and it is invariably fatal. Until recently,
there was little hope that the widespread muscle
degeneration that accompanies this disease could
be combated. However, stem cell therapy now
offers that hope. Like other degenerative
disorders, DMD is the result of loss of cells that
are needed for correct functioning of the body. In
the case of DMD, a vital muscle protein is
mutated, and its absence leads to progressive
degeneration of essentially all the muscles in the
body. To begin to approach a therapy for this
condition, we must provide a new supply of stem
cells that carry the missing protein that is lacking
in DMD. These cells must be delivered to the
body in such a way that they will engraft in the
muscles and produce new, healthy muscle tissue
on an ongoing basis. We now possess methods
whereby we can generate stem cells that can
become muscle cells out of adult cells from skin
or fat by a process known as "reprogramming".
Reprogramming is the addition of genes to a cell
that can dial the cell back to becoming a stem          $2,325,933 Muscular Dystrophy
The goal of our team is to capitalize on the
remarkable advances in stem cell biology to apply
those advances to the treatment of human
diseases, disorders, and injuries. We are planning
to develop and initiate a clinical trial that would
use stem cells for the treatment of muscular
dystrophies. This application of stem cell therapy
has the potential to benefit thousand of
individuals, adults and children alike, who have
one of the many different types of muscular
dystrophy. Moreover, the success of this clinical
trial would open the door for the possible use of
stem cells in a much wider range of muscle
disorders that afflict our population including the
treatment of muscle wasting that accompanies
prolonged bedrest, many chronic diseases such as
AIDS and cancer, and even the muscle loss that
accompanies normal aging. Additionally, because
we have the advantage of a unique opportunity
to study stem cell therapeutics in these well-
defined muscular dystrophies, the technological
advances that will accompany these studies will
likely be applicable to the use of stem cells for the
treatment of diverse chronic and degenerative
conditions of other solid tissues such as the heart,      $52,650
Type 1 Diabetes (T1D) occurs as a consequence of
uncontrolled immune activation, culminating in
the destruction of insulin-producing beta-cells.
Efforts to prevent or reverse diabetes have been
limited by the lack of safe and effective
immunotherapies coupled with the inability to
restore insulin producing beta-cells. We believe
proper immune control to self-tissues to be a
fundamental requirement for any effective
therapy, whether the goal is prevention of early
beta-cell loss, beta-cell regeneration at disease
onset, or ultimately beta-cell replacement in
cases of established T1D. To impact disease, any
effective therapy must first restore a glucose-
responsive insulin-producing beta-cell population.
Stem cells represent one of the most promising
alternative sources of insulin-producing cells.
Second, a therapy must combat the persistent
autoimmune attack, as well as any attack
directed at foreign tissues following
transplantation. The goal of this project is to
bring together research efforts in these two
complementary areas to fill these critical gaps.
Previous studies have focused on the use of
regulatory T cells (Tregs) as one key means of
restoring immune tolerance in T1D. A key             $1,152,768
The goal of this Bridges to Stem Cell Research
program is to produce students that are capable
of carrying out independent research projects
and can easily integrate into existing stem cell
research groups. The proposed program will train
30 undergraduate students in 3 cohorts over 3
years. Selected students will participate in a
rigorous curriculum at the home institution that
will provide both the conceptual basis for
understanding stem cells and a working
knowledge of techniques in stem cell research. An
established stem cell laboratory course at the
home institution will provide students with 16
weeks of hands-on technical experience with
stem cells. Students will also complete 6 months
of independent research on a stem cell-related
project in one of four research laboratories at the
home institution prior to their internship at a
host institution. Students will become acquainted
with the ongoing research in many stem cell
laboratories at the host institutions through
discussions of scientific articles published from
these labs. The combination of classroom work
and 6 months of research experience at the home
institution will facilitate rapid assimilation of the
intern into ongoing projects at the host                $2,710,703
Modified viruses can be used to infect tumor cells
and alter the tumor cell to make anti-tumor
proteins. Most researchers use virus that can
infect and modify the tumor cell it enters, but can
not make more of itself to infect additional cells
surrounding the original infected cell. This type of
virus is called replication-incompetent virus. Use
of replication-incompetent virus is considered
safe because no additional virus, which
potentially could get out of control, is generated
inside of the tumor. However such therapies have
been shown to have only limited beneficial
effects, presumably because too many tumor
cells never get infected. Newer approaches
investigate the use of replication-competent
viruses to achieve highly efficient gene transfer to
tumors. A successfully transduced tumor cell
itself becomes a virus-producing cell, sustaining
further transduction events even after initial
administration. We propose here to use a type of
replication-competent virus that only infects
dividing cells and therefore will infect the rapidly
dividing cancer cells but not normal brain cells.
The use of replication-competent virus is
potentially more risky but is well justified in         $3,370,607 Brain
Arthritis is the result of degeneration of cartilage
(the tissue lining the joints) and leads to pain and
limitation of function. Arthritis and other
rheumatic diseases are among the most common
of all health conditions and are the number one
cause of disability in the United States. The
annual economic impact of arthritis in the U.S. is
estimated at over $120 billion, representing more
than 2% of the gross domestic product. The
prevalence of arthritic conditions is also expected
to increase as the population increases and ages
in the coming decades. Current treatment
options for osteoarthritis is limited to pain
reduction and joint replacement surgery. Stem
cells have tremendous potential for treating
disease and replacing or regenerating the
diseased tissue. This grant proposal will be
valuable in weighing options for using stems cells
in arthritis. It is very important to know the effect
of aging on stems cells and how stem cell
replacement might effectively treat the causes of
osteoarthritis. We will establish conditions for
stem cells to repair a surgical defect in laboratory
models and test efficacy in animal models of
cartilage defects. We will demonstrate that stem        $3,118,431 Arthritis, Bone or Cartilage Disease
Amyotrophic lateral sclerosis (ALS), a lethal
disease lacking effective treatments, is
characterized by the loss of upper and lower
motor neurons. 5-10% of ALS is familial, but the
majority of ALS cases are sporadic with unknown
causes. The lifetime risk is approximately 1 in
2000. This corresponds to ~30,000 affected
individuals in the United States and ~5000 in the
Collaborative Funding Partner country. There is
currently only one FDA-approved compound,
Rilutek, that extends lifespan by a maximum of
three months. Although the causes of ALS are
unknown and the presentation of the disease
highly variable, common to all forms of ALS is the
significant loss of motor neurons leading to
muscle weakness, paralysis, respiratory failure
and ultimately death. It is likely that many
pathways are affected in the disease and focusing
on a single pathway may have limited impact on
survival. In addition, as ALS is diagnosed at a time
that significant cell loss has occurred, an attempt
to spare further cell loss would have significant
impact on survival. Several findings support the
approach of glial (cells surrounding the motor
neurons) transplants. Despite the relative             $10,857,762 Amyotrophic Lateral Sclerosis
Brain tumors (BTs) are incurable, whether they
start in the brain or spread there from other sites.
Despite advances in surgical, radiation,
pharmacologic, and gene therapies, survival with
a BT remains dismal. Current therapies are
limited by their inability to reach widely
disseminated tumor cells that become dispersed
within normal brain structures. Interestingly, the
therapeutic property that is needed to overcome
this major obstacle to effective treatment of BTs
matches well with one of the better accepted
attributes of neural stem cells (NSCs): an
attraction for sites of pathology in the adult
brain, including primary & metastatic cancer. If
armed with a proper tumor-killing gene, NSCs
(whether administered into the brain or into the
bloodstream), that are drawn to cancers, will
dramatically reduce tumor burden, and will track
after even single migrating tumor cells. The NSCs
perform this action without themselves becoming
tumorigenic or augmenting the pre-existing
tumor, and this can be assured by having NSCs
express a suicide gene that can be activated and
cause NSCs to die. The tumor homing
phenomenon of NSCs was first revealed by               $19,162,435 Brain
Brain tumors (BTs) are incurable, whether they
start in the brain or spread there from other sites
(e.g., lung, colon, breast, skin). Indeed, the latter
situation is even more common & often more
frustrating – although we’ve made inroads in
treating such non-neural cancers, once brain
metastases are discovered, hope is largely
abandoned. Current therapies are limited by their
inability to reach widely disseminated tumor cells
that become insinuated within normal brain
structures. Despite advances in surgical,
radiation, pharmacologic, & gene therapies,
survival with a BT remains dismal. Interestingly,
the property that might circumvent this major
obstacle to therapy – i.e., delivery of therapeutic
molecules to the cells that need to be eliminated -
- matches one of the better accepted attributes
of the neural stem cell (NSC) – an attraction (over
even great distances) for sites of pathology in the
adult brain, including primary & metastatic
cancer. If armed with a proper tumor-killing gene,
the NSCs (whether administered into the brain or
into the bloodstream), when drawn to these
cancers, will dramatically reduce the tumor
burden, including even single invading tumor            $55,000
Despite aggressive multimodal therapy and
advances in imaging, surgical and radiation
techniques, malignant brain tumors (high-grade
gliomas) remain incurable, with survival often
measured in months. Treatment failure is largely
attributable to the diffuse and invasive nature of
these brain tumor cells, ineffective delivery of
chemotherapeutic agents to tumor sites, and
toxic side-effects to the body, which limits the
dose of drug that can be given. Therefore, new
tumor-selective therapies are critically needed.
Neural stem cells (NSCs) offer an unprecedented
advantage over conventional treatment
approaches because of their unique ability to
target tumor cells throughout the brain. This
ability allows NSCs to be used to deliver prodrug-
activating enzymes to tumors, where these
enzymes will generate high concentrations of
powerful anti-cancer agents selectively at tumor
sites. We will use an established human NSC line
to develop a novel NSC-based product to deliver
the enzyme carboxylesterase (CE), which will
activate a systemically administered prodrug, CPT-
11, to a powerful chemotherapeutic agent, SN-
38, selectively at tumor sites, destroying invasive
glioma cells while sparing normal tissues. Based      $18,015,429 Brain
This proposal will define the biology of stem cell
engineering to produce a cancer-fighting immune
system. The immune system protects our body
against most outside threats. However, it
frequently fails to protect us from cancer. The T
cell receptor (or TCR), a complex protein on the
surface of an immune cell (or lymphocyte), allows
to specifically recognize cancer cells. The TCR
functions like a steering wheel for lymphocytes,
allowing them to travel around the body and
specifically find and attack cancercells. The goal
of this research is to put TCR genes into stem cells
to generate a renewable source of cancer-fighting
lymphocytes. The studies in mice provide
compelling evidence that inserting TCR genes into
stem cells has several advantages for the progeny
lymphocytes, allowing them to better fight
cancer. The next step is to bring this approach to
patients with cancer. The main reason is that the
TCR genes inserted into stem cells allow the
generation of a larger army of TCR re-directed
cancer-fighting killer lymphocytes. I have
dedicated most of my prior work to make the
transition from studies in mice to the bedside. I
have gaind the expertise to conduct clinical trials     $3,247,000 Melanoma
The targeted disease is retinitis pigmentosa (RP),
a severe form of blindness that runs in families.
This disease is not common, yet represents an
attractive near term target for stem cell therapy
for a number of reasons: 1) RP destroys the light
detecting cells of the retina but generally leaves
the rest of the visual system and body unharmed,
so the clinical goal is circumscribed; 2) RP is
prototypical of degenerations of the nervous
system, so a cure for this less common disease
would accelerate progress towards new therapies
for a range of more familiar conditions; 3)
scientific research has shown that the rods and
cones can be spared in animals by either
delivering molecules known as growth factors or
by transplanting particular types of stem cells, so
the scientific feasibility of treating RP has already
been established in principle. The therapeutic
approach is to save the light sensing cells of the
eye using modified stem cells. The problem with
the molecules (“growth factors”) that are capable
of saving the light detecting cells (rods and cones)
is that they are rapidly degraded in the body, so a
method of long term delivery in needed. Stem
cells can be genetically modified to manufacture          $37,367
Lung cancer is the most deadly cancer worldwide
and accounts for more deaths than prostate
cancer, breast cancer and colon cancer
combined. Non small cell lung cancer (NSCLC)
accounts for about 85% of all lung cancers. The
current 5-year survival rate for all stages of NSCLC
is only 15%. Although early stage lung cancer has
a much better survival rate. Current therapeutic
strategies of chemotherapy, radiation therapy
and trials with new targeted therapies have only
demonstrated, at best, extension in survival by a
few months. Clearly, a novel approach is required
to develop new therapies for this devastating
disease and to detect the disease at an early
stage. Cancer stem cells have been identified as
the initial cell in the formation of carcinomas.
Chemotherapy, radiation and even targeted
therapies are all designed to eliminate dividing
cells. However, cancer stem cells “hide out” in the
quiescent phase of growth. This provides an
explanation as to why our cancer therapies may
produce an initial response but are often
unsuccessful in curing patients. Lung cancer
develops through a series of step wise changes
that result in the progression of pre-malignant        $2,556,572 Lung
This project aims to use a powerful combined
stem cell and gene therapy approach to treat
patients with amyotrophic lateral sclerosis (ALS or
Lou Gehrig's Disease). ALS is a devastating disease
for which there is no treatment or cure.
Progression from early muscle twitches to
complete paralysis and death usually happens
within 4 years. Every 90 minutes someone is
diagnosed with ALS in the USA, and every 90
minutes someone dies from ALS. In California the
death rate is one person every one and a half
days.
Stem cells have been shown to produce support
cells for dying motor neurons called astrocytes
which may slow down disease progression.
Furthermore, many studies have shown that
growth factors such as glial cell line-derived
growth factor (or GDNF) can protect motor
neurons from damage in a number of different
animal models including those for ALS. However,
delivering GDNF to the spinal cord has been
almost impossible as it does not cross from the
blood to the brain tissue. The idea behind the
current proposal is to modify stem cells to
produce GDNF and then transplant these cells
into patients. A number of advances in human
stem cell biology along with new surgical
approaches has allowed us to put together this
disease team approach - a first in man study to
deliver cells modified to release a powerful
growth factor that are expected to slow down the
death of motor neurons and paralysis in patients.



The focus of the proposal will be to perform
essential preclinical studies in both small and
large animals that will establish optimal doses
and safe procedures for translating this stem cell
and gene therapy into human patients. The Phase
1 clinical study will include 30 ALS patients from
the state of California. This will be the first time
this type of stem cell and gene therapy has been
available to any ALS patients in the world.            $89,834 Amyotrophic Lateral Sclerosis
The applicant institution will partner with a CIRM
Shared Research Laboratory to create a
comprehensive curricular program that will
produce 30 masters degree graduates with the
scientific foundation, research experience,
practical laboratory skills and motivation to
pursue careers in stem cell research. Graduates of
the masters program will develop knowledge and
skills suitable for basic research as well as its
translation into clinical applications for patients.
Graduates will help fill the future demand for
laboratory managers and other research-support
professionals in a growing number of laboratories
devoted to stem cell research. Rather than a
traditional, independent master’s thesis project,
students engage in activities specifically intended
to improve the professional preparation of
graduates desiring industry or laboratory careers
in applied biosciences. The masters program
builds upon curricular strengths in cellular and
molecular biology at the applicant institution and
the outstanding research facilities of the CIRM
Shared Research Laboratory. The twenty-month
program of study consists of graduate courses
taken at the applicant institution and an
internship at the CIRM Shared Research Facility.       $2,773,463
Stem cells, including human embryonic stem
cells, provide extraordinary new opportunities to
model human diseases and may serve as
platforms for drug screening and validation.
Especially with the ever-improving effective and
safe methodologies to produce genetically
identical human induced pluripotent stem cells
(iPSCs), increasing number of patient-specific
iPSCs will be generated, which will enormously
facilitate the disease modeling process. Also given
the advancement in human genetics in defining
human genetic mutations for various disorders, it
is becoming possible that one can quickly start
with discovery of disease-related genetic
mutations to produce patient-specific iPSCs,
which can then be differentiated into the right
cell type to model for the disease in vitro,
followed by setting up the drug screening
paradigms using such disease highly relevant
cells. In the context of neurological disorders,
both synaptic transmission and gene expression
can be combined for phenotyping and phenotypic
reversal screening and in vitro functional
(synaptic transmission) reversal validation. The
missing gap for starting with the genetic mutation
to pave the way to drug discovery and                 $1,382,400 Autism, Rett's Syndrome
One in every ten thousand people in the USA
have Huntington's Disease, and it impacts many
more. Multiple generations within a family can
inherit the disease, resulting in escalating health
care costs and draining family resources. This
highly devastating and fatal disease touches all
races and socioeconomic levels, and there are
currently no cures. Screening for the mutant HD
gene is available, but the at-risk children of an
affected parent often do not wish to be tested
since there are currently no early prevention
strategies or effective treatments. HD is a
challenging disease to treat. Not only do the
affected, dying neurons need to be salvaged or
replaced, but also the levels of the toxic mutant
protein must be diminished to prevent further
neural damage and to halt progression of the
movement disorders and physical and mental
decline that is associated with HD. Our
application is focused on developing a safe and
effective therapeutic strategy to reduce levels of
the harmful mutant protein in damaged or at-risk
neurons. We are using an RNA interference
strategy                                               $2,753,559 Huntington's Disease
There is a critical need for new technologies to
facilitate growth and differentiation of human
embryonic stem cells (hESC) using clinically
acceptable, animal-free reagents. In particular,
most currently used culture conditions are not
acceptable for standardized production of clinical
grade cell products. We propose to develop
novel, well-defined, synthetic extracellular
matrices for growth and differentiation of hESC.
Our approach is to first understand how hESC
interact with extracellular matrix materials by
analyzing candidate adhesive substrate proteins
and integrin receptors that mediate attachment,
survival, proliferation and differentiation.
Biomimetic, synthetic matrices will be developed,
with components and strategies informed by our
knowledge of fundamental cell biology. We have
established an active, interdisciplinary
collaboration between experts in cell biology,
stem cell culture, peptide chemistry and materials
research. Preliminary data have identified crucial
receptors that mediate adhesion and survival of
hESC. As proof of concept, novel, biocompatible
hydrogel polymers have been developed and
analyzed for physical properties, cellular toxicity,    $599,998
Vertebral compression fractures are the most
common fractures associated with osteoporosis.
Approximately 700,000 osteoporosis-related
vertebral compression fractures (OVCFs) occur
each year in the US. Currently, treatment is
focused primarily on prevention. When fractures
occur in patients with osteoporosis, treatment
options are limited because open surgery with
implants often fails. Recently, new therapies
involving injection of cement into the vertebral
body were developed. Unfortunately, these
procedures do not regenerate bone tissue, but do
incur risks of leakage and emboli. Hence, we need
new treatments that directly address both the
underlying cause of OVCFs (bone loss) and the
inadequate repair mechanisms when fractures
occur. We propose to develop a therapy that
exploits mesenchymal stem cells (MSCs)
stimulated in vivo with PTH (parathyroid
hormone) to accelerate bone repair. PTH alone
can accelerate fracture repair in healthy animals
by activating bone marrow MSCs. However,
osteoporotic patients have either decreased
numbers of MSCs, dysfunctional MSCs, or both. In
these patients, injection of MSCs combined with a
PTH regimen could be an effective therapy for the     $1,927,698 Bone or Cartilage Disease
Approaches to repair the injured brain or even
prevent age-related neurodegeneration are in
their infancy but there is growing interest in the
role of neural stem cells in these conditions.
Indeed, there is hope that some day stem cells
can be used for the treatment of spinal cord
injury, stroke, or Parkinson's disease and stem
cells are even mentioned in the public with
respect to Alzheimer's disease. To utilize stem
cells for these conditions and, equally important
to avoid potential adverse events in premature
clinical trials, we need to understand the
environment that supports and controls neural
stem cell survival, proliferation, and functional
integration into the brain. This "neurogenic"
environment is controlled by local cues in the
neurogenic niche, by cell-intrinsic factors, and by
soluble factors which can act as mitogens or
inhibitory factors potentially over longer
distances. While some of these factors are
starting to be identified very little is known why
neurogenesis decreases so dramatically with age
and what factors might mediate these changes.
Because exercise or diet can increase stem cell       $1,522,800
The rapid progress of embryonic stem cell,
induced-pluripotent cell, and adult stem cell
research opens the door to thousands of
promising, new medical applications and
discoveries. However, one of the major obstacles
in translating these basic science discoveries into
safe therapies for patients is the risk of acquiring
mutations from viral and DNA vectors. Exposure
of stem cells to DNA vector can result in
integration of the DNA element into the
chromosome of the stem cell and thereby
potentially induce a malignant mutation.
Consequently, to clinically develop stem cell
therapies, there is a great need to develop
reagents and protocols that do not expose the
stem cells to DNA vectors. Over the last 10+ years
our lab has developed small domains from
proteins called cell-permeable peptides or
peptide transduction domains (PTDs) that enter
cells, including embryonic stem cells and non-
dividing adult stem cells, in a non-cytotoxic
manner that is independent of exposing the stem
cells to DNA vectors. We have generated over 50
transducible proteins that enter the entire
population of all cell types tested, including          $925,200
Despite the enormous potential for human
embryonic stem cells (hESCs) and human induced
pluripotent stem cells (hiPSCs) for development
of new treatments for human disease, there still
remain important gaps in our knowledge about
the molecular mechanisms regulating
establishment and maintenance of the
pluripotent state. Improved understanding of
fundamental mechanisms regulating pluripotency
could improve the ability to establish pluripotent
stem cells, in understanding how to maintain
them in the undifferentiated state and how to
differentiate them into specific cell lineages. The
research proposed here seeks to provide a
fundamentally better understanding of
pluripotency and how it is controlled in hES cells
and closely related iPCs. Maintenance of stem
cells is known to be controlled by a group of core
proteins that keep them in an undifferentiated
state. When these proteins are downregulated
they undergo differentiation into specialized cell
types. Little is known about how the master
regulatory circuitry is regulated other than
feedforward positive interaction between the
three core regulatory factors. Here we propose to      $1,277,101
Stem cells therapies hold great promise in the
treatment of cardiac diseases such as coronary
heart disease or congestive heart failure. Thanks
to their ability to transform into almost any kind
of tissue, engrafted stem cells can potentially
replace damaged heart tissues with healthy
tissues, effectively restoring the heart              $634,287 Heart Disease
The successful use of human embryonic stem
cells (hESCs) as novel regenerative therapies for a
spectrum of currently incurable diseases critically
depends upon the safety of such cell transfers.
hESCs contain roughly 3 million "jumping genes"
or mobile genetic retroelements that comprise up
to 45% of their genetic material. While many of
these retroelements have been permanently
silenced during evolution by crippling mutations,
many remain active and capable of moving to
new chromosomal locations potentially
producing disease-causing mutations or cancer.
More mature differentiated cells control
retroelement movement (retrotransposition) by
methylating the DNA comprising these elements.
Strikingly, such DNA methylation is largely absent
in hESCs because these cells must be able to
develop into a wide spectrum of different tissues
and organs. Thus, in order to protect the integrity
of their genomes, hESCs must deploy an
additional defense to limit retroelement
retrotransposition. Recent studies of HIV and
other exogenous retroviruses have identified the
APOBEC3 family of genes (A3A-A3H) as powerful
anti-retroviral factors. These APOBEC3s interrupt
the conversion of viral RNA into DNA (reverse
transcription), a key step also used by               $777,467
Investigators from three major regional research
and clinical institutions have instituted a stem cell
research center. Numerous collaborations among
our community of investigators have successfully
utilized both Federal registry and non-registry
human embryonic stem cell (hESC) lines in the
center; however, the available resources for the
culture and maintenance of these lines place
inherent limitations on the research. We
therefore propose to establish a Human
Embryonic Stem Cell (hESC) Shared Research
Laboratory for cell culture and investigation,
which will serve as a central resource to greatly
enhance stem cell science and technology in the
region. This resource will greatly benefit
numerous ongoing research project areas. First,
the ability of human embryonic stem cells to self-
renew, that is grow and maintain their ability to
differentiate into presumably every cell type in
the adult body, is a hallmark property this is
incompletely understood. Investigations of self-
renewal mechanisms will lead to improved
approaches to mass produce these cells for
numerous therapeutic and diagnostic
applications. In addition, understanding how
hESCs differentiate into blood cells will enhance       $2,929,237
Our institution is a tertiary-care academic
pediatric medical center that combines care of
severely ill children, research into the causes and
treatments of childhood disorders, and training of
the next generation of pediatric clinical
physicians, nurses and allied health care
professionals and biomedical scientists. A unique
focus of the research in our institution is on
applications to pediatric disorders such as
diabetes, inherited disorders (cystic fibrosis,
muscular dystrophy, sickle cell disease, etc),
cancer and congenital birth defects. It is our
central hypothesis that childhood disorders will
be especially responsive to therapies produced by
the use of stem cells; advances in the use of stem
cells to treat childhood illnesses will then lead the
way to treatments for the many disorders that
occur later in life. For over a decade, the Stem
Cell Program at our institution has been at the
leading edge of translational research for cell and
gene therapy and tissue engineering, with
outstanding research programs in stem cells,
gene therapy, developmental biology,
organogenesis and transplantation immunology.
Active research programs studying adult stem            $3,756,666


In therapeutic cloning, a patient                       $2,530,000
Human embryonic stem cells (hESC) have an
inexhaustible ability to divide and renew, and
under the appropriate conditions, differentiate
and change into any cell type in the body. This
balance between pluripotency and self-renewal is
a complex and carefully choreographed response
of the hESC to local microenvironmental cues.
Understanding the molecular regulators of this
balance, and the various signals that are
integrated by hESC to maintain their pluripotency
and self-renewal characteristics are critical for the
expansion and differentiation of hESC to specific
cell types, which is the ultimate goal of
regenerative medicine. EphrinB2 and ephB4
belong to a large family of cell surface signaling
molecules, so called receptor tyrosine kinases
(RTKs), that mediate and transduce signaling
cascades upon interaction with each other. Cell-
cell contacts between ephrinB2 and ephB4
expressing cells provide guidance cues for cell
migration and boundary formation in many
developmental systems such as the formation of
neurons and blood vessels. Importantly, ephrinB2
has been determined to be a molecular marker of
"stemness" and is expressed in human embryonic
stem cells, neural stem cells and hematopoietic         $1,371,936
Embryonic stem cells have the potential to
generate all tissue types that could be used for
regenerative medicine, such as replacement of
damaged neurons, replenish of insulin secreting
beta cells, or generation of blood cells. The
discovery of in vitro reprogramming of somatic
cells (normal cells in our body) into induced
pluripotent stem cells (iPS, which has the
potential to differentiate into many different cell
types) offers an exciting reality that patient
specific pluripotent stem cells could be obtained.
Cells derived from patient specific iPS cells would
less likely to cause immune rejection when
transplanted back into the patient. The rapid
progresses in stem cell research make
regenerative medicine from scientific fiction close
to medical reality. However, many key issues,
such as the efficiency of iPS induction and
efficiency of stem cell differentiation in vitro
(outside of our body), remain to be resolved
before stem cell therapy becomes a routine
medical practice. YAP is a transcription co-
activator, which can help certain transcription
factors to stimulate gene expression. Previous
studies have shown that elevated YAP activity         $1,340,565
The CIRM Shared Human Embryonic Stem Cell
Core Laboratory will provide shared research
facilities for use by California scientists. This
laboratory will be hosted by a research institution
focused on basic research into three of the most
important medical problems of modern times:
cardiovascular disease, AIDS, and
neurodegenerative disorders. Each of these
research areas addresses promising targets for
regenerative medicine. We propose to develop a
laboratory (1108 sq ft) for hESC tissue culture
with specialized microscopy, and an animal
holding and procedure space (500 sq ft) for in
vivo pre-clinical studies of hESCs in mouse models
of disease. The proposed laboratory will also help
to train students from a nearby college be
become laboratory technicians. This facility will
contain advanced equipment for analyses of
hESCs and complement existing space and
incorporate hESC work provided by other core
laboratories such as the genomics and flow
cytometry cores that serve a broad community of
researchers. The host institution is renowned for
the quality and administration of its extensive
core facilities. Highly productive cores have
always been at the heart of this institution            $2,621,345
We are proposing a certificate program in stem
cell biology research and regenerative medicine
at our institution. Our objective is to train up to
30 students from diverse socioeconomic and
ethnic background in the modern aspects of stem
cell biology, it implications in regenerative
medicine, and social and ethical issues in the use
of stem cell technology. Specifically, the program
will have two components. Students from our
university will take the courses we offer in cellular
and molecular biology. They will also complete at
least one semester of independent research,
which will enhance their training in experimental
research design, basic methods, and good
laboratory practices. The next phase of the
program will require training in embryonic stem
cell laboratory techniques at either [REDACTED]
or [REDACTED], our “host” institutions. Up to ten
undergraduates/year for three years will be
selected to participate in a 12 month research
internship at either [REDACTED] or at
[REDACTED]. In preparation for these internships,
trainees must show outstanding achievement in
cellular and molecular biology coursework and           $3,497,510
Our understanding of the effect of
immunosuppressive agents on stem cell
proliferation and differentiation in the central
nervous system is limited. Indeed, even the
necessity for long-term immunosuppression to
promote the survival of stem cells grafted into
the "immunoprivileged" central nervous system
(CNS) is unknown. Grafting multipotent stem cells
into the injured CNS often results in a failure of
the cells to survive. If the cells survive, often they
differentiate into astrocytes, a cell-type not
considered beneficial. We recently grafted human
stem cells (hCNS-SC) into spinal injured mice and
observed behavioral improvements coupled with
differentiation of these human cells into neurons
and oligodendrocytes. We also observed mouse-
human synapse formation and remyelination. The
mice we used lacked a functional immune
system, enabling us to grafting human cells into
the mice without the use of
immunosuppressants. When these same cells
were grafted into spinal injured rats with a
normal immune system, we had to
immunosuppress the animals. Exposure of these
human stem cells to immunosuppressive drugs
resulted poor cell survival. The cells that did          $619,223 Spinal Cord Injury
Regeneration of lost body parts has long
fascinated humans, yet regeneration remains one
of the great mysteries in biology. Forty years ago,
studies on the mammalian brain provided
evidence that new neurons are generated
throughout life. It is now widely accepted that
neurons are born (neurogenesis) in a wide range
of animals, including humans, from neural stem
cells maintained in the adult brain. Neural stem
cells, however, do not readily compensate for lost
neurons after injury or due to diseases of the
nervous system, such as Parkinson’s or
Alzheimer’s disease. The existence of neural stem
cells has raised hopes that in the future we may
be able to manipulate or promote stem cells in
living organisms to divide, acquire the fate of
specific cell types, migrate to the proper location
and replenish lost neurons. Alternatively, another
source of stem cells for tissue replacement could
be stem cells derived from adult, embryonic, or
cells re-programmed to acquire a stem cell-like
state. All of these prospects will require that we
fully understand how stem cells can be signaled
to divide, acquire the desired cell fate and
integrate into a functional nervous system. Our       $1,725,830
One important aspect of regenerative medicine is
the ability to introduce functional stem cells into
patients to restore tissue function. This type of
therapeutic approach will not be commonly used
until several major potential problems have been
addressed, including immune rejection and the
risk of developing cancer. Induced pluripotent
stem cells (iPSCs) hold great promise in
regenerative medicine: these cells are similar to
embryonic stem cells (ESCs) but can be derived
upon "reprogramming" of any mature cell type
isolated from a patient. Thus, tissue-specific stem
cells derived from iPSCs and re-injected into the
same patient may not trigger immune rejection.
However, before the full potential of iPSCs is
achieved, we need to learn how to better
generate these cells, control their maturation into
tissue-specific stem cells and progenitors, and
harness their tumorigenic potential. Interestingly,
ESCs and iPSCs share many characteristics of
cancer cells, including their unlimited
proliferation potential, and emerging evidence
suggests that the mechanisms underlying the
infinite proliferation of cancer cells and ESCs are
intimately intertwined. Similarly, the progressions   $1,436,185 Solid Tumor
Stem cells have the remarkable ability to renew
themselves and to generate multiple different cell
types. This allows them to generate normal
tissues during development and to repair tissues
following injury, but at the same time, renders
them highly susceptible to mutations that can
result in cancer. Only by understanding the
signals that control growth and differentiation of
stem cells can we learn to harness their
regenerative capacity and restrain their
malignant potential. The research described in
this proposal is aimed at elucidating the role of
neural stem cells in development, regeneration
and tumor formation in the cerebellum. Our
previous studies identified a population of neural
stem cells in the developing cerebellum. We now
propose to use genetic approaches to mark these
cells and identify the cell types that they generate
during normal development. In addition, we plan
to examine the capacity of these cells to
regenerate the cerebellum following radiation.
Finally, we propose to study the ability of these
cells to give rise to brain tumors, and use the
models that result from these studies to develop
and test novel approaches to therapy. These
studies will pave the way towards use of stem          $5,919,616
There are thousands of cell types in the animal
body, many of which can be derived from
embryonic stem cells (ES cells), a pluripotent cell
type that thrive in cell culture condition. ES cells
differentiate into various cell type in a tissue
culture dish in response to different growth
factor/cytokine treatment, which can be
transplanted back into animals for regenerative
medicine application. In recent years, scientists
have generated another type of pluripotent stem
cell population, designated as induced
pluripotent stem cells (iPS cells). These iPS cells
are derived from adult cell types, and capable of
differentiating into a variety of cell types in a
tissue culture dish. Both ES cells and iPS cells not
only provide a unique paradigm to study early
mammalian development, but also hold great
promise for regenerative medicine. Therefore,
understanding the molecular network that
regulate stem cell maintenance and stem cell
differentiation of these cell types are very
important for their application in regenerative
medicine. In the studies we proposed, we will
examine a novel class of gene regulators for their
functions to maintain the stem cell population, as     $1,499,994
The goal of this proposal is to establish a
premiere center for human embryonic stem cell
(hESC) research and education in the state of
California. Our center builds on the established
excellence of faculty with research organized into
four thematic areas: 1. Human embryology,
derivation of hESC lines, including disease-specific
lines, and SCNT, 2. Cell fate specification and
hESC reprogramming, 3. Cancer and cancer stem
cells, and 4. Directed differentiation to cardiac
and neural lineages. Here, we seek funding to
renovate facilities that will house a human
embryo/oocyte resource center and database,
hESC line derivation, as well as other research
and educational training including a central
repository for growth, characterization and
distribution of hESC lines to scientists in our
community. The success of the faculty in this
Center in garnering funding for hESC research,
including CIRM funding, mandates the expansion
of our research facilities. In addition, an
accompanying curriculum in Stem Cell Techniques
Courses is complementary to the research efforts
and builds on a history of teaching excellence.
This curriculum will encompass three areas: 1.         $5,819,047
Human embryonic stem cells (hESC) are being
considered for a wide range of research and
therapeutic uses. Cell therapy is the most
challenging of the potential clinical applications
and its success will depend on the ability to guide
differentiation of hESC into clinically useful cell
types. The ideal cell types would possess three
features: the capacity to restore lost functions,
the ability to survive after transplantation, and
the absence of malignant potential. A major
roadblock in the development of stem cell
therapies is the lack of tools for quality control,
characterization, and identification of human
pluripotent stem cells and differentiated
populations. As new cell lines are developed and
new differentiation techniques are tested, the
need for validation of the cells becomes more
and more critical if the cells are to be used in a
clinical setting. We have developed a new
method for unequivocally identifying pluripotent
stem cell populations using molecular analysis
tools developed for the Human Genome Project.
We have identified a molecular fingerprint that is
shared by all pluripotent cells, human or mouse,
embryo-derived or produced from adult cells
through new induced pluripotence technologies.        $1,141,124
Pluripotent stem cell research is just on the verge
of beginning to fulfill its promise to revolutionize
medicine. Whether they are derived from
embryos, or from adult cells that have been
reprogrammed, human pluripotent stem cells can
be propagated indefinitely in the laboratory and
can turn into a wide range of mature cell types,
providing an renewable source of a wide range of
types of human tissue for research or therapy.
We are still learning about the best ways to grow
and manipulate pluripotent stem cells, and how
best to reprogram adult cells to the pluripotent
state. In fact, our concept of what a pluripotent
stem cell is and what it looks like is still emerging.
Recent work has shown that pluripotent stem
cells, in the embryo or in the laboratory, are not
simply homogeneous monocultures. Rather, stem
cell cultures are complex and highly dynamic
ecosystems. They contain a spectrum of cell
types, from the most primitive cells, to cells that
are already well on the way to becoming
particular specialized types of cell. Different
subpopulations of cells within these ecosystems
communicate with one another, and these
interactions dictate cell behavior. Cells even
produce a type of scaffold on which they grow,           $1,440,822
Regenerative medicine is an emerging area that
will only realize its great potential through novel
collaborative research approaches, and the
University of California at Santa Barbara (UCSB) is
well positioned to make significant contributions
by leveraging fundamental biomedical research
efforts with enabling technologies in materials,
microfluidics and bioengineering. This proposal
details plans for the development and renovation
of shared-use laboratory facilities for the culture
of human embryonic stem cells (hESC). The
Laboratory for Stem Cell Biology and Engineering
will be designed to promote stem cell research by
investigators at UCSB, as well as those at
neighboring universities and research institutions
on the California central coast. Availability of a
core stem cell laboratory will facilitate expansion
of current stem cell studies at UCSB and stimulate
new investigations into the biology and
engineering of stem cells. The Laboratory will be
embedded within a new UCSB Center for Stem
Cell Biology and Engineering that is planned for
the 3rd and 4th floors of Biological Sciences 2
building. Our clientele will include researchers in
13 different Departments and Institutes at UCSB,      $3,161,329


The University of California, San Francisco (UCSF)
has a long history of making innovative
discoveries that change the way scientists and
clinicians think about disease processes and their
approaches to finding cures. Accordingly,
researchers at this institution were quick to
appreciate the enormous promise of human
embryonic stem cells (hESCs) as research tools for
understanding how the body normally works,
thus laying the groundwork to identify disease-
related aberrations. Therefore, in 2001, when the
federal government decided to limit government
funding to work with existing hESCs, which they
banked, U.S. scientists were faced with a
dilemma. Would we abide by these
unprecedented restrictions, which meant that
research would be limited to first-generation
cells, or could we find ways to develop second-
generation, higher-quality hESCs? Investigators
on our applicant team took both approaches.
Since UCSF contributed two hESC lines to the
federal registry, our team members participated
in the government                                     $5,546,877
A major goal of the Shared Research Laboratory
(SRL) is to foster the development of new
treatments for human diseases and disorders by
serving as a leading regional center for human
embryonic stem cell (hESC) research, clinical
applications, and training. A critical component of
this vision is a full service SRL. The SRL will
provide space and equipment that is free of
federal funding to allow pursuit of any study
needed to discover the basic properties of hESCs,
to understand disease processes, to accelerate
drug development and to develop cell-based
therapeutics. The research in the SRL includes a
balance of studies into the basic biology of hESCs,
disease mechanisms, and potential therapeutics.
Results of these studies will increase our
understanding of the causes and potential
treatments of spinal cord injury, retinal disease,
motoneuron diseases, Huntington                         $5,572,979
Cancer is a major cause of human death
worldwide. The vast majority of cancer patients
suffer from solid tumors whose growth destroys
vital organs. We propose to develop novel
therapeutic drugs that target solid tumors
affecting the brain, colon and ovaries. These
cancers account for a significant proportion of
currently intractable solid malignancies. Scientists
have made great strides in understanding the
molecular and cellular changes that cause cancer
but the approval of new therapeutics that can
specifically kill cancer cells has lagged behind.
This disparity suggests that there must be critical
bottlenecks impeding the process of turning a
basic research discovery into a finished anti-
cancer drug. Research over the past decade has
given rise to the idea that one of these
bottlenecks may be caused by the existence of
cancer stem cells. According to the cancer stem
cell hypothesis, there is a minor population of
cancer stem cells that drives the growth of the
entire tumor. However, cancer stem cells are very
rare and hard to identify. Technical innovations
have recently allowed the identification, isolation
and growth of these cells in the laboratory, and it
has become clear that they have properties that        $19,979,660 Solid Tumor
Retinal degeneration represents a group of
blinding diseases that are increasingly impacting
the health and well being of Californians. It is
estimated that by 2020, over 450,000 Californians
will suffer from vision loss or blindness due to the
age-related macular degeneration (AMD), the
most common cause of retinal degeneration
diseases in the elderly. Furthermore, retinitis
pigmentosa is the leading cause of inherited
blindness in younger people. Currently there are
no cures for these diseases. A layer of cells at the
back of the eye called the retinal pigment
epithelium (RPE), provide support, protection,
and nutrition to the light sensitive retina, and
cooperate with other retinal cells to maintain
normal visual function. The dysfunction and/or
loss of these RPE cells play a critical role in the
development of the previously described blinding
diseases. We suggest that effective treatment of
retinal degeneration could be achieved by the
proper replacement of damaged RPE and retinal
cells with healthy ones. However, lack of the
reasonable supply of healthy human eye cells
hampers the application of this therapeutic
approach. Recent advances in knowledge and              $684,322 Aging, Vision Loss
This proposal focuses on the role of the immune
system in transplantation of derivatives of human
pluripotent stem cells (hPSCs). A critical
roadblock to successful cell replacement
therapies, no matter what the disease or injury, is
the fact that the immune system's main function
is to prevent the introduction of foreign
substances into our bodies. Unfortunately, this
means that transplantation of organs or cells will
inevitably lead to rejection unless the immune
system is repressed or "tricked" into accepting
the transplants as non-foreign. Long term
immune suppression is harmful, because of the
toxicity of the drugs used and because the
repressed immune system is unable to protect
against infections and monitor for cancerous
cells. Our strategy is to "trick" the immune system
into recognizing the cells used for replacement
therapy as "self" rather than as foreign. We have
had early success with these methods, and now
propose to test them in a realistic situation that
may lead directly to human applications. Each
human being has a particular complement of
proteins that are exposed on the surfaces of cells
and serve to distinguish "self" from "non-self".       $1,269,844
This Level II Training Grant will support seven PhD
Post-Doctoral and three MD Clinical Fellows at
Keck/USC and CHLA for training in stem cell
biology, and the clinical and ethical implications
of stem cell research. CHLA                            $2,390,826
We will exploit the unique strengths of The
Scripps Research Institute (TSRI) in Chemistry and
Biology to provide an interdisciplinary stem cell
training program that incorporates teaching and
research in chemistry, functional genomics, and
molecular genetics. The goal of this proposal is to
train scientists for future careers in basic or
applied research in the field of stem cell biology.
In particular, the aim of this program is to train
coworkers who can work at the interface of
chemistry and biology in order to more effectively
apply chemical tools and approaches to basic
research and the development of new
therapeutic approaches in regenerative medicine.
This requires a training program that brings
together graduate students and postdoctoral
fellows from the biology and chemistry disciplines
in order to (1) educate them in the basic biology,
methods, and applications in embryonic and
adult stem cell biology; (2) cross train them in the
principles and approaches that chemists and
biologists apply to biological problems; (3) foster
research collaborations between chemists and
biologists in the stem cell field; and (4) stimulate
an awareness of the problems and ethical issues        $1,059,300
Stem cell research holds great promise for
developing cell-based therapies for common
diseases. Scientists at UCSF have contributed new
insights that have enhanced our understanding of
stem cell biology, including identification of
neural stem cells, derivation and characterization
of greatly-improved human embryonic stem cell
lines, and application of innovative islet
transplantation methods to treat diabetes. These
discoveries highlight the need for scientists who
can bridge basic and clinical sciences to fully
realize the clinical potential of stem cells. The
goal of the UCSF Training Program in Stem Cell
Research is to train CIRM scholars in basic
research who are cognizant of clinical needs, as
well as scholars in clinical disciplines who are
grounded in the basic science of stem cell
research. We will achieve this long-term goal by:
(1) capitalizing on our strong, multidisciplinary
faculty engaged in stem cell-related research to
provide training in neural stem cells, cardiac
repair and regeneration, angiogenesis, diabetes,
developmental biology, hematopoiesis and
cancer stem cells, mesenchymal biology,
bioengineering, and human embryonic stem cells;
(2) exploiting our world-class graduate programs      $3,620,652

This Level II Training Grant will support seven PhD
Post-Doctoral and three MD Clinical Fellows at
Keck/USC and CHLA for training in stem cell
biology, and the clinical and ethical implications
of stem cell research. CHLA                           $2,318,580
Stem cells are the primitive cells that give rise to
the different tissue types in the body. In a way,
stem cells are the universal cells from which all
cells are derived. Their unlimited proliferation
and differentiation potential raises the prospect
that stem cells could be used as therapeutic tools
offering hope for millions who suffer from
debilitating diseases and conditions for which
there are limited or no treatments including:
neurological disease, cardiovascular disease,
autoimmune diseases, diabetes, and
osteoporosis. Furthermore, stem cells may serve
as diagnostic tools, cancer perhaps being one of
the most promising areas. But before these
potential applications become a reality, scientists
need to be educated and trained so to have a
better understanding of the mechanisms by
which human embryonic stem cells renew
themselves indefinitely as well as the cellular and
molecular mechanisms that control their
differentiation to the different type of cells and
tissues of the human body. This Training program
is designed to develop and enhance research
opportunities for postdoctoral fellows training for
careers in the field of human stem cell biology.
Our goals are to develop a curriculum of study         $3,062,677
This is a Type III CIRM Training Proposal for 6
postdoctoral fellows to be educated at the Salk
Institute. This Program is designed to develop and
enhance research opportunities for postdoctoral
fellows training for careers in the field of human
stem cell biology. Our goals are to develop a
curriculum of study and research experiences
necessary to provide high quality research
training and to ensure a continuing supply of well-
trained scientists prepared to conduct cutting-
edge health-related research in human
embryonic stem cell biology. The rationale for
this Training Program is that a deep
understanding of the biology of human
embryonic stem cells will be essential for utilizing
them successfully to develop new therapies for
human diseases. For this purpose we suggest a
full range of multi-disciplinary training activities
that range from the study of basic principles of
stem cell biology, encompassing genetic,
biochemical, and cellular approaches, to
theoretical and practical aspects of stem cell
related emerging technologies, to ethical, legal,
and social issues involved with stem cell research,
to colloquiums, lectures and seminars, with the
ultimate goal of providing a well rounded training     $1,496,880
We propose to continue our successful
interdisciplinary Training Program in Stem Cell
Biology and Engineering (CIRM Type III). The
program will educate the next generation of stem
cell researchers and provide the ethical
background and research skills necessary for
them to succeed in this rapidly moving,
multifaceted field. The training grant will support
research in two broad but interrelated areas: 1.
Inquiries into the fundamental molecular biology
of stem cell proliferation and differentiation,
using powerful methods of modern molecular
biology. 2. Bioengineering approaches will be
used to develop novel biotechnologies for stem
cell research, taking advantage of state of the art
research and facilities. Postdoctoral and pre-
doctoral trainees will be immersed in a highly
interactive and supportive program that
facilitates research and instruction in stem cell
biology and engineering. Trainees will be involved
in groundbreaking research that will solve key
problems and help bring stem cell therapies into
practice. We will continue very successful courses
initiated in the previous funding period, in stem
cell biology and stem cell ethics. The training
environment will be enriched by seminars from         $2,451,273
Our goal is to continue the Type I CIRM-funded
Comprehensive Training Program that was
established at this institution nearly 3 years ago.
Specifically, we want to support 6 graduate
students, 6 postdoctoral (Ph.D.) fellows, and 4
clinician-scientists (M.D. and or Ph.D.). We
provide a unique training environment for
students at all levels who are pursuing careers in
regenerative medicine. Specifically, our
institution offers a world-class research training
experience in the context of an equally
prestigious medical school and clinical enterprise.
We are also noted for our faculty, a diverse and
talented group of individuals—1,500 full-time
members who are renowned for their dedication
to the training process. Additionally, this
institution has a long history of supporting
human embryonic stem cell research within a
framework of the highest ethical standards of
conduct. In this productive research
environment, our Institute for Regeneration
Medicine (IRM) fosters work toward regenerative
medicine therapies. The IRM has 7 pipelines that
are designed to promote the development of cell-
based therapies for repair/regeneration of            $7,946,605

We propose to develop a Type III Specialized
Training Program, to include 6 trainees               $1,217,132
We will provide an interdisciplinary stem cell
training program that incorporates teaching and
research in chemistry, functional genomics, and
molecular genetics. The goal of this proposal is to
train scientists for future careers in basic or
applied research in the field of stem cell biology,
with a particular emphasis on training coworkers
at the interface of chemistry and biology in order
to more effectively apply chemical tools and
approaches to basic research and the
development of new therapeutic approaches in
regenerative medicine. An important component
of the training program will be to introduce
trainees to the most modern techniques in
chemistry, genomics and genetics and their
application to stem cell research. This requires a
training program that brings together graduate
students and postdoctoral fellows from the
biology and chemistry disciplines in order to (1)
educate them in the basic biology, methods, and
applications in embryonic and adult stem cell
biology; (2) cross train them in the principles and
approaches that chemists and biologists apply to
biological problems; (3) foster research
collaborations between chemists and biologists in
the stem cell field; and (4) stimulate an             $4,058,362
Congenital and acquired defects of cardiac
pacemakers are leading causes of morbidity and
mortality in our society. Dysfunctions of the SA
node and the lower conduction cells lead to a
variety of complex arrhythmias that typically
necessitate anti-arrhythmic therapy and
implantation of devices. These treatments have
significant limitations in their efficacy and risk-
benefit ratio. Thus, it would be ideal to generate
cell-based therapeutic approaches towards
treating arrhythmias. Experimental data has
provided compelling evidence that pacemaker
and conduction cells of the heart separate early
in development from the working myocardium
and retain a relatively undifferentiated state.
Prior cell-based approaches in regenerating
myocardial damage in the heart have met limited
success in part due to implantation of a diverse
population of cells. This generally results in poor
engraftment and undesirable outcomes. There is
now evidence for resident conduction progenitor
cells in myocardium that orchestrate the process
of cell recruitment into the conduction tissue. In
the current proposal we aim to identify the
molecular events that lead to differentiation and
formation of cardiac pacemaker cells. We will         $3,149,806 Heart Disease
Embryonic Stem (ES) cells can be grown
indefinitely in the lab and can be turned into any
cell type of the human body. Because of these
properties, it may one day be possible to use ES
cells to generate cell types in the lab that can
then be transplanted into patients that need
them. This approach may provide new
treatments for devastating and presently
incurable conditions such as type I diabetes,
Parkinson's disease, muscular dystrophies, spinal
cord injuries, and many others. However, before
human ES cells can safely be used in the clinic, it
will be essential to understand how they
function. For example, if rapid cell division is not
kept in check in ES cells, they can give rise to
tumors upon transplantation. Our proposal is
directly aimed at understanding the genetic
regulation of human ES cells. We developed a
very innovative approach to understand how
gene activity is regulated in human ES cells. Our
very significant progress so far it can be
summarized as follows: - we identified the genes
that are preferentially activated in ES cells; - we
discovered several DNA sequences that act as
genetic switches to turn ES cell genes on or off; -    $618,901


The 3D imaging techniques of CT and MRI have
virtually eliminated the need for exploratory
surgery - a procedure which was common in
difficult cases just 20-30 years ago. Not only is
imaging used to discover the extent of disease, it
is now used to measure the effect of therapies.
The "size" of a tumor is stabilized under effective
treatment - and this arrested growth can be
measured with CT or MRI. New "molecular
imaging"•  techniques (eg, SPECT) can create
images of the biological processes associated with
the cancer - the aggressive metabolism of cancer
cells and the invasive signatures of uncontrolled
growth. Images of the cessation of these
processes provide a much earlier (hours-days
rather than weeks-months) assessment for
physicians to decide quickly upon alternative
treatments if the therapy is not working.
We propose to create an imaging tool for stem
cell therapies that combines the strengths of two
powerful imaging modalities currently in use in
both pre-clinical research and clinical practice:
MRI and SPECT. Our goal is to translate this tool
to the clinic to provide answers to three
fundamental questions of any stem cell therapy:
1) where are the stem cells located? 2) what is
the status of the stem cells? and 3) is the curative
biological effect taking place? The SPECT/MRI
imaging tool will be used for pre-clinical research
with laboratory mice and rats. It will use MRI to
provide the anatomical context - the 3D
environment of the cells - by using its exquisite
ability to visualize soft tissue anatomy. In the
proposed pre-clinical prototype, we will use the
SPECT imaging to "zoom in" on the stem cells
themselves through the use of ultra-high
resolution techniques that we are developing in
an ongoing CIRM project. This "zoom"•    SPECT will
be combined with the ability to simultaneously
image biological processes with a second SPECT
contrast agent. This use of multiple contrast
agents is a unique functionality of SPECT. Our
preliminary research results show SPECT imaging        $1,528,599
Over twenty human genetic diseases are caused
by expansion of simple DNA sequences composed
of repeats of three nucleotides (such as CAG,
CTG, CGG and GAA) within essential genes. These
repeats can occur within the region of a gene that
encodes the protein, generally resulting in
proteins with large stretches of repeats of just
one amino acid, such as runs of glutamine. These
proteins are toxic, cause the death of specific
types of brain cells and result in diseases such as
Huntington’s disease (HD) and many of the
spinocerebellar ataxias (a type of movement
disorder). Other repeats can be in regions of
genes that do not code for the protein itself, but
are copied into messenger RNA, which is a copy
of the gene that serves to generate the protein.
These RNAs with expanded repeats are also toxic
to cells, and sometimes these RNAs sequester
essential cellular proteins. One example of this
type of disease is Myotonic Dystrophy type 1, a
form of muscular dystrophy. Lastly, there are two
examples of repeat disorders where the repeats
silence the genes harboring these mutations:
these are Friedreich’s ataxia (FRDA) and
Fragile X syndrome (FXS). One limitation in the        $1,755,861 Huntington's Disease
The physiological template of our genome, called
chromatin, is composed of DNA wrapped around
histone proteins. In the process of development
the genome is interpreted in a way that is
dynamic, and yet, often heritable, to produce
different specialized tissues and organs. A
substantial portion of information that is required
for proper interpretation of the genome is
transmitted in a form of methylation of histones
and associated DNA. Methylation marks are
written by specific enzymatic activities, called
methyltransferases. Different methyltransferases
can activate or repress genes, and the right
balance between the two is critical for proper
execution of the developmental programs. Thus,
not surprisingly, deregulation of
methyltransferases leads to human disease, most
notably cancer. Here we propose to address how
the interplay between “activating” and
“silencing” methylation signals regulates gene
expression patterns in embryonic stem cells and
during their differentiation along the neural
lineage. These studies will advance our
knowledge of the unique properties of chromatin
in embryonic stem cells and will address the
mechanisms of gene expression during neural
commitment. This basic science foundation will         $2,374,020

Human embryonic stem (ES) cells have the
potential to form any cell type, but ironically, the
first cell lineage to form during development still
represents a surprising challenge. The first cell
type to become specialized is an epithelial cell
that later defines the boundary between the
embryo and mother for the formation of the
placenta. The placenta is the key organ that
permits the blood of the mother to provide
oxygen and nutrients to the fetus. It is composed
of multiple cell types that are specialized for
different functions but most of the fetal
contributions are derived from the trophoblast
cell lineage. Nearly 3% of human pregnancies are
threatened by deficiencies of the function of the
placenta to provide sufficient blood flow. This
condition can result in dangerous increases in the
mother                                                  $748,240 Fertility
The therapeutic use of stem cells in regenerative
medicine will require the ability to control stem
cell expansion and differentiation into specific
tissue types, such as pancreatic ?-cells, heart
tissue, bone or specific neuronal lineages. We
have taken a chemical approach toward this
problem in which large collections of synthetic
small molecules are being screened in cell-based
assays to identify drug-like molecules that control
stem cell processes. Preliminary experiments in
our institute have demonstrated that we can
identify molecules that control the self-renewal
and directed differentiation of murine embryonic
stem cells. The characterization of the biological
mechanisms of the molecules has also provided
new insights into the underlying biology of stem
cells. We now propose to extend these studies to
hESC lines not eligible for federal funding, for
which our research activities have been restricted
to date. In addition, such lines may be better
suited for specific applications, including the use
of small molecules to derive specific cell lineages
and investigate ES derived cell-based models of
genetic disease. To this end, we would like to
establish a human embryonic stem cell core
facility. This facility will house the necessary      $3,828,751
This application is to renew our CIRM type III
program to train post-doctoral scientists. Our
faculty direct a large stem cell research and
teaching enterprise that comprises over 100
biologists, chemists, engineers and clinicians with
extensive expertise in stem cell biology and in
allied disciplines dedicated to stem cell-based
therapies for cardiovascular, neurodegenerative,
hematopoietic and metabolic disorders. Our
current CIRM program curriculum included
intensive lecture courses on Stem Cell Biology,
and Ethics, Intellectual Property and Regulatory
Affairs and a hands-on, intensive laboratory
course required of all trainees. The program also
funded instructors to provide specialized
workshops in hESC techniques and our trainees
attended local and statewide trainee meetings to
augment interchange and education. In addition,
the training program provided a research stipend
to defray the costs of the trainees’ research and,
in some cases, the presence of CIRM trainees
established hESC biology in mentors’ laboratories.
The proposed program will feature the following:
• Train a steady state of 6 postdoctoral
fellows/year, with PhD and/or MD degrees,
admitted on a competitive basis. • Mandatory           $2,856,694


Human embryonic stem cells (hESCs) or induced
pluripotent stem cells (iPSCs) provide an
invaluable resource for regenerative medicine
and disease modeling. To be able to use these
cells in the clinic, hESCs and iPSCs need to be
expanded without introducing genetic instability.
However, current protocols of hESC and iPSC
propagation frequently result in aneuploidy, a
potentially tumorigenic cell state. Because of
their tumorigenic potential, undifferentiated
hESCs have to be removed from cell populations
prior to transplantation, yet efficient ways to
securely achieve this have not been developed.
Together, these limitations greatly limit the use of
hESCs or iPSCs in regenerative medicine.
Here, we propose to dissect and manipulate
mechanisms of hESC division and survival. Based
on our preliminary data and previous
observations in embryonic cells, we will initially
dissect the role and regulation of the anaphase-
promoting complex (APC/C), an essential
component of the core cell cycle machinery, and
Cul3, an enzyme required for the integration of
extracellular signaling into the hESC division
program. These experiments will make use of our
experience in developing biochemical systems to
dissect complex pathways in vitro, combined with
an in-depth analysis of cell cycle control in hESCs
in vivo. Understanding hESC division control by
APC/C and Cul3 will identify the mechanisms
generating aneuploidy during hESC culture.
Subsequently, we will isolate novel hESC-specific
ubiquitination enzymes required for division and
survival by using siRNA screens in hESCs. We will
identify the substrates of critical enzymes to
determine their role in division and survival
control. Manipulating the activity of hESC-specific
enzymes or substrates will allow the removal of
undifferentiated cells from cell populations, an
essential step prior to transplantation.


The results from these studies will provide critical
insight into the mechanisms controlling hESC
division and survival. Based on findings on
division control, we will be able to develop
protocols for faithful hESC or iPSC expansion in
culture, while understanding the mechanisms of
hESC survival will point to strategies for the
selective elimination of undifferentiated cells
from cell populations. Both outcomes of this
study will greatly expand the use of stem cells for
regenerative medicine.                                 $1,364,091
The Stem Cell Training Program includes:
experienced, well-funded mentors; essential
techniques, methodologies, and facilities relevant
to basic, translational, and clinical training in
stem cell research; established graduate and
training programs that provide the spectrum of
training experiences; a clinical enterprise that
includes a medical school, teaching hospital, and
exceptional infrastructure including a CIRM
Shared Research Facility and CIRM Stem Cell
Institute; core facilities that provide essential
equipment and expertise in stem cell biology and
related areas such as animal models,
bioengineering, genomics, and imaging; and a
clinical program to ensure the translation of
bench research to new therapies for human
diseases. The program also includes a strong,
collaborative framework in which to mentor and
cultivate students and young investigators using a
team approach. The overarching objective is to
provide chosen scholars an integrated experience
with state-of-the-art multidisciplinary team
training to ensure they become productive,
critical thinking, highly trained, and well-rounded
collaborative scientists with research careers in     $7,358,024
The intent of the proposed shared research
facility is to provide a state-wide resource for
qualified scientists in California to study human
embryonic stem cells (hESC) without federal
restrictions. The shared facility will encourage a
spirit of collaboration and include laboratories for
investigators to culture, collect, store, and
analyze hESC, provide necessary services that will
be cost-effective and assist with research
productivity, and ensure an environment that will
facilitate the essential interactions among
scientists. This approach will advance the use of
hESC for regenerative medicine purposes and aid
in developing new technologies and therapies for
the treatment of human disease. Using
established methods that have proven successful
for other collaborative and service-based
structures, this facility will encourage scientists to
work together and provide the necessary
resources to ensure their success. Investigators
new to hESC research will benefit greatly by
having this facility available because it will have a
centralized supportive structure where
experienced personnel will provide the necessary
assistance and guidance. For those investigators
with hESC research experience, new                       $3,709,631

We propose a CIRM Special Program (Research
Element X), supporting basic and discovery
research that will fund renovation of space to
provide for the establishment of a new Center for
Stem Cell Biology and Engineering. CIRM funding
will allow us to expand our growing basic
research on human embryonic stem cells (hESC)
by creating a state-of-the-art facility for new
faculty, for collaborative work and for core
facilities. We will transform antiquated,
inadequate laboratory space to allow research
that will be free of federal restrictions.
Research in the proposed Center will focus on
two areas of basic and discovery stem cell
research: Molecular Mechanisms and
Bioengineering. First, studies will focus on the
fundamental molecular mechanisms of stem cell
growth and differentiation, using hESC and stem
cells in simpler organisms that are useful models
of developmental processes and disease
pathobiology. The second goal will be to
investigate novel methods for stem cell growth,
differentiation, sorting and delivery, using
synergistic cell biological, biomaterial, and
bioengineering technologies. The long-term goal
will be the application of results to the
development of stem cell-based therapeutics for
human disease.


Renovation of about 10,000 asf of space, most of
it adjacent to the CIRM-funded shared hESC lab,
is proposed to accommodate the following three
program elements:



 1. Space for new faculty members. Laboratory
 space will be renovated to provide for two new
 senior faculty members, for which searches are
 underway. The first, in the area of molecular
 mechanisms, will fill an endowed chair and act
 as director of the new Center. The second, in
 the area of bioengineering and systems biology,
 will fill another endowed chair.

 2. Space for collaborative work. Space free of
 federal restrictions will be renovated to provide
 for the expansion of ongoing collaborative work
 between investigators at our institution and
 those outside our institution. This will stimulate
 collaboration and exchange of ideas that would
 otherwise not be possible.
 3. Core Facilities. A much needed Flow
 Cytometry Core will be established within the
 facility. Additional renovated space will house
 Center equipment rooms, meeting rooms, and
 offices. Finally, several vivarium rooms in the
 same building will be renovated to
 accommodate stem cell experiments in animal
 models. These core facilities will be used by
 researchers at our institution with ongoing
 stem cell projects.


This CIRM Special Project will provide crucial
funding that will greatly stimulate growth of stem
cell research. It will facilitate new,
interdisciplinary collaborations that would
otherwise be impossible due to federal
restrictions and lack of suitable space.             $3,205,800
Here we propose a comprehensive doctoral,
postdoctoral and clinical researcher training
program designed to develop the next generation
of researchers in the field of regenerative
medicine. This field, which is centered around the
comprehensive understanding, use and
manipulation of stem and progenitor cells,
promises to revolutionize the way that human
diseases and disorders are treated. Advancing the
goals of CIRM to develop new treatments for
human disease based on stem and progenitor
cells will likely require the understanding and
application of multiple technologies. Researchers
in this field will need to understand multiple
disciplines and participate in multi-disciplinary
research teams where each of the participants
understands the capabilities and shortcomings of
each other's technologies. Trainees will be
recruited from within existing labs and by
external recruitment. Our stem cell training
program will emphasize broad, cross-disciplinary
training, exposing trainees to concepts and
techniques in diverse fields such as stem cell
biology, biomedical engineering, pre-clinical
development and clinical practice. Courses have
been tailored to address the needs of the            $6,827,148
Our Type I, Comprehensive Training Program will
train basic scientists, engineers, and physicians to
become leaders in stem cell research in academia
and industry. The Stem Cell Research Center will
coordinate the training of 5 pre-doctoral, 6 post-
doctoral, and 5 clinical Scholars, each of whom
will acquire (a) a thorough and critical
background in stem cell biology, (b) an
understanding of human disease and
regenerative medicine, and (c) knowledge of how
to translate basic research findings to the clinic.
[REDACTED] provides state of the art research
opportunities and mentoring for training Scholars
in stem cell biology and regenerative medicine as
evidenced by the past success of their publication
of important papers in Nature, Blood, PNAS,
Cancer Research, Cell Stem Cell, and Stem Cells.
Scholars achieve the program goals through a
coordinated approach integrating: 1)
Coursework: A 10-week course on ‘Stem Cell
Biology and Regenerative Medicine’ includes
lectures and discussion of organogenesis,
derivation and maintenance of human embryonic
stem cells (hESC), induced pluripotent stem cells
(iPSC), various tissue specific stem cells, clinical
trials, and the social, legal, and ethical aspects of
stem cell research; 2) Seminars/Symposia:               $7,982,293
Human embryonic stem cells (hES cells) are
immortal pluripotent cells with the potential to
differentiate into derivatives of all three germ
layers. They offer enormous potential in the
emerging field of regenerative medicine and for
illuminating basic developmental biology in vitro,
although regulatory mechanisms that control
their differentiation are not understood. Despite
this potential, due to the fact that they originate
from preimplantation embryos, they have
generated great ethical controversy. To help
young scientists sort out fact from fiction, and to
offer them training as well as ethical guidance in
hES research, we propose a level III training
program for pre and post-doctoral scientists. The
goal of the training program is twofold: 1) to
teach young scientists to think critically and
independently about hES cell research and 2) to
apply this knowledge to the practical applications
of hES cells in regenerative medicine. The focus of
research will be an interdisciplinary approach to
understanding how hES differentiation can be
regulated to produce ocular cells, which might be
useful in the treatment of eye disease. The
research program will take advantage of unique
strengths present at UCSB in the Department of        $1,343,859
We propose a CIRM Training Program in Systems
Biology of Stem Cells featuring formal and
supplemental education in a collaborative,
interdisciplinary biomedical research
environment. As part of the Institute for Biology
of Stem Cells, this program brings together the
unique strengths of faculty with expertise in key
areas for advancing basic stem cell research. Our
labs are developing computer and mathematical
programs to analyze large volumes of stem cell
data and to understand stem cell behavior. We
have experts on DNA and RNA structure who are
learning how those biomolecules instruct stem
cells to self-renew or develop into specialized cell
types. Other faculty are using animal models and
advanced techniques to investigate important
questions in stem cell biology, and our engineers
are working on improving the technology for
studying and utilizing stem cells. This program will
provide an in-depth understanding of the biology
of stem cells, the skills to use stem cells in one’s
own research, and the ability to create computer
programs and use the results of computer
analyses in one’s own research. It will also
provide the tools to make well-informed
decisions regarding the ethical and social issues      $4,591,616

We have assembled a team of researchers with
the aim of elucidating the molecular and cellular
mechanisms that regulate stem cell self renewal
and differentiation. Drawing on their broad range
of expertise in development, genetics, genomics,
molecular, cell and computational biology, these
researchers will use interdisciplinary approaches
to tackle problems concerning how genes are
regulated in human embryonic stem cells (hESCs),
and how this regulation influences their ability to
both self-renew and differentiate into specific
cellular subtypes. Defining and ultimately
controlling this process is an essential step in
designing stem cell-based therapies. These
projects are aimed at providing insights and tools
for neurological and genetic conditions such as
Parkinson                                              $3,588,740
With funding from CIRM, 18 high school students
from backgrounds underrepresented in the
sciences will have the opportunity to pursue a
summer research project in stem cell biology at a
major research university. Students will spend the
bulk of their summer conducting research under
the guidance of a mentor scientist. In addition,
they will meet weekly to build strong ties with
their peers and learn to: 1) successfully apply to
college and for financial aid, 2) communicate in
writing about their research, and 3) give a poster
presentation and a scientific talk.


Alumni from this program have been shown to
pursue careers in the sciences in great numbers;
thus, many of these students will likely continue
working in stem cell research. Irrespective of their
career choice, all CIRM-funded alumni will
understand the importance of stem cell research,
thereby becoming "stem cell ambassadors" who
can help others in California understand this work
and advocate for continued funding.                     $143,550

Hematopoietic stem cell transplantation is the
treatment of choice for many hematologic
malignancies, and it is used to treat an expanding
number of congenital blood disorders. However,
only ~30% of patients who can benefit from this
treatment have a matched sibling that can serve
as the ideal donor. While the national marrow
donor program and umbilical cord blood
programs provide unrelated donor cells to many
patients lacking a sibling donor, a large
percentage of patients remain without a suitable
donor, leaving them with suboptimal therapeutic
options. This problem is more severe in certain
ethnic populations, including people of Latino
and Asian descent, groups that constitute a large
part of California                                     $2,566,702
The goal of this research is to utilize novel
research tools to investigate the molecular
mechanisms that cause Parkinson's disease (PD).
The proposed work builds on previous funding
from CIRM that directed the developed patient
derived models of PD. The majority of PD patients
suffer from sporadic disease with no clear
etiology. However some PD patients harbor
specific inherited mutations have been shown to
cause PD. The most frequently observed form of
genetic parkinsonism is caused by the LRRK2
G2019S mutation it the most common. This
mutation accounts for approximately 1.5-2% of
patients with apparently sporadic PD, increasing
to 4-6% of patients with a family history of PD,
and even higher in isolated populations.
Importantly, LRRK2 induced PD is clinically and
pathologically largely indistinguishable from
sporadic PD.


This proposal focuses on studying the most
frequent cause of familial PD and induces disease
that is clinically and pathologically identical to
sporadic PD cases. It is likely that LRRK2 regulates
a pathway(s) that is important in the more
common sporadic form of PD as well. Therefore
by employing relevant models of PD, we hope to
drive the biological understanding of LRRK2 in a
direction that facilitates the development of
disease therapeutics in the future. We
ascertained patients harboring mutations in
LRRK2 [heterozygous (+/G2019S) and
homozygous (G2019S/G2019S)] as well as
sporadic cases and age matched controls. We
have successfully derived iPSCs from each
genotype and differentiated these to DA neurons.
We will use these as a model system to
investigate these LRRK2 based models of PD.
We will adapt current biochemical assays of
LRRK2, which are source material intensive, to
the small culture volumes required for the
differentiation of iPSCs to DA neurons. This is a
crucial necessity for development for utilizing
iPSC derived DA neurons as tractable models of
LRRK2 based PD. We will then probe the roles of
LRRK2 in neuronal cell differentiation and
survival. We will also ask whether the mutant
LRRK2 induces changes in autophagy, as this has
been postulated as a mechanism of LRRK2
induced pathogenesis. By studying wild-type and
disease mutant LRRK2, in DA models of PD we
hope to provide crucial understanding of the role
mutant LRRK2 has in disease.                           $1,482,822 Parkinson's disease
To realize the potential of human embryonic
stem cells (hESC) in research and medicine, it is
essential to disseminate state of the art
technology in this field to the scientific
community at large. The Shared Research
Laboratory (SRL) of the Center for Stem Cell and
Regenerative Medicine (CSCRM) at the University
of Southern California will aim to provide a
comprehensive support service for hESC
researchers at our University and at neighboring
institutions. The mission of the SRL will include
the following goals: 1) to supply scientists with
quality controlled stem cell lines for use in their
research, including cell lines that are not eligible
for use in NIH-funded projects; 2) to provide
space and equipment for scientists new to the
field to carry out pilot projects, in order to help
them to integrate the hESC platform technology
into their own research programs; 3) to develop
and validate new and improved methods for
growing hESC in the laboratory; 4) to operate a
formal practical course in hESC laboratory
techniques to scientists from throughout the
region. The facility will be situated in the new       $5,355,969
This study will use Ataxia-Telangiectasia (A-T), an
early-onset inherited neurodegenerative disease
of children, as a model to study the mechanisms
leading to cerebellar neurodegeneration and to
develop a drug that can slow or halt
neurodegeneration. We will start with skin cells
that were originally grown from biopsies of
patients with A-T who specifically carry
"nonsense" type of mutations in the ATM gene.
We will convert these skin cells to stem cells
capable of forming neural cells that are lacking in
the brain (cerebellum) of A-T patients;
presumably these neural cells need ATM protein
to develop normally. We will then test the effects
of our most promising new "readthrough
compounds" (RTCs) on the newly-developed
neural cells. Our lab has been developing the
drugs over the past six years. At present, there is
no other disease model (animal or in a test tube)
for evaluating the effects of RTCs on the nervous
system and its development. Nor is there any
effective treatment for the children with A-T or
other progressively-deteriorating ataxias. Success
in this project would open up at least three new
areas for understanding and treating
neurodegenerative diseases: 1) the laboratory         $1,833,054 Neurological Disorders
Spinal muscular atrophy (SMA) is one of the most
common autosomal recessive disorders that
cause infant mortality. SMA is caused by loss of
the Survival of Motor Neuron (SMN) protein,
resulting in motor neuron (MN) degeneration in
the spinal cord. Although SMN protein plays
diverse roles in RNA metabolism and is expressed
in all cells, it is unclear why a deficiency in SMN
only causes MN degeneration. Since patient
samples are rarely available, most knowledge in
SMA is gained from animal model studies. While
these studies have provided important
information concerning the cause and mechanism
of SMA, they are limited by complicated genetic
manipulation. Results from different models are
also not always consistent. These problems can
be resolved if SMA patient’s MNs become
readily available. Recent progress in the
generation of induced pluripotent stem (iPS) cells
from differentiated adult cells provides an
opportunity to establish human cell-based
models for neurodegenerative diseases. These
cells, due to their self-renewal property, can
provide an unlimited supply of the affected cell
type for disease study in vitro. In this regard, SMA
iPS cells may represent an ideal candidate for         $1,268,868 Spinal Muscular Atrophy
Spinal Muscular Atrophy (SMA) is one of the most
common lethal genetic diseases in children. One
in thirty five people carry a mutation in a gene
called survival of motor neurons 1 (SMN1) which
is responsible for this disease. If two carriers have
children together they have a one in four chance
of having a child with SMA. Children with Type I
SMA seem fine until around 6 months of age, at
which time they begin to show lack of muscular
development and slowly develop a "floppy"
syndrome over the next 6 months. Following this
period, SMA children become less able to move
and are eventually paralyzed by the disease by 3
years of age or earlier. We know that this
mutation causes the death of motor neurons -
which are important for making muscle cells
work. Interestingly, there is a second gene which
can lessen the severity of the disease process
(SMN2). Children with more copies of this
modifying gene have less severe symptoms and
can live for longer periods of time (designated
Type II, III and IV and living longer periods
respectively). There is no therapy for SMA at the
current time. One of the roadblocks is that there
are no human models for this disorder as it is very     $1,933,022 Spinal Muscular Atrophy
A variety of stem cells exist in humans throughout
life and maintain their ability to divide and
change into multiple cell types. Different types of
adult derived stem cells occur throughout the
body, and reside within specific tissues that serve
as a reserve pool of cells that can replenish other
cells lost due to aging, disease, trauma,
chemotherapy or exposure to ionizing radiation.
When conditions occur that lead to the depletion
of these adult derived stem cells the recovery of
normal tissue is impaired and a variety of
complications result. For example, we have
demonstrated that when neural stem cells are
depleted after whole brain irradiation a
subsequent deficit in cognition occurs, and that
when muscle stem cells are depleted after leg
irradiation an accelerated loss of muscle mass
occurs. While an increase in stem cell numbers
after depletion has been shown to lead to some
functional recovery in the irradiated tissue, such
recovery is usually very prolonged and generally
suboptimal. Ionizing radiation is a physical agent
that is effective at reducing the number of adult
stem cells in nearly all tissues. Normally people
are not exposed to doses of radiation that are           $625,617 Cancer, Neurological Disorders, Skeletal Muscle
Alzheimer’s Disease (AD) is a progressive
incurable disease that robs people of their
memory and ability to think and reason. It is
emotionally, and sometimes financially
devastating to families that must cope when a
parent or spouse develops AD. Unfortunately,
however, we currently lack an understanding of
Alzheimer’s Disease (AD) that is sufficient to drive
the development of a broad range of therapeutic
strategies. Compared to diseases such as cancer
or heart disease, which are treated with a variety
of therapies, AD lacks even one major effective
therapeutic approach. A key problem is that
there is a paucity of predictive therapeutic
hypotheses driving the development of new
therapies. Thus, there is tremendous need to
better understand the cellular basis of AD so that
effective drug and other therapies can be
developed. Several key clues come from rare
familial forms of AD (FAD), which identify genes
that can cause disease when mutant and which
have led to the leading hypotheses for AD
development. Recent work on Drosophila and
mouse models of Alzheimer’s Disease (AD) has
led to a new suggestion that early defects in the      $2,512,664 Aging, Alzheimer's disease, Genetic Disorder

The goals of this study are to develop patient-
specific induced pluripotent cell lines (iPSCs) from
patients with Parkinson’s disease (PD) with
defined mutations and sporadic forms of the
disease. Recent groundbreaking discoveries allow
us now to use adult human skin cells, transduce
them with specific genes, and generate cells that
exhibit characteristics of embryonic stem cells,
termed induced pluripotent stem cells (iPSCs).
These lines will be used as an experimental pre-
clinical model to study disease mechanisms
unique to PD. We predict that these cells will not
only serve an ‘authentic’ model for PD when
further differentiated into the specific
dopaminergic neurons, but that these cells are
pathologically affected with PD.
The specific objectives of these studies are to (1)
establish a bank of iPSCs from patients with
idiopathic PD and patients with defined
mutations in genes associated with PD, (2)
differentiate iPSCs into dopaminergic neurons
and assess neurochemical and neuropathological
characteristics of PD of these cells in vitro, and (3)
test the hypothesis that specific pharmacologic
agents can be used to block or reverse
pathological phenotypes.



The absence of cellular models of Parkinson’s
disease represents a major bottleneck in the
scientific field of PD, which, if solved in this
collaborative effort, would be instantly translated
into a wide range of clinical applications,
including drug discovery. This research is highly
translational, as the final component is aimed at
testing lead compounds that could be
neuroprotective, and ultimately at developing a
high-throughput drug screening program to
discover new disease modifying compounds. This
is an essential avenue if we want to offer our
patients a new therapeutic approach that can
give them a near normal life after being
diagnosed with this progressively disabling
disease.                                                 $3,701,766 Parkinson's disease

Stem cells are endowed with the ability to self-
renew, that means to give rise to other cells with
the same potential to regenerate a tissue.
Recently, we found a gene that also regulates this
mechanism. In addition, expression of high levels
of this gene can reduce the number of stem cells
in the bone marrow and possibly the brain. This
gene is expressed in the Chromosome 21 and
hence can potentially contribute to the pathology
of people with Down Syndrome (people with
Down Syndrome has three copies of
Chromosome 21). In line with that, we observed
that mouse models for Down Syndrome have less
stem cells in their bone marrow.

We therefore want to study the mechanism of
action of this gene and its effects on stem cells in
the bone marrow and other tissues.
Outcomes from this study will shed more light in
understanding not only the normal process of
stem cell maintenance, but also in deciphering
the complex biology underlying Down Syndrome.
In particular, this study will potentially help to
understand why Down Syndrome carriers have a
defect in learning. We hypothesize that a defect
in neural stem cells leads to abnormal brain
development. If so, then pharmacologic agents
that inhibit the function of this gene might
ameliorate the pathology of Down Syndrome.




Another important aspect of our research on this
pertains to cancer development: indeed cancer
initiating cells take advantage of the normal self-
renewal machinery to proliferate without
restraint. Our preliminary data suggest that high
levels of this gene could potentially counteract
some solid tissue tumors, putting a brake on
cancer cells proliferation. Interestingly, people
with Down Syndrome have a much lower risk of
developing solid tumors than the general
population. We will use human cancer samples,
in particular breast and colon tumors, that we
receive directly from Stanford Hospital to analyze
this gene's contribution to cancer development.
These studies will give us important hints to
discover alternative strategies for cancer
treatment.                                            $1,425,600 Genetic Disorder
Coronary heart disease is the leading cause of
death in the developed world. This disease results
from atherosclerosis or fatty deposits in the
vessel wall that causes blockage of coronary
arteries. Blockage of these arteries cut off
supplies of nutrients and oxygen to the heart
muscle, causing heart attacks, heart failure or
sudden death. To restore coronary blood supply,
physicians use guide-wires to position an
inflatable balloon at the blockage site of the
artery, where the balloon is inflated to open up
the artery. This procedure is called percutaneous
transluminal coronary angioplasty or PTCA, which
is usually accompanied by the placement of a
metal tube (or stent) at the diseased site to
maintain vessel opening. PTCA is the dominant
procedure to restore blood flow in coronary
arteries- in the United States alone nearly 1.3
million PTCA procedures were performed in 2004.
However, as a response to PTCA-related vessel
wall damage, cells from the vessel wall are
activated to divide and grow into the vessel
lumen, causing re-narrowing or restenosis of the
artery. Restenosis of the vessel lumen is the
major hurdle limiting the success of PTCA. It           $3,330,931 Heart Disease
Human cytomegalovirus (HCMV) is the major
cause of birth defects, almost all of which are
neuronal in origin. Approximately 1% of
newborns are infected, and of the 13% that are
symptomatic at birth, 50% will have severe
permanent hearing deficits, vision loss, motor
impairment, and mental retardation. At least 14%
of asymptomatic infants also will later show
disabilities. Much of this effect is likely caused by
HCMV affecting neural development in the fetus.
Embryonic stem cells are an excellent source of
human progenitors, which are cells that can turn
into mature neurons i.e. neural differentiation.
We know from published cell culture studies that
HCMV affects neural progenitor cells during
neural differentiation, but it is unclear as to what
are the underlying molecular mechanisms for its
effect. A major goal of our research is to
understand at a high-resolution how HCMV
controls the way neural progenitors become
proper neurons. Elucidation of the genes that are
affected will serve as a basis for therapeutic
strategies to ameliorate the effects of HCMV
infection in newborns.



The significance of our studies also extends to the
serious problem of HCMV infection in
immunocompromised individuals, with recipients
of allogeneic transplants having a high risk of
severe disease and allograft rejection. This
potential problem in stem cell therapy has
received little attention thus far. The proposed
use of stem cell transplantation in treating
neuronal injury and neurodegenerative diseases,
as well as transplantation of other organ-specific
precursors, makes it imperative to understand
how disseminated HCMV infection in
immunosuppressed recipients will affect the
function and differentiation of the cells.             $1,372,660 Infectious disease, Neurological Disorders
With their ability to develop into virtually all
mature cell types, human pluripotent stem cells
(hPSC) represent a unique and powerful research
tool to study the fundamental mechanisms
regulating human development. In addition, hPSC
provide the "raw material" for the development
of cell-based therapies of presently incurable
diseases, such as cancer, cardiovascular disease,
and neurodegenerative disorders. However, our
understanding of the basic mechanisms
underlying stem cell biology is incomplete, and
the processes by which individual cells organize
each other to give rise to the complexity of
multicellular life remain mysterious. At the heart
of embryonic development lies an intricate
process of cell communication. Individual cells
within the developing organism produce and
release signals, known as growth factors, that
instruct neighboring cells to assume specific
behaviors and properties. Unique combinations
of such growth factors regulate a multitude of
developmental processes, including the growth
and differentiation of hPSC. Wnt proteins
represent a major class of growth factors with
potent effects on stem cells and developmental
processes. However, despite nearly 30 years of       $1,376,802
Some years ago it was discovered that patients
homozygous for a natural mutation (the delta-32
mutation) in the CCR5 gene are generally
resistant to HIV infection by blocking virus entry
to a cell. Building on this observation, a study
published in 2009 reported a potential "cure" in
an AIDS patient with leukemia after receiving a
bone marrow transplant from a donor with this
delta-32 CCR5 mutation. This approach
transferred the hematopoietic stem cells (HSC)
residing in the bone marrow from the delta-32
donor, and provided a self-renewable and lifelong
source of HIV-resistant immune cells. After
transplantation, this patient was able to
discontinue all anti-HIV drug treatment, the CD4
count increased, and the viral load dropped to
undetectable levels, demonstrating an effective
transplantation of protection from HIV and
suggesting that this approach could have broad
clinical utility. But donors with the delta-32 CCR5
mutation are not generally available, and so how
could we engineer an analogous CCR5 negative
state in human HSC needed for bone marrow
transplantation? A potential answer comes from
zinc finger nucleases (ZFNs) which have been
demonstrated to efficiently block the activity of a   $14,583,187 HIV/AIDS, Immune Disease

				
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