ANNUAL REPORT FOR CALENDAR YEAR s ALABAMA Birmingham University

ANNUAL REPORT FOR CALENDAR YEAR(s): 2006 2007 2008 2009 ALABAMA Birmingham - University of Alabama David Curiel, M.D., Ph.D. RG Exploiting transcytosis to facilitate adenovirus-mediated muscle cell transduction $90,000.00 Summary : 7/1/2005 6/30/2006 Year 3 This proposal seeks to improve systemic delivery of Ad vectors into muscle by targeting the vectors to the albumin transcytosis pathway, a cellular process employed by albumin to cross the endothelial barrier along the vessel walls. ARIZONA Phoenix - Barrow Neurological Institute Ruolan Liu, M.D., Ph.D. DG Induction of regulatory cells as a therapeutic strategy in experimental myasthenia $45,000.00 $45,000.00 $45,000.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 In this proposal, the investigators will evalutate the effects of a synthetic glycolipid agonist of NKT cells, a-galactosylceramide (a-GalCer) as a novel approach to treat experimental myasthenia via induction of regulatory cells. They expenct to identify a set of reagents that can be utilized to specifically induce beneficial regulatory cells and prepare for clinical trials using these reagents in MG patients. Phoenix - St. Joseph's Hospital & Medical Center Fu-Dong Shi, M.D., Ph.D. RG Immune therapy with Atorvastatin in murine models for clinical application to myasthenia gravis $80,000.00 1/1/2006 12/31/2006 Year 2 There is emerging evidence that statins have beneficial clinical effects in inflammatory and autoimmune diseases. In this project, investigators will determine the clinical efficacy, dosage, mechanisms of action and combination of statin with other therapy in myasthenia gravis. Summary : Phoenix - Translational Genomics Research Inc Dietrich A. Stephan, Ph.D. EMG Resequencing the variable human genome in sporadic ALS $652,056.00 Summary : 3/1/2006 2/28/2007 Year 1 Tucson - University of Arizona Page 1 Of 91 Ronald E. Allen, Ph.D. RG Regulation of skeletal muscle satellite cell activity $100,000.00 Summary : 1/1/2006 12/31/2006 Year 3 Muscle repair is critical to alleviating problems associated with Duchenne dystrophy, and the special repair cells, satellite cells, have also been suggested as potential replacement cells in stem cell therapy. Therefore, it is important to understand how satellite cells are regulated. Hepatocyte growth factor (HGF) is a key regulator of satellite cell activation and its action is regulated in stretched or injured muscle by releasing it from the surfac eof muscle fibers. The proposed experiments will investigate how HGF is released in response to mechanical perturbation of muscle. Understanding this process may enable the effectiveness of muscle stem cell therapy and muscle repair to be improved. Vince Guerriero, Ph.D. RG Neuromuscular diseases and misfolded proteins $57,040.00 $57,025.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 The purpose of this proposal is to provide new information on a cellular repair mechanism that could lead to the development of new therapies for the neuromuscular diseases oculopharyngeal muscular dystrophy and spinal and bulbar muscular atrophy. F. John Meaney, Ph.D. RG Promoting health and well-being in boys with muscular dystrophy $101,431.00 Summary : 1/1/2006 12/31/2006 Year 3 The objectives of the proposed research are: 1) to assess differences in the use and duration of use of assistive technology (AT) devices in a population of boys ages 5-21 years with Duchenne and Becker muscular dystrophy and 2) to investigate the effects of AT devices on health, well-being and quality of life. AT includes devices that enable a person with a disability to be more productive and independent in daily activities. The study will use existing data in medical records and data gathered from standardized questionnaires completed by subjects and their parents. Subjects will be recruited from a population-based study funded by the Centers for Disease Control and Prevention to investigate Duchenne and Becker muscular dystrophy. CALIFORNIA Davis - University of California Ricardo Maselli, M.D. RG Congenital myasthenic syndromes: Pathogenesis and treatment $100,000.00 Ricardo Maselli, M.D. RG Microarray analysis of congenital myasthenic syndromes $70,622.00 Summary : 1/1/2006 12/31/2006 Year 3 7/1/2005 6/30/2006 Year 2 The goal is to develop a high-throughput system based on microarray technology to search for genetic mutations in patients affected with congenital myasthenic syndromes, a heterogenous group of inherited diseases that result in variable degrees of muscle weakness and fatigue. Microarrays, small quartz elements that can hold millions of DNA probes, can interrogate genetic defects in multiple genes in a single biochemical reaction. Once developed, this tool can be used to investigate many other genetic disorders. Page 2 Of 91 Irvine - University of California Klemens J. Hertel, Ph.D. RG An alternative gene therapy approach for spinal muscular atrophy (SMA) $68,104.00 Summary : 1/1/2006 12/31/2006 Year 1 Because SMN2 cannot compensate for mutations within SMN1, SMN1 is the SMA-determining gene. More importantly, however, because all individuals with SMA have retained their SMN2 allele, therapy directed towards increasing SMN2 expression and/or SMN2 exon 7 inclusion could prove promising in lowering the clinical severity of SMA. In this proposal they will pursue a gene therapy based approach to correct SMN2 pre-mRNA splicing. They will also determine if the reduction in SMN compromises pre-mRNA splicing, as essential component of gene expression. John H. Weiss, M.D., Ph.D. RG Motor neuron ROS, glutamate transport disruption and amyotrophic lateral sclerosis (ALS) $100,000.00 $100,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 Using simple models, researchers have found that glutamate stimulation causes MNs to produce unusually large quantities of injurious free radicals. Furthermore, these free radicals can leave the MNs and disrupt nearby astrocyte glutamate pumps. These observations provide the basis for a new vicious cycle model of ALS. The proposed project aims to further test this model, and to examine therapeutic interventions suggested by the model that may slow disease progression. Sara Winokur, Ph.D. RG Investigation of FSHD as a nuclear envelope disease $90,000.00 Summary : 7/1/2005 6/30/2006 Year 2 Expression profiling and cellular assays of FSHD indicate a defect in myogenesis. As 4q35 gene expression does not appear to be altered in FSHD via a position effect, it is proposed that FSHD may result from improper nuclear localization and anchoring of 4q35 chromatin to the nuclear envelope. This hypothesis is supported by the peripheral localization of 4qter FSHD gene region and the disruption of this localization in lamin A/C deficient fibroblasts. Kyoko Yokomori, Ph.D. RG Genome-wide analysis of silenced chromatin structures in normal and facioscapulohumeral dystrophy (FSHD) patient cells $100,000.00 1/1/2006 12/31/2006 Year 1 $100,000.00 1/1/2007 12/31/2007 Year 2 Facioscapulohumeral muscular dystrophy (FSHD) is associated with shortening of the D4Z4 repeat sequences on chromosome 4. How this leads to the disease remains unclear. The investigators identified specific protein binding and histone modificatons that determine the special chromatin structure of this repeat region, which is disrupted in FSHD. Since chromotin structures determine gene expression, they plan to characterize the requirement and timing of this special structure formation, and to search for any secondary changes of chromatin structures in FSHD using a high-throughput genome-wide microarray technique. Summary : La Jolla - Ludwig Institute for Cancer Research Page 3 Of 91 Christine Van de Velde, Ph.D. DG The contribution of mitochondria to mutant SOD1-mediated motor neuron degeneration in ALS $45,000.00 7/1/2005 6/30/2006 Year 1 $45,000.00 7/1/2006 6/30/2007 Year 2 $45,000.00 7/1/2007 6/30/2008 Year 3 Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by the selective loss of motor neurons. The biological basis for this selective killing remains unknown. The investigator intends to determine the basis for this specificity and determine the role of mitochondria (the energy centers within cells) in this form of motor neuron degeneration. Summary : La Jolla - University of California John Ross, Jr., MD RG Cardiac gene therapy in muscular dystrophies $264,000.00 Summary : 1/1/2006 12/31/2006 Year 3 Many patients with Duchenne and Becker muscular dystrophy have cardiomyopathy and severe cardiac dysfunction. Investigators have developed a new gene therapy approach to prevent heart failure progression in experimental models of genetic myopathies that correspond to forms of human muscular dystrophy. Koji Yamanaka, M.D., Ph.D. DG The role of ALS2 in the post-natal survival of human motor neurons $45,000.00 $45,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 Two genetic causes of ALS are now known, including a mutation (named ALS2) which generates a motor neuron disease in infants and juveniles that progresses. The Researchers will focus on identifying how the loss of the ALS2 protein gives rise to the selective death of the motor neurons. Loma Linda - Musculoskeletal Disease Center Ashok Kumar, Ph.D. RG Myogenic signaling and Duchenne muscular dystrophy (DMD) $75,000.00 Summary : 1/1/2006 12/31/2006 Year 3 DMD patients appear perfectly normal at birth and develop dystrophic phenotypes only around eighteen months to four years of age. Using a mouse model of DMD, researchers will study the abnormal cell signaling in skeletal muscles before the onset of the disease. The findings will help in development of effective means for molecular/pharmacological intervention, allowing correction of the aberrant cellular physiology that results in the dystrophy. Los Angeles - University of California Fabian Chen, M.D., Ph.D. RG Analysis of a Mbn12 mutant mouse model of myotonic dystrophy (DM) $140,000.00 $140,000.00 $140,000.00 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 Page 4 Of 91 Summary : DM is associated with abnormal RNA expansions in two genes. The generation of mutant RNAs affects the muscleblind family of molecules ability to control mRNA processing. As a result, defective molecules are produced in the skeletal muscle and other organs affected in DM patients. Muscleblind2 (Mbnl2) is potentially important in the pathogenesis of DM. Investigators propose to analyze Mbnl2 using C2C12 skeletal myoblasts, and a mouse mutant of Mbnl2 that they generated. This will lead to an improved understanding for myotonic dystrophy. Rachelle H. Crosbie, Ph.D. RG Role of Akt signaling in muscular dystrophy $120,000.00 $120,000.00 $120,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 The objective of this proposal is to directly test a new therapy to decrease muscle wasting and improve muscle growth in animal models of various forms of muscular dystrophy, including DMD, AR-LGMD, and CMD. The investigators propose that early therapeutic intervention to boost Akt signaling may be beneficial in enhancement of muscle growth and prevention of muscle wasting associated with many chronic diseases. Future studies also include the establishment of an ELISA assay to screen for small molecules that upregulate Akt activation in muscle cells. Michael Graves, M.D. EMG Restricted funds for support of the MDA/ALS Clinic and Research Center $10,500.00 Summary : 4/1/2005 3/31/2006 Year 3 Carla M. Koehler, Ph.D. RG Strategies to characterize mitochondrial myopathies and develop therapeutics $107,633.00 $110,557.00 $114,177.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 The goal of this proposal is to understand the underlying mechanism by which mitochondrial dysfunction contributes to myopathy by investigating the pathways in the mouse model. The investigator will expand the small molecule studies into cultured cells and the mouse model to serve as a platform for developing therapeutics. York Marahrens, Ph.D. RG Designer proteins to identify FSHD genes and control mechanism $22,550.00 Summary : 7/1/2005 6/30/2006 Year 3 FSHD is a neuromuscular disorder that arises when patients are missing a number of tandemly repeated DNA sequences, located near the end of chromosome 4. It is thought that an unidentified disease gene, located somewhere far away from the repeats, malfunctions when the repeats are missing. Based on what we know about how repeats work, researchers hypothesize that looping interactions bring the repeats in physical contact with the FSHD gene, allowing the repeats to influence the gene. They propose to identify the FSHD gene by attaching a chemical to the repeats in live cells that modifies chromosomal sites that it contacts. The FSHD gene is then identified by virtue of it smodification that occurs when it touches the repeats/chemical. Page 5 Of 91 Gaynor Miller, Ph.D. DG Alternate splicing of sarcospan: Insights into muscular dystrophy $45,000.00 Summary : 1/1/2006 12/31/2006 Year 3 The current proposal is focused on isolation and characterization of novel isoforms of sarcospan, an integral component of the dystrophin-glycoprotein complex (DGC). This research will advance our understanding of the role of the DGC in normal muscle and in dystrophic muscle. In the long term, the results may lead to the identification of novel muscular dystrophies and contribute to the discovery of their treatment. Melissa Spencer, Ph.D. RG Proteomic analysis of calpain 3 and muscle remodeling $100,000.00 $100,000.00 Melissa Spencer, Ph.D. RG Investigation of Trim32 using biochemistry and mouse models to understand LGMD2H and SMA $109,450.00 1/1/2006 12/31/2006 Year 1 $109,450.00 1/1/2007 12/31/2007 Year 2 $109,450.00 1/1/2008 12/31/2008 Year 3 The investigators are investigating the protein mutated in limb girdle muscular dystrophy 2H and sarcotubular myopathy to gain insight into disease mechanisms. 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 Summary : James Tidball, Ph.D. RG Nitric oxide synthase modulation of dystrophinopathy $90,000.00 James Tidball, Ph.D. RG Inflammatory cell-mediated pathology in dystrophin-deficient mdx diaphragm muscle $100,000.00 James Tidball, Ph.D. RG Regulation of neurogenesis in the brains of mdx mice by systemic delivery of nitric oxide $100,000.00 $100,000.00 $100,000.00 Summary : 7/1/2005 6/30/2006 Year 3 1/1/2006 12/31/2006 Year 2 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 DMD is associated with deficiencies in learning and memory that are consistent with defects in the formation of new neurons in specific areas of the brain. The investigators have shown that increased production of a molecule called mitric oxide by muscle can correct defects in brain neurogenesis in the mdx mouse model of DMD. In this investigation, they will test whether defects in nitric oxide production by mdx muscle cause perturbations in brain neurogenesis. They will also test whether pharmacological treatments to increase NO in circulation can correct defects in brain neurogenesis in mdx mice. Michelle Wehling-Henricks, Ph.D. DG $45,000.00 $45,000.00 $45,000.00 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 Page 6 Of 91 Summary : The general objective of this study is to further understand the pro-fibrotic mechanisms in dystrophin-deficient muscle and more specifically, how inflammatory cells and nitric oxide (NO) deficits may contribute to the fibrosis. In the long term, the results of this study may lead to the development of anti-fibrotic therapies for DMD patients. Martina Wiedau-Pazos, M.D., Ph.D. RG Motor neuron specific gene expression profile in amyotrophic lateral sclerosis (ALS) $98,349.00 $72,489.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 1 Year 2 Mechanism-based therapies of amyotrophic lateral schlerosis are unavailable because cell mechanisms that underly selective motor neuron vulnerability remain a mystery. To discover early triggers of neurodegeneration, the investigators propose to identify key gene expression changes specific to motor neurons before disease onset from two mouse models of motor neuron disease. Consequently, early genetic markers and pathways specific for motor neuron disease will be identified. Fruther functional assessment of identified genes may provide the framework of candidates therapeutic targets for ALS prevention and treatment. Los Angeles - University of Southern California Valerie Askanas, M.D., Ph.D. RG Mechanisms involved in protein aggregation in s-IBM $100,000.00 $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 Sporadic inclusion-body myositis (s-IBM), the most common muscle desease of patients age 50 years and older, is of unknown cause and pathogenesis. Its steadily progressive course leads to severe disability, and there is no successful treatment available. The investigators have previously demonstrated that amyloid-beta and several other proteins that are accumulated in the brains of patients with Alzheimer disease are accumulated within s-IBM muscle fibers, and that small aggregates of those proteins could be very toxic to muscle fibers. In this proposal the investigators will study the mechanisms of how the toxic aggregation of proteins occurs and how to prevent it. W. King Engel, M.D. EMG Restricted funds for neuromuscular disease research $327,236.00 Summary : 4/1/2005 3/31/2006 Year 3 Sita Reddy, Ph.D. RG Role of the muscleblind proteins in myotonic dystrophy (DM) $110,000.00 Sita Reddy, Ph.D. RG Dissecting CNS dysfunction in myotonic dystrophy (DM) $95,000.00 1/1/2006 12/31/2006 Year 3 1/1/2005 6/30/2006 Year 3 Page 7 Of 91 Summary : DM1 patients suffer from progressive degenerative changes in the brain and the development of psychiatric illness. In this application, researchers propose to determine the molecular basis for the development of pathology in the brain in DM1. The proposed drug rescue experiments will facilitate the identification of one or more classes of drugs that could ameliorate features of psychiatric disease in DM1 patients. Thus, these experiments will provide key insights into the molecular mechanisms underlying the development of brain dysfunction in DM1 and facilitate the development of a therapy for this incurable disorder. Palo Alto - Stanford University Alessandra Sacco, D.Sc. DG Molecular mechanisms underlying the fusion of myelomonocytic precursors with muscle cells $45,000.00 1/1/2006 12/31/2006 Year 1 $45,000.00 1/1/2007 12/31/2007 Year 2 $45,000.00 1/1/2008 12/31/2008 Year 3 The goal of the current proposal is to identify proteins involved in the fusion of bone marrow derived cells with muscle cells, as these factors could substantially increase the frequency of BMDC contribution to skeletal muscle in vivo and be used as powerful tools for ameliorating muscle wasting diseases including muscular dystrophies. Summary : Pasadena - California Institute of Technology David C. Chan, M.D., Ph.D. RG Role of mitochondrial fusion in mitochondrial myopathies $75,000.00 Summary : 7/1/2005 6/30/2006 Year 2 Researchers will use mouse models to elucidate the role of mitochondrial fusion in adult skeletal and heart muscle. These studies will advance the understanding of how mitochondria within human tissues cooperate, and have important implications for the pathogenesis and possible treatment of mitochondrial myopathies. Sacramento - University of California David Pleasure, M.D. RG Neuropilin-2 facilitates axonal regeneration in PNS $95,064.00 Summary : 7/1/2005 6/30/2006 Year 3 Investigators have shown that neuropilin-2 (NP2) facilitates axonal regeneration. They will investigate the mechanism of this trophic effect of NP2, and its relevance to therapy for motor neuron diseases. San Diego - San Diego State University Sanford I. Bernstein, Ph.D. RG Analysis and amelioration of defective protein folding in skeletal muscle $98,933.00 1/1/2006 12/31/2006 Year 3 Page 8 Of 91 Summary : Defects in protein folding cause a number of neuromuscular diseases. Researchers propose to determine how mutations in a molecular chaperone, a protein that normally aids in protein folding, affect muscle development and function. Further, they will use novel genetic and transgenic approaches to suppress the myopathies that result from the chaperone mutations. Their research will lead to a better understanding of how defective protein folding causes abnormalities in muscle structure and function. The studies designed to suppress muscle defects engendered by the mutations in the molecular chaperone will provide insights as to how such human myopathies can be ameliorated. San Francisco - California Pacific Medical Center Robert Miller, M.D. EMG Restricted funds for support of the MDA Clinic - Zimmerman Fund $238,480.59 Robert G. Miller, M.D. TRA C Summary : 4/1/2005 3/31/2006 Year 7 MDA/ALS Web-based Database $160,848.00 8/1/2005 7/31/2006 Year 3 The information retrieved from the MDA/ALS Web-based Database will help determine the cause of ALS and aid patients and physicians in managing ALS. San Francisco - San Francisco State University Laura W. Burrus, Ph.D. RG Analysis of Pax-3/7 and Wnt signaling in embryonic myogenic progenitor cells $100,000.00 $100,000.00 $100,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 Researchers will study the molecules involved in the specification and maintenance of embryonic muscle progenitor cells. Insights about the molecular nature of these cells will enable the design of therapies to generate health muscle tissue from embryonic stem cells. San Francisco - University of California Sachiko Hoshino, M.D., Ph.D. DG CHC22 clathrin in normal and regenerating muscle $45,000.00 $45,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 This research will test the hypothesis that CHC22 plays a role in specialized muscle organization during development and regeneration of muscle and will have a long term impact on understanding muscle disease and repair mechanisms to design therapy. Mei Li, M.D., Ph.D DG Analysis of the effects of ROCK inhibitor Y-27632 in an SBMA mouse model $45,000.00 $45,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 This project will test the therapeutic effects of Y-27632 in mouse models of neurodegenerative disease. Page 9 Of 91 Charles Ordahl, Ph.D. RG Myogenic progenitor cells: A new muscle stem cell class $81,793.00 Summary : 7/1/2005 6/30/2006 Year 3 Successful myoblast transfer therapy depends upon the ability of implanted myogenic cells to build and organize new muscle tissue from scratch. A newly discovered type of embryonic stem cell, named Myogenic Progenitor Cells, possess this essential characteristic. Researchers have successfully isolated thse cells and analyzed their activities in vivo, both in situ and after transplantation. The research proposed here is directed at growing (expanding) MPCs in vitro and identifying the cellular and molecular properties that confer their tissue building capacities. These properties are expected to yield new information about how therapeutic myoblast transfer might be improved to the point of being practical. Jieya Shao, Ph.D. DG Importance of AR/Actin interaction in spinobulbar muscular atrophy pathogenesis $45,000.00 $45,000.00 $45,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 This project seeks to determine the molecular mechanism of a promising therapeutic compound for SBMA. Additionally, by exploring the role of the cytoskeleton in regulating pathogenesis, it may lead to the discovery of a novel regulatory mechanism for SBMA and possibly other related neurodegenerative diseases. San Jose - Edison Pharmaceuticals Guy Miller, M.D., Ph.D. EMG Restricted funds for neuromuscular research $100,000.00 Summary : 4/1/2005 3/31/2006 Year 1 Stanford - Stanford University Carmen Bertoni, Ph.D. DG Oligonucleotide mediated gene repair for Duchenne muscular dystrophy (DMD) $45,000.00 Summary : 1/1/2006 12/31/2006 Year 3 DMD is a devastating disease caused by defects in the dystrophin gene. The goal is to correct the genetic defects using DNA molecules called oligonucleotides. Every living cell has the ability to repair gene mutations naturally occuring (for example in cells that are exposed to sun damage). Those repair mechansisms are present in DMD patients. Using oligonucleotides, they can send a message to the cells informing them that the dystrophin gene is mutated and in which region the mutation needs to be repaired. This type of technology has the potential to treat the disorder efficiently and permanently and holds great promise for the treatment of DMD patients. Guowei Fang, Ph.D. RG Role of ubiquitin-mediated proteolysis in muscular dystrophies $106,335.00 1/1/2006 12/31/2006 Year 3 Page 10 Of 91 Summary : Muscle wasting, or muscle atrophy, occurs as a consequence of denervation at the neuromuscular junction and is associated with diseases of neuromuscular junctions, such as myasthenia gravis and Lambert-Eaton syndrome. Muscle atrophy is also associated with cancer, AIDS and other systemic diseases. Muscle atrophy primarily results from accelerated protein degradation in affected muscle cells. Investigators propose experiments here to investigate molecular defects that cause muscle atrophy, which will provide molecular targets for pharmaceutical intervention, leading to the development of novel therapies for the treatment of atrophy in muscular dystrophies. David A. Lyons, Ph.D. DG Characterization and rescue of a zebrafish kif1b mutant, a model of Charcot-Marie-Tooth disease type 2A (CMT2A) $45,000.00 1/1/2006 12/31/2006 Year 1 $45,000.00 1/1/2007 12/31/2007 Year 2 $45,000.00 1/1/2008 12/31/2008 Year 3 In this proposal the researchers describe a series of experiments that aim to test the function of a gene called kif1b during nervous system development in zebrafish. Mutations in this gene can cause a form of CMT, CMT2A, in humans. The researchers also propose a strategy to identify compounds that can cure the defects in zebrafish with defective kif1b. This may provide the opportunity for future therapeutic intervention into CMT2A. Summary : Lorene M. Nelson, Ph.D. RG Cholesterol-lowering medication as risk and prognostic factors for ALS $99,035.00 $102,352.00 $93,915.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 The primary objective of this study is to investigate whether the use of cholesterol-lowering medications increases the risk of developing ALS or influences the rate of disease progression among individuals who have ALS. If cholesteral or cholesterol-lowering medications are shown to play a role in development or prognosis of ALS, this will contribute to knowledge about the biological mechanisms of motor neuron disease. Thomas A. Rando, M.D., Ph.D. RG Integrase-mediated gene therapy for muscular dystrophy $120,000.00 $120,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 Investigators will use a new technology to incorporate a normal copy of the dystrophin gene into muscle that lacks dystrophin. This technique does not involve the use of any viruses and will allow for long-term dystrophin expression. The results of the studies will advance the field of non-viral gene therapy for Duchenne muscular dystrophy and provide a basis for the translation of this approach from animal models to humans. Ching H. Wang, M.D., Ph.D. RG A pilot therapeutic trial of hydroxyurea on type 1 spinal muscular atrophy (SMA) $100,000.00 Ching Wang, Ph.D. SG International Conference on Standard of Care for Chiildren with Spinal Muscular Atrophy $20,000.00 3/1/2006 3/30/2006 Year 1 7/1/2005 6/30/2006 Year 3 Page 11 Of 91 Summary : Hai Wu, Ph.D. DG Calcineurin/NFAT signaling and the generation of V1 interneurons $45,000.00 Summary : 7/1/2005 6/30/2006 Year 2 This proposal seeks to elucidate the mechanisms by which NFATc signaling patterns the spinal cord. The research will provide insights into the embryonic development of spinal cord neurons that coordinate muscular actions. In doing so they will define a new set of targets for therapeutic development and intervention against motor diseases. COLORADO Boulder - University of Colorado Hugo Olguin, Ph.D. DG Pax-7 role in satellite cell self-renewal $45,000.00 $45,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 Investigators have recently found that a transcription factor (crucial for satellite cell specification during development) is able to induce a quiescent and undifferentiated state in activated satellite cells even in the presence of proliferation signals. They hope that manipulating satellite cell differentiation and renewal would improve muscle regeneration causing delayed loss of muscle function in dystrophic patients. Denver - University of Colorado William Betz, Ph.D. RG Synaptic vesicle recycling in motor nerve terminals $66,000.00 Summary : 7/1/2005 6/30/2006 Year 3 A resting skeletal muscle fiber is like a sleeping giant. To arouse it to contract, a motor nerve terminal - which is about 10,000 times smaller than the muscle fiber it innervates must secrete large amounts of acetylcholine, faithfully and repeatedly to keep the muscle fiber contracting. A collection of acetylcholine storage vesicles inside the nerve terminals is repeatedly emptied and refilled to accomplish this. Investigators study this synaptic vesicle recycling in the belief that a better understanding of fundamental processes will be beneficial in treating neuromuscular diseases. Page 12 Of 91 CONNECTICUT New Haven - Yale University Anton M. Bennett, Ph.D. RG Muscle cell survival by protein tyrosine phosphatases in muscular dystrophy (MD) $100,000.00 Summary : 1/1/2006 12/31/2006 Year 3 Cell life and death are regulated by a process called protein tyrosine phosphorylation. This application will focus on elucidating how molecules which regulate protein tyrosine phosphorylation are involved in coupling the dystrophin glycoprotein complex to muscle cell survival. DIST OF COLUMBIA Washington - Children's National Medical Center Eric P. Hoffman, Ph.D. RG Transcriptional cascades in muscle regeneration $90,000.00 $90,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 The proposed research takes advantage of new technologies to study the action of all genes in the genome during the process of regeneration. The previous and proposed research provides enormous amounts of data, and has implemented public access tools so that scientists worldwide are able to easily study the data from this grant. Kanneboyina Nagaraju, EMG Restricted funds for research of Duchenne muscular dystrophy $67,117.76 Summary : 4/1/2005 3/31/2006 Page 13 Of 91 FLORIDA Gainesville - University of Florida Brian Harfe, Ph.D. RG Role of dicer and miRs in muscle development, maintenance and regeneration $110,452.00 $110,000.00 $110,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 The investigators propose to investigate the role of microRNAs in muscle development and/or regeneration by removing Dicer, a gene that is essential for processing microRNAs to their mature form, specifically in muscle cells. Analysis of the defects produced in these mutant mice will help to understand the role these factors have in regulating gene expression in human muscle cells. Lucia Notterpek, Ph.D. RG Protein aggregation and degradation in Charcot-Marie-Tooth (CMT) disease $117,147.00 Summary : 1/1/2006 12/31/2006 Year 3 Utilizing cells from CMT disease mice, investigators will explore if stimulating endogenous glial mechanisms that may have become less efficient with age, can provide viable targets for therapy. Jacksonville - Mayo Clinic Jacksonville Terrone Rosenberry, Ph.D. RG Interactions in the active site of acetylcholinesterase $56,000.00 Summary : 1/1/2006 12/31/2006 Year 3 The catalytic activity of the enzyme acetylcholinesterase is essential for normal cholinergic transmission and neuromuscular function. These studies will clarify features of the catalytic mechanism that are not yet well understood. Inhibitors fo this enzyme have been useful in diagnosis of myasthenia gravis and treatment of Alzheimer's disease. One of the long-term goals is to utilize new insights to design inhibitors that will selectively block the inactivation of AChE by organophosphate pesticides and nerve gas agents. Miami - University of Miami Antoni Barrientos, Ph.D. RG Role of evolutionary conserved cytochrome c oxidase assembly factors $75,000.00 $75,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 The main objective of this proposed research is to investigate COX assembly in wild type cells and in cells with mutations in three evolutionary conserved assembly factors, using the yeast Saccharomyces cerevisiae as a model. Walter Bradley, M.D. EMG Restricted funds for support of the Kessenich Family MDA/ALS Center $150,000.00 4/1/2005 3/31/2006 Year 7 Page 14 Of 91 Walter Bradley, DM, FRCP PPG Hyperbaric oxygen therapy in amyotrophic lateral sclerosis (ALS) $256,770.00 Summary : 1/1/2006 12/31/2006 Year 1 This study will determine if Hyperbaric Oxygen therapy is of benefit with a double blind placebo controlled trial of HBO versus sham hyperbaric treatment. Preliminary studies suggest that HBO improves strength in the disease. This project is of relevance to the mission of MDA to find effective treatments for ALS. A positive outcome in this trial would lead to the development of more practical ways of administering high dose oxygen for the treatment of ALS patients. Alison Grossman, Ph.D. DG Impact of psychosocial factors on ALS onset and disease progression $45,000.00 Summary : 7/1/2005 6/30/2006 Year 3 There is a widespread belief among ALS physicians that those patients who "fight the disease" have a slower rate of progression, and that the disease preferentially affects "nice" people. Investigators study will provide scientific evidence on these beliefs that at present are based on anecdotal observations, using novel approaches. Part A of the study will investigate how psychosocial variables related to "fighting spirit" impact upon ALS progression, adherence to medical recommendations, forced vital capacity and functional status. Part B will examine how "niceness," or premorbid personality characteristics are associated with development of ALS. They will analyze family members' ratings of sporadic ALS patients' premorbid personality traits. Stephen Lipschultz, EMG Restricted funds for neuromuscular research $300,000.00 Summary : 4/1/2005 3/31/2006 Year 1 Karl Magleby, Ph.D. RG Modulation of BK channels by beta subunits $77,337.00 Summary : 7/1/2005 6/30/2006 Year 3 The mechanism by which ion channels (small proteins) are modulated to control the activity of nerve and muscle cells will be examined. Carlos Moraes, Ph.D. RG Mitochondrial dysfunction in amyotrophic lateral sclerosis (ALS) $98,906.00 Summary : 7/1/2005 6/30/2006 Year 3 Several lines of evidence showed that mitochondria is involved in the pathogenesis of ALS. A transgenic model harboring a mutated SOD1 gene also showed mitochondrial abnormalities. Investigators plan to explore this concept and produce transgenic mice that express the mutant protein in the mitochondria. If the disease is also observed in these models, they will have gained valuable information on the mechanisms related to the pathogenesis of ALS. Spiridon Papapetropoulos, M.D., Ph.D. RG Cyanobacterial toxin (BMAA) in postmortem brain tissue and hair samples of ALS patients $110,000.00 $110,000.00 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 1 Year 2 Page 15 Of 91 Summary : Exposure to high concentrations of a naturally occurring, non-protein amino acid called beta-N-methylamino-l-alanine (BMAA) has been associated with a rare form of ALS found n the south pacific island of Guam. Recently, examination of brain tissue of ALS patients in Guam and a very small number of sporadic ALS and Alzheimier's disese cases in the US and Canada revealed high concentrations of BMAA. The objective of this application is to study this association by meaasuring BMAA concentration in brain tissue and hair samples of ALS, Alzheimer's disease and Parkingson's disease patients. The results may have an impact on prevention, etiology and treatment of ALS. St. Augustine - University of Florida Fumihito Ono, M.D., Ph.D. RG Molecular basis of myasthenia-like syndromes in mutant synapses $99,000.00 $99,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 Researchers have identified zebrafish locomotion mutants with genetic defects related to those seen in human neuromuscular diseases. They will use these mutants to study the disease process. GEORGIA Athens - University of Georgia Lance Wells, Ph.D. RG Glycan site-mapping and characterization of alpha-dystroglycan $90,509.00 $93,224.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 1 Year 2 Several forms of congenital muscular dystrophy are caused by genetic mutations that affect the normal ability of cells to add sugars onto specific proteins. These sugar modifications are often times necessary for proteins to function properly. The investigators shall determine what sugars are added and where they are found on aplha-dystroglycan, a modified protein that works improperly in several forms of congenital muscular dystrophy. This work will lay the necessary groundwork for the assignment of functional consequences to the sugar additions and the development of rational sugar-based therapeutics. Atlanta - Emory University Gary J. Bassell, Ph.D. RG Axonal function of the survival of motor neuron protein $75,000.00 Summary : 1/1/2006 12/31/2006 Year 3 Spinal muscular atrophy (SMA) is caused by mutations or deletions in a gene (SMN). In this proposal, researchers will test the hypothesis that one important function for SMN is to participate in the mechanism of mRNA localization within neurons, which is essential for the normal development of nerve cells. Grace Pavlath, Ph.D. RG Regulation of myoblast migration and fusion by class III semaphorins $80,000.00 1/1/2006 12/31/2006 Year 2 Page 16 Of 91 Summary : Class III semaphorins are secreted molecules that influence cell migration and tissue development. To date, the role of semaphorins in muscle cells has never been studied. Investigators will determine if such semaphorins regulate migration of muscle cells as well as their ability to form differentiated myotubes. Molecules that control muscle cell migration and fusion are of great interest from a therapeutic standpoint to enhance growth of muscle or to alleviate the loss of muscle mass found in dystrophies. Augusta - Medical College of Georgia Lin Mei, M.D., Ph.D. RG Erbin regulation of AChR expression $90,000.00 Lin Mei, M.D., Ph.D. RG Molecular mechanisms of neuromuscular junction formation $100,000.00 $100,000.00 $100,000.00 Summary : 7/1/2005 6/30/2006 Year 3 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 Muscle contraction occurs when the neurotransmitter acetlycholine binds to its receptor (AChR). This receptor needs to be concentrated at the neuromuscular junction (NMJ) where the nerve contacts the muscle for efficient neurotransmission. Improper localization and malfunction of the AChR is implicated in neurological disorders including the congenital myasthenic syndrome and myasthenia gravis. The proposal is aimed at understanding mechanisms of AChR clustering. It is prerequisite to a better understanding of NMJ disorders and development of therapeutic interventions. ILLINOIS Chicago - Northwestern University Robert Goldman, Ph.D. RG Functional aspects of nuclear lamins in muscular dystrophy $116,557.00 Summary : 7/1/2005 9/30/2006 Year 3 This research is aimed at determining the functional alterations in lamins that are related to EDMD and LGMD mutations. The biochemical and structural information obtained from these studies will provide important insights into the molecular basis of these diseases. The results will be useful in the development of therapies for these forms of muscular dystrophy. Jianhua Yan, M.D. DG A molecular target for amyotrophic lateral sclerosis (ALS) therapy: A gene for ALS/FTD $45,000.00 Summary : 7/1/2005 6/30/2006 Year 3 Identification of the causative gene of ALS/FTD will lead to the development of specific therapy. They can establish animal models to study mechanism of the disease, to identify molecular targets to develop therapy which can be tested on the animal models. It will also be possible to offer highly accurate diagnostic tests and provide clinical screening and genetic counseling to patients with ALS/FTD. These experiences could also be utilized in studying other forms of ALS. Chicago - University of Chicago Page 17 Of 91 Michael J. Allikian, Ph.D. DG Drosophila models to dissect sarcoglycan trafficking and function $45,000.00 $45,000.00 $45,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 In progressive forms of limb girdle muscular dystrophy the exact function of this complex of sarcoglycans is unknown. The fruit fly contains a simpler sarcoglycan complex than what is found in man. This simpler system should be easier to study while remaining highly relevant to humans. James R. Brorson, M.D. RG Glutamate receptors on corticospinal motor neurons and amyotrophic lateral sclerosis (ALS) $38,125.00 7/1/2005 6/30/2006 Year 3 The corticospinal neurons, carrying the brain's directions for motor activity to the spinal centers enervating the muscles, are essential to all coordinated movement. These cells are a vulnerable population in diverse conditions ranging from the motor neuron degeneration of ALS to spinal cord traumatic injuries. Nevertheless, little is known about their functional properties. Through a fluorescence labeling technique and application of electrical recording techniques, we can characterize in detail their possession of the receptors activated by the neurotransmitter glutamate, and discover whether overactivation of these receptors is an important cause of toxicity in these neurons. Summary : Elizabeth McNally, M.D., Ph.D. RG Stem cell transplantation in limb-girdle muscular dystrophy $88,007.00 7/1/2005 6/30/2006 Year 3 Elizabeth McNally, M.D., Ph.D. SG New Directions in Muscle Biology and Disease Meeting $25,000.00 Summary : 4/1/2006 4/30/2006 Year 1 This meeting is to bring together experts to discuss muscle disorders of various types and to evaluate potential avenues for therapy in the muscular dystrophies. Raymond Roos, M.D. EMG Restricted funds for neuromuscular research $5,965.00 Summary : 4/1/2005 3/31/2006 Year 1 Kamal Sharma, Ph.D. RG SMN regulates motor neuron subtype identity $100,000.00 $100,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 The proposal to determine the function of SN in the development of embryonic motor neurons and to define the latest stage at which decrease of SMN protein expression is reversible directly attacks the problem at hand. The assay we have developed to assess the role of SMN in motor neurons is ideal for rapid testing of potential therapeutic reagents. Page 18 Of 91 Chicago - University of Illinois Brian Ackley, Ph.D. DG Nidogen and LAR phosphatase function during the formation of C. elegans neuromuscular junctions $45,000.00 1/1/2006 12/31/2006 Year 2 The extracellular matrix provides both instructive and supportive roles at the neuromuscular junctions (NMJs). To reform NMJs as part of effective MD therapies it is essential to understnd how the ECM functions distinctly to instruct neurons to find muscle and subsequently form NMJs. Summary : David Featherstone, Ph.D. RG Molecular mechanisms regulating extracellular glutamate $80,985.00 Summary : 1/1/2006 12/31/2006 Year 3 All forms of amyotrophic lateral sclerosis (ALS) seem to involve abnormally high levels of extracellular glutamate. Glutamate is the major excitatory neurotransmitter in the central nervous sytem, and high extracellular levels of glutamate have long been known to be neurotoxic and are implicated in many neurodegenerative diseases. It is likely that abnormal extracellular glutamate levels cause or contribute to ALS. Using Drosophila genetics, researchers will relatively quickly identify the molecular mechanisms by which extracellular glutamate is regulated in the neuromuscular system. This will help us understand what causes ALS and also identify potential new drug targets. Springfield - Southern Illinois University Julio A. Copello, Ph.D. RG Coordinated gating of ryanodine receptor channels $80,000.00 Summary : 1/1/2006 12/31/2006 Year 3 Ryanodine receptors (RyR1) are ion channels that permit calcium to enter the cytoplasm of muscle cells and trigger contraction. The RyR1 channels turn-on and turn-off in a highly synchronous way. Investigators will isolate and study groups of RyR1 channels from skeletal muscle in order to establish the nature of the molecular mechanisms that synchronize their operation in cells. This knowledge will provide important insights into the initiation and termination of RyR1-mediated intracellular calcium signals in muscle. These studies are essential to understand normal muscle physiology as well as lay the basis to understanding anomalies of intracellular calcium mobilization in muscle diseases. Urbana - University of Illinois Suzanne Berry, Ph.D. DG Integrin enhancement of mesoangioblast cell therapy $45,000.00 $45,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 The proposed research will focus on using vessel-derived stem cells expressing the alpha7beta1 integrin to alleviate the development of muscle disease in mouse models for limb-girdle muscular dystrophy and Duchenne muscular dystrophy. Stephen Kaufman, Ph.D. RG Integrin alleviation of muscular dystrophy $90,000.00 7/1/2005 6/30/2006 Year 2 Page 19 Of 91 $90,000.00 Summary : 7/1/2006 6/30/2007 Year 3 The proposed research is aimed at determining whether increasing integrin levels in mice with mutations in other genes that cause muscle diseases in humans will prevent development of those diseases. The Researchers will also develop an experimental system to identify compounds that can increase integrin in muscle and inhibit the development of these diseases. Derek Milner, Ph.D. DG Alpha-7 beta-1 integrin mediated alleviation of muscular dystrophy $45,000.00 Summary : 7/1/2005 6/30/2006 Year 3 Investigators propose to determine if enhanced expression of the alpha-7 beta-1 integrin can ameliorate the development of pathology seen in mouse mutant models for several forms of muscular dystrophy. INDIANA Muncie - Ball State University Derron Bishop, Ph.D. RG Axon loss in a mouse model of amytrophic lateral sclerosis (ALS) $83,867.00 Summary : 7/1/2005 6/30/2006 Year 3 This project will resolve the cellular defects within degenerating motoneurons in a mouse model of ALS using three-dimensional confocal and electron microscopy. Page 20 Of 91 IOWA Iowa City - The University of Iowa Kevin P. Campbell, Ph.D. SG Frontiers in Myogenesis Conference $15,000.00 Summary : 4/1/2006 5/31/2006 Year 1 The purpose of this conference is to present and discuss recent major advances in basic muscle development and genetics. Iowa City - University of Iowa Kevin P. Campbell, Ph.D. EMG Restricted funds for limb-girdle research $60,480.00 Kevin Campbell, Ph.D. RG Development of treatment strategies for LGMD2I $100,000.00 $100,000.00 Summary : 4/1/2005 3/31/2006 Year 3 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 This project focuses on exploring the therapeutic potential of two very interesting molecules (LARGE and dysferlin) that are essential for normal muscle function. The overall results of these experiments will assess the possibility that increased LARGE or dysferlin expression can compensate for the loss of FKRP function in LGMD2I patients. Focusing on endogenous proteins will bypass acquired immune responses and also provide a new strategy for developing drugs to upregulate LARGE or dysferlin expression or activity in order to treat LGMD2I. Shawn W. Flanagan, Ph.D. RG The effect of mitochondrial anti-oxidant manipulation on mutant SOD1 cytotoxicity $79,884.00 Summary : 1/1/2005 3/30/2006 Year 2 Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, with little therapeutic treatment currently available. While the majority of cases are sporadic and the cause unknown, a small proportion are linked to mutations in superoxide dismutase 1 (SOD1), the gene encoding the antioxidant CuZnSOD. This proposal will examine the hypothesis that mutant SOD1-induced mitochondrial damage is a pivotal event leading to subsequent cell death utilizing a novel adenovirus based system in differentiated human neuroblastoma cells. Lori Wallrath, Ph.D. RG Drosophila as a model for Emery-Dreifuss muscular dystrophy $82,484.00 Summary : 7/1/2005 6/30/2006 Year 3 Emery-Dreifuss muscular dystrophy is a rare muscular dystrophy characterized by muscle wasting and heart problems. Mutation of lamins, proteins that provide structural support in the nucleus of a cell, is one known cause of EDMD. It is hypothesized that cells undergoing mechanical stress, such as muscle cells, are sensitive to mutations in lamins. This proposal describes experiments to develop the fruit fly as a model system to test this "mechanical stress hypothesis." The fruit fly is well characterized model system in whcih genetics and locomotion assays can easily be performed. This research will she dlight on the intracellular defects associated with EDMD and lead to new strategies for therapy. Page 21 Of 91 KANSAS Kansas City - University of Kansas Medical Ctr Richard J. Barohn, M.D. RG MYO-029 RFA $35,035.00 Summary : 1/1/2006 12/31/2006 Year 1 The site is participating in a multicenter trial sponsored by Wyeth. This trial is studying the safety and effectiveness of MYO-029 in patients with Becker, facioscapulohumeral and limb-girdle muscular dystrophies. To participate in the trial, subjects need to have their diagnosis confirmed by wither genetic testing or the detection of abnormal protein in their muscle biopsies. A number of potentially eligible subjects followed in the clinic have not had any confirmatory testing. Genetic testing would not alter the management of these patients in the clinic. However, the results of this testing could allow them to be eligible for the MYO-029 trial. The investigators are requesting supplemental funds to cover the costs of confirmatory genetic testing in patients who do not have insurance to cover this. MAINE Bar Harbor - Jackson Laboratory Roger Sher, Ph.D. DG Role of choline kinase beta in a murine muscular dystrophy $45,000.00 $45,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 A mutation in Chk-b has been found in a mouse colony. A mutation in Chk-b does not correspond to any currently identified human muscular dystrophy. Understanding the biology of this mouse line may provide important insight into the biological pathways leading to muscular dystrophy and muscle repair. Orono - University of Maine Clarissa Henry, Ph.D. RG Myofiber Development in both Wild-type Zebrafish and a Mutant with Fiber Defects $71,948.00 $68,191.00 $69,291.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 The investigators are utilizing the zebrafish as a model system to understand embryonic muscle development and the recovery of muscle fiber development in Hedgehog pathway mutant zebrafish. The intention is to understand normal muscle development and recovery of muscle development when it is disrupted may lead to a greater understanding of potential therapies for muscle diseases and traumatic muscle injury. Page 22 Of 91 MARYLAND Baltimore - Johns Hopkins University Daniel B. Drachman, M.D. RG Specific immunotherapy of myasthenia gravis by gene transfer $133,900.00 Summary : 7/1/2005 6/30/2006 Year 3 This proposal is to continue work on a powerful gene transfer strategy to treat MG. Researchers have made extensive progress indicating that their method will lead to practical beneficial therapy for MG, and are now improving its efficiency in a mouse model of MG. This strategy will yield information that is scientifically important and will be applicable to other autoimmune neuromusuclar diseases in addition to MG. Douglas A. Kerr, M.D., Ph.D. RG Utilization of embryonic stem cells in motor neuron diseases $73,356.00 $73,356.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 Researchers will transplant ES-derived motor neurons from normal mice into SMA mice to investigate its potential as a therapeutic strategy. They will investigate strategies to enhance the abilities of ES-derived motor neurons to extend axons into peripheral nerves and form functional junctions with muscle. Sanjay Keswani, MBBS, MRCP RG Erythropoietin-mediated prevention of axonal degeneration $80,000.00 $80,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 1 Year 2 Erythropoeitin (EPO) prevents axonal degeneration, and thus may have therapeutic relevance to CMT. In this proposal, the investigators will investigate the molecular mechanisms underlying EPO's ability to prevent axonal degeneration. The investigators will do this by delineating signaling pathways induced by EPO in cultured neurons that have relevance to axonal integrity, maintenance and transport. The investigators will also investigate how Nitric Oxide functions as an axonal injury signal, inducing EPO production from adjacent Schwann cells. Finally, the investigators will evaluate if EPO administration prevents axonal degeneration and neurological disability in an animal model of CMT (PMP22 transgenic rat). Vassilis Koliatsos, M.D. RG Neural stem cells as experimental therapies for motor neuron disease $167,071.00 Summary : 1/1/2005 6/30/2006 Year 3 Researchers will establish the preclinical requirements for the consideration of neural stem cells as experimental therapies to replace dead motor neurons in motor neuron disease. Se-Jin Lee, M.D., Ph.D. RG Regulation of myostatin latency $145,465.00 $152,104.00 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 Page 23 Of 91 Summary : It is becoming increasingly apparent that targeting myostatin may be an effective strategy for enhancing muscle growth and regeneration in the setting of muscle degenerative diseases. The studies proposed here will elucidate the mechanisms by which myostatin activity is regulated extracellularly. Understanding how myostatin activity is normally regulated is critical to developing novel therapeutics targeting myostatin for the treatment of patients with muscular dystrophy. Jeffrey Rothstein, M.D. EMG Restricted funds for ALS research - Wings Over Wall Street $499,039.24 Summary : 4/1/2005 3/31/2006 Year 2 Kazim Sheikh, M.D. RG Quantitative MRI of the muscle in SOD1 mice $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 1 Year 2 This grant proposes to examine the utility, specificity, and sensitivity of muscle MRI as a tool to monitor disease course and as an outcome measure for preclinical drug screening in a well characterized animal model of amyotrophic lateral sclerosis. These experimental studies could potentially help in the development of imaging techniques and protocols that can be directly applicable to patients with neuromuscular disorders such as ALS and neuropathies. The working model and rationale of such an approach is spupported by the immense impact of brain MRI disease management and drug screening in mulitple sclerosis. Kathryn R. Wagner, M.D., Ph.D. RG Evaluation of myostatin mutations and expression for human therapy $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 1 Year 2 Loss of myostatin improves several of the features of the mdx mouse model of muscuular dystrphy. A clinical trial in adult muscular dystrophy with an inhibitor of myostatin has been initiated. The investigators propose experiments that will be helpful to understand the long term effects of modulating myostatin and in which disease settings myostatin modulation may be particularly useful. Baltimore - University of Maryland Robert J. Bloch, Ph.D. RG Intermediate filaments that organize the sarcolemma $99,337.00 $104,312.00 Robert Bloch, Ph.D. RG Signaling by the RhoGEF domain of obscurin $88,882.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 1/1/2006 12/31/2006 Year 2 Investigators are studying a giant protein, called "obscurin," that surrounds every contractile unit in every muscle fiber in both heart and skeletal muscle. Obscurin -it is not at all "obscure," but quite prominent - plays a key role in organizing the contractile apparatus. Investigator's think that obscurin also sends a signal with every contraction, and that the strength of its signal reflects the strength and duration of each contraction. Page 24 Of 91 Aikaterini Kontrogianni-Konstantopoulos, Ph.D. DG Proteins organizing the sarcomere and the SR of skeletal muscle $45,000.00 Summary : 7/1/2005 6/30/2006 Year 3 This proposal aims towards the functional characterization of the factors that govern the coordinated assembly of the SR with nearby sarcomeres and specify the diameter of the myofibrils. MASSACHUSETTS Allston - Brigham and Women's Hospital Ronan Walsh, MB, BCh, FRCPC CRT G Clinical Research Training $90,000.00 $87,500.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 1 Year 2 The Clinical Research Training Grant is designed to provide promising young physicians the research training opportunities that are needed to become productive clinical investigators in neuromuscular diseases. Grantees will receive training in the diagnosis and management of adults and children with neuromuscular diseases, complete formal coursework in clinical research methodologies, and complete a clinical research project during the two years of fellowship training. Amherst - University of Massachusetts Priscilla Clarkson, Ph.D. SG Sixth Annual S. Mouchly Small Muscle Symposium: Apoptosis $3,224.00 Summary : 3/1/2006 7/30/2006 Year 1 This conference is designed to bring scientists and clinicians together to learn more about how muscle cells die, a process called apoptosis. Boston - Boston University William Lehman, Ph.D. RG An atomic structure of dystrophin bound on F-actin $76,338.00 Summary : 1/1/2006 12/31/2006 Year 3 Researchers will determine dystrophin and utrophin cytoskeletal interactions to assess genetic replacement of defective dystrophin with utrophin in Duchenne and Becker muscular dystrophies. Boston - Brigham and Women's Hospital Steven Greenberg, M.D. RG Single cell molecular methods in the inflammatory myopathies $69,069.00 $71,093.00 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 Page 25 Of 91 Steven Greenberg, M.D. RG Drug discovery for the treatment of dermatomyositis $99,908.00 $99,908.00 $99,908.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 The investigators propose to begin a drug discovery using high-througput assays to screen approximately 110,000 candidate compounds for their ability to inhibit production of interferon-alpha plasmacytoid dendritic cells. Yaming Wang, M.D. RG Study of Msx1-dedifferentiated cells for cell therapy of muscular dystrophies $98,204.00 $98,204.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 Researchers will perform in vitro and in vivo experiments to evaluate whether it is possible to generate stem cell like cells, which possess advantage in muscle engraftment, by inducing expression of msx1 in primary myoblasts. Karen Westerman, Ph.D. RG Treatment of LGMD by homing therapeutic cells to muscle $85,000.00 $85,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 The basic hypothesis is that expressing an adhesion molecule normally expressed on the surface of white blood cells on the surface of transplanted cells will enhance the migration of the transplanted cells to sites of muscle injury. This adhesion molecule plays a signaificant roll in the homing of white blood cells to sites of injury and inflammation and should improve the homing and migration of transplanted cells to sites of muscle injury. Boston - Children's Hospital Alan H. Beggs, Ph.D. RG Molecular genetics of congenital myopathies $100,000.00 $100,000.00 $100,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 The investigators propose to understand the patho-physiology of congenital myopathies. The investigators are a building a registry and bank of clinical datato identify genes responsible for these disorders. These studies will provide crucial information for eventual development of effective therapies. Emanuela Gussoni, Ph.D. RG Myogenic potential and systemic delivery of human muscle SP cells $45,000.00 Summary : 7/1/2005 6/30/2006 Year 3 The major goal of this proposal is to identify a fraction of stem cells within human muscle able to efficiently target dystrophic skeletal muscle upon systemic injection into the circulation. Identification of such cells will be a first important step in the optimization of muscle stem cell-mediated therapy for Duchenne muscular dystrophy. Page 26 Of 91 Jeffrey Guyon, Ph.D. DG Isolation of zebrafish with mutations causing muscular dystrophy $45,000.00 Summary : 7/1/2005 6/30/2006 Year 3 Zebrafish are small vertebrates with similar muscle structure and protein composition as mammals suggesting that these animals may be good organisms for modeling human muscle disease. In addition, the molecular similarities between zebrafish and mammals suggest that findings made using zebrafish will likely be applicable to humans. We now propose to use the zebrafish to genetically isolate mutations in genes causing muscular dystrophy. As this proposal provides for the first large scale genetic analysis selecting for muscular dystrophy in vertebrates, this approach is likely to isolate mutations in novel genes which will broaden our understanding of the disease. Louis Ph.D. Kunkel, EMG Restricted for research at the Children's Hospital of Boston $193,473.00 Summary : 4/1/2005 3/31/2006 Year 4 Kinga K. Tomczak, M.D. DG Myotubularin biology and its role in X-linked myotubular myopathy $45,000.00 $45,000.00 $45,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 X-linked myotubular myopathy (XLMTM) is a congenital muscle disease affecting newborn boys that is characterized by generalized muscle weakness. The gene mutated in XLMTM patients is called myotubularin. The purpose of this study is to elucidate potential therapeutic targets to treat XLMTM. These experiments will examine alterations in gene expression, protein expression and interactions associated with myotubularin deficiency. With this knowledge pharmacologic agents could be designed to ameliorate this often fatal and always debilitating disorder. Boston - Dana-Farber Cancer Institute Christoph Handschin, Ph.D. DG The role of PGC-1 in neuromuscular junction formation $45,000.00 $45,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 This proposal plans to study the molecular mechanisms that underlie PGC-1alpha functions in skeletal muscle. Because of the central role of PGC-1alpha, pharmacological targeting of its regulation, its interaction with other proteins and its effect on other genes could have therapeutic effects on a variety of human muscular diseases, including type-2 diabetes, disorders with aberrant proportions of muscle fiber-types, mitochondrial myopathies and muscular dystrophies. Boston - Harvard Medical School Alfred L. Goldberg, Ph.D. RG Protein breakdown in muscle in normal and disease states $98,514.00 1/1/2006 12/31/2006 Year 3 Page 27 Of 91 Summary : The ubiquitin-proteasome pathway is the enzyme system responsible for the enhanced protein destruction in atrophying muscle, and researchers have discovered a key new component of this process which they named atrogin-1. To learn how protein degradation is activated in atrophying muscle, they are studying the factors controlling the production of atrogin-1. They hope to identify agents or rational treatments that may block its production and may thus prevent muscle wasting. Richard C. Mulligan, Ph.D. TRA C Summary : Clinical manufacturing of AAV1 vector in support of a phase I/II gene transfer study in limb-girdle muscular dystrophy type 2D $300,000.00 3/1/2006 11/30/2006 Year 1 Boston - Harvard University Tiffany Reiter, Ph.D. DG Heme oxygenase in motor neuron resistance to NO toxicity $45,000.00 $45,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 Nitric oxide (NO) and its chemical by-products have been implicated for a role in the development of ALS. Heme oxygenase-1 (HO-1), an enzyme, has recently been implicated for a role in motor neuron resistance to NO toxicity. Researchers propose to study the mechanism(s) by which HO-1 prevents NO toxicity. Further understanding of the mechanism(s) of NO-resistance in motor neurons will contribute to the design of therapeutic agents to treat ALS. Cambridge - ALS Therapy Development Foundation Daniel Benjamin, Ph.D. TRA C Summary : Pharmacokinetic analysis of putative ALS drugs: do they reach the spinal cord? $165,447.00 3/1/2006 11/30/2006 Year 1 Investigators plan to re-test prominent FDA-approved drugs that have failed clinically, and correlate efficacy results to spinal cord drug levels. Results from these studies should help to save cots of clinical trials and the time and suffering of ALS patients by better focusing future clinical trials and drug discovery efforts. Cambridge - Whitehead Institute for Biomedical Research Prakash Rao, Ph.D. DG The role of microRNAs in myogenesis $45,000.00 $45,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 The experiments outlined in this proposal are designed to enhacne the understanding of how newly discovered molecules called microRNAs regulate stem cell function. If the results of these experiments suggest that micro RNAs are important in muscle stem cell biology then that provides a whole new area of theapeutics that can be exploited in the treatment of dystrophy. Charlestown - Massachusetts General Hospital Page 28 Of 91 Susanna Benn, Ph.D. DG Studies of the therapeutic effect of Hsp27 in amyotrophic lateral sclerosis (ALS) mice $45,000.00 Summary : 1/1/2006 12/31/2006 Year 3 Investigators aim to breed mice that express a small heat shock protein known as Hsp27, which both prevents protein clumping and inhibits apoptosis, in the ALS mice. This information may support the exploitation of Hsp27 for the treatment of patients with ALS. Robert Brown, Jr., D.Phil, M.D. RG High throughput drug screening in SOD1-mediated amytrophic lateral sclerosis $85,228.00 Summary : 1/1/2006 12/31/2006 Year 2 ALS is a progessive neurodegenerative disease involving loss of large motor neurons in the brain and spinal cord. The goal of this study is to identify small molecules able to reduce the production of toxic proteins in SOD1-mediated ALS. Merit Cudkowicz, M.D., M.Sc. RG Safety and dose escalating study of oral sodium phenylbutyrate in subjects with ALS $113,769.00 Summary : 1/1/2005 6/30/2006 Year 1 ALS is aprogressive disease for which there is no known cure. Strategies that target transcription dysfunction, such a ssodium phenylbutyrate (NaPB), may delay clinical progression in ALS. Investigators will test the safety and tolerability of NAPB by escalating the dose from 9g/day to 18g/day and finally 27g/day over a course of 20 weeks in 80 people with ALS. Louise Glover, Ph.D. DG Functional analysis of mini-dysferlins for AAV-delivery $45,000.00 $45,000.00 $45,000.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 Two rare forms of muscular dystrophy (MD) are caused in the gene that produces the muscle protein dysferlin. Loss of dysferlin renders the cell incapable of repair after normal wear-and-tear injuries, causing cell damage and eventual degeneration of the entire muscle. The goals of this project are to study the biology of dysferlin and to use gene therapy to replace the missing protein in affected muscle. Kimi Kong, Ph.D. DG Investigation of stem cell therapy in Miyoshi myopathy and LGMD-2B $45,000.00 Summary : 7/1/2005 6/30/2006 Year 3 This is a proposal to investigate whether transplantation of human umbilical cord blood stem cells can rescue the dystrophic phenotype in sjl mice, which is a nature model for MM and LGMD-2B. Davide Trotti, Ph.D. RG Symoylation of the glutamate transporter EAAT2 in the pathology of ALS $96,701.00 $96,811.00 $95,161.00 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 Page 29 Of 91 Summary : The goal of this study is to understand the pathophysiological mechanisms responsible for EAAT2 impairment in ALS. The investigators believe that this impairment not only leads to excitotoxic cell death by glutamatergic overstimulation of motor neurons in the spinal cord, but also that fragments of the EAAT2 protein generated by pathological reactions occurring in ALS sustain or worse this disease. Clifford Woolf, M.D., Ph.D. RG Hsp27 and motor neuron survival $91,109.00 Summary : 7/1/2005 6/30/2006 Year 3 This study will test if lack of expression of heat shock protein 27 (Hsp27) contributes to an increased susceptibility for motor neurons to die, and if gene therapy with Hsp27 has potential benefit for preventing or delaying neuron loss in motor neuron diseases such as ALS. Watertown - Boston Biomedical Research Institute Xingbin Ai, Ph.D. RG Regulation of satellite cell development and muscle regeneration by extracellular heparan sulfate 6-O endosulfatases $100,000.00 1/1/2006 12/31/2006 Year 1 $100,000.00 1/1/2007 12/31/2007 Year 2 $100,000.00 1/1/2008 12/31/2008 Year 3 The proposed studies investigates Sulf regulation of growth factor signaling for satellite cell growth and differentiation in uninjured and regnerating muscles using cell-based and live animal techniques. Results will lay ground for HS-dependent approaches in stem-cell based therapy for muscular dystrophy. Summary : Jeffrey B. Miller, Ph.D. RG Apoptosis in CMD and LGMD $100,000.00 $100,000.00 $100,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 The investigators goal is to develop therapies that can improve outcome in particular types of congenital muscular dystrophy and limb-girdle muscular dystrophy. The investigators will use drugs and genetic interventions in mouse models of these diseases to test a possible therapeutic strategy which is based on inhibiting a type of cell death called apoptosis. The results will show whether this strategy might be of potential therapeutic benefit to people with these diseases. Worcester - University of Massachusetts Laxman D. Gangwani, Ph.D. RG To define the function of the Zinc Finger Protein ZPR1 in spinal muscular atrophy (SMA) $112,476.00 Summary : 1/1/2006 12/31/2006 Year 3 SMA is caused by mutation of the survival motor neurons (SMN1) gene. The zinc-finger protein (ZPR1) interacts with SMN and ZPR1 is required for the nuclear accumulation of SMN. The interaction of ZPR1 with SMN is disrupted in patients with Werdnig-Hoffman syndrome (SMA1) that have SMN mutations. The goal of this research is to determine the function of ZPR1 in SMA by studying the effect of Zpr1 mutation in vivo using a mouse model of SMA. Page 30 Of 91 Ravindra N. Singh, Ph.D. RG Restoration of full-length SMN protein in SMA $80,000.00 $80,000.00 $80,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 The investigators have discovered a novel intronic target site (ISS-N1) that facilitates exon 7 exclusion in SMN2. In this grant proposal, the investigators will explore the therapeutic potential of the antisense oligos by targeting ISS-N1 in SMA patient cells and SMA mouse models. Yong-Xu Wang, Ph.D. RG The nuclear receptor PPARd and its agonists in the treatment of Duchenne muscular dystrophy (DMD) $110,000.00 1/1/2006 12/31/2006 Year 1 $100,000.00 1/1/2007 12/31/2007 Year 2 $100,000.00 1/1/2008 12/31/2008 Year 3 Utrophin is a protein that can functionally replace the missing protein dystrophin in Duchenne muscular dystrophy (DMD). Using mdx mice as a model, the researchers will examine the beneficial effects of these small molecules in muscular dystrophy and evaluate whether these molecules are promising drug candidates for the treatment of DMD. Summary : MICHIGAN Ann Arbor - University of Michigan Denise A. Figlewicz, Ph.D. RG New models of familial amyotrophic lateral sclerosis (FALS): Unmasking modifier genes $85,446.00 Denise A. Figlewicz, Ph.D. RG IGF-I signaling pathways in FSHD myoblasts $80,000.00 Summary : 1/1/2006 12/31/2006 Year 3 7/1/2005 6/30/2006 Year 1 The insulin-like-growth factor-I (IGF-I) is known to play a role both in muscle precursor satellite cell (myoblast) proliferation and in maintenance of muscle following differentiation, and the effects of IGF-I are mediated by different intracellular signaling pathways for proliferation vs. differentiation. The preliminary data demonstrates a decreased expression of the IGF-I receptor in FSHD myoblasts. IGF-I is currently a putative therapeutic agent for several neuromuscular diseases. Whether or not it will be useful in stimulating FSHD myoblast proliferation will be determined in these studies. Andrew P. Lieberman, M.D., Ph.D. RG A knock-in mouse model of Kennedy's disease $100,000.00 $100,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 Researchers will characterize a mouse model of Kennedy's disease created by inserting the human mutation into the mouse gene so as to understand how the disease occurs and how it can be treated. Page 31 Of 91 Daniel E. Michele, Ph.D. RG Cardiomyopathy in muscular dystrophies $93,339.00 $93,339.00 $93,339.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 Heart disease is a significant clinical problem in many muscular dystrophy patients. Recently, several muscular dystrophies have been shown to result from abnormal processing of the protein dystroglycan that disrupts its function as a receptor for proteins outside muscle cells. Genetic disruption of the dystroglycan gene in mouse heart cells and/or blood vessels will demonstrate how abnormal processing and disrupted dystroglycan function causes heart disease at the organ and cellular level. Understanding heart disease in dystroglycan-, and dystrophin-glycoprotein complex-associated muscular dystrophies should demonstrate important targets for disease therapies. Mark Russell, M.D. RG Obscurin's role in myofibril assembly and structural support $87,500.00 $87,500.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 This study will determine whether obscurin, a novel muscle protein, is part of the dystrophin-dystroglycan support structure or functions independently as part of a parallel network, one that might be enhanced to treat many forms of muscular dystrophy. Soichiro Yasuda, M.D., Ph.D. DG Poloxamer therapy for cardiomyopathy associated with muscular dystrophy $45,000.00 $45,000.00 $45,000.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 In this project, the investigators will study the effect of a membrane sealing chemical to correct the abnormality of heart cells from mice which are model animals of human muscular dystrophy, and compare the chemical sealant with other class of drugs to determine the optimal agent. This study will probably provide us a new therapeutic strategy against heart failure in patients suffering from muscular dystrophy. Detroit - Wayne State University Gyula Acsadi, M.D., Ph.D. RG Gene therapy for amyotrophic lateral sclerosis (ALS) by AAV mediated gene transfer $93,696.00 Gyula Acsadi, M.D., Ph.D. RG The effects of SMN depletion on the expression of genes participating in axonal growth and transport $93,985.00 1/1/2006 12/31/2006 Year 1 $93,985.00 1/1/2007 12/31/2007 Year 2 $93,985.00 1/1/2008 12/31/2008 Year 3 Studying the functions of the SMN protein, as well as the consequences of its decrease in neurons, would extend current knowledge about the disease mechanism. This proposal aims to investigate the effects of SMN loss on nerve cell development and function. Identification of neuron-specific molecular pathways relaed to SMN loss will promote the developemnt of effective therapies for SMA. Page 32 Of 91 1/1/2005 3/31/2006 Year 3 Summary : William S. Brusilow, Ph.D. RG Effect of methionine sulfoximine and ketoacids on the amyotrophic lateral sclerosis (ALS) mouse $91,520.00 1/1/2006 12/31/2006 Year 1 ALS is a fatal neurodegenerative disorder that results, in part, from defects in the brain metabolism of the molecule glutamate. This research will tret a mouse model of ALS with compounds known to lower brain glutamate, to determine if altering glutamate levels directly will have an impact on the onset or progression of the disease. Summary : John Kamholz, M.D., Ph.D. RG Structural analysis of the extracellular domain of MPZ from patients with Charcot-Marie-Tooth type 1B (CMT1B) $100,000.00 1/1/2006 12/31/2006 Year 2 $100,000.00 1/1/2007 12/31/2007 Year 3 CMT1 is a group of inherited diseases of the peripheral nerves characterized by weakness and sensory loss in the arms and legs. One of this group, CMT1B, is caused by mutations in the gene encoding the myelin protein zero (MPZ), the major building block of the myelin sheath, the insulation surrounding peripheral nerves. In this grant we will determine the three dimensional structure of MPZ and several of its mutants identified in patients with CMT1B. This information will be important for understanding how these mutations cause symptoms in patients, and may lead to improved and/or novel treatments. Summary : Jun Li, M.D., Ph.D. RG The utility of skin biopsy in the evaluation of inherited neuropathy $100,000.00 $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 The genetic cause of the most common form of Charcot-Marie-Tooth disease, CMT1A, has been known for almost 15 years but as yet there is no effective treatment. In part this is due to difficulties to obtain nerves from patients to determine how the nerve damage occurs. The investigators have developed the technique of evaluating CMT nerves from small pieces of skin. In this proposal, the investigators wish to investigate these dermal nerves in CMT1A patients to determine how the neuropathy occurs and how the neuropathy progresses so that they can evaluate the effects of future treatments for CMT1A. Detroit - Wayne State University Michael E. Shy, M.D. RG GDNF gene therapy in Charcot-Marie-Tooth type 1 (CMT1) $100,000.00 Summary : 1/1/2006 12/31/2006 Year 3 CMT1 is an inherited disease affecting the insulation, called myelin, of peripheral nerves. The damage to myelin secondarily damages the nerve which degenerates causing disability. There is no cure for CMT1. In this proposal, investigators will use pieces of a harmless virus, called adeno associated virus, to introduce a growth factor into a mouse model of CMT1 to develop a treatment for the disease. Detroit - Wayne State University Michael E. Shy, M.D. TRA C CMT North American Database $85,000.00 1/1/2006 12/31/2006 Year 2 Page 33 Of 91 $85,000.00 Summary : 1/1/2007 12/31/2007 Year 3 This Database will allow investigators to determine which mutations cause severe forms of CMT and to identify groups of patients who may be afflicted with novel forms of CMT. Patient confidentiality is strictly maintained in the Database. MINNESOTA Minneapolis - University of Minnesota Atsushi Asakura, Ph.D. RG Transplantation of myogenic-endothelial progenitors for muscular dystrophies $100,000.00 Summary : 1/1/2006 12/31/2006 Year 2 In the proposed research, investigators will extend their knowledge of how stem cells differentiate into skeletal muscle and vascular cells, and will help develop a novel stem cell transplantation method to treat muscular dystrophy. Christopher M. Gomez, M.D., Ph.D. RG Cysteine proteases in the slow-channel myasthenic syndrome $106,826.00 $109,681.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 Researchers have found that protein-defrading enzymes, called cysteine proteases are activated at the degenerating neuromuscular synapses in SCS and in an animal model of SCS. In this study investigators will use calcium- and protease-sensitive dyes and protease inhibitors to investigate how the enzymes are activated and explore the contribution of each protease to the process neuromuscular degeneration. David Thomas, Ph.D. RG Spectroscopic probes of muscle degeneration $90,000.00 $90,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 Researchers are developing molecular diagnostic tools to detect the protein structural changes responsible for the loss of force in muscular dystrophy. Wei Wang, M.D. DG AChR epitopes restricted by DR and DQ molecules relevant to myasthenia gravis (MG) $45,000.00 Summary : 7/1/2005 6/30/2006 Year 3 Investigators want to determine the epitope repertoire of anti-AChR CD4+ T helper cells recognized in association with the DR2, DR3, DR4, DQ6 or DQ8 molecules, to identify characteristics that correlate with susceptibility or resistance to MG. Rochester - Mayo Clinic Andrew Engel, M.D. EMG Restricted funds for support of congenital myasthenia gravis research $10,050.00 4/1/2005 3/31/2006 Year 4 Page 34 Of 91 Summary : Bruce Horazdovsky, Ph.D. RG Regulation of IGF-1 receptor signaling and trafficking in ALS2 $100,000.00 $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 Amyotrophic lateral sclerosis (ALS) is characterized by the progressive death of neurons that control muscles. The gene mutated in ALS2 codes for a protein called Alsin that plays an important role in preventing neurons from dying. The researchers hope that by dissecting Alsin function they will gain new insights into the causes of ALS and in doing so identify new targets for treatment. Xiaolei Xu, Ph.D. RG Genetic studies of titin in myofibrillogenesis and muscular dystrophy $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 Using a novel morpholino antisense technology, they will generate a series of mutations in titin that will allow us to answer why different mutations in this gigantic protein results in different human diseases. Their studies in this ropical fish are a stepstone for next generation genetic screens that will ead to novel therapies of muscular dystrophy. Rochester - Mayo Clinic Rochester Andrew Engel, M.D. RG Congenital myasthenic syndromes $117,887.00 Summary : 1/1/2006 12/31/2006 Year 3 Congenital myasthenias will be studied by a multifaceted approach to gain better insights into pathologic mechanisms, diagnosis, treatment, and prevention. MISSISSIPPI Jackson - University of Mississippi Michael Hebert, Ph.D. RG Regulation of coilin and SMN interaction by coilin associated proteins $80,000.00 Michael Hebert, Ph.D. EMG Restricted funds for research $17,800.00 Summary : 7/1/2005 6/30/2006 Year 3 4/1/2005 3/31/2006 Year 1 Page 35 Of 91 MISSOURI Columbia - University of Missouri Dongsheng Duan, Ph.D. RG AAV-mediated micro-dystrophin gene therapy of the mdx heart disease $140,000.00 Summary : 1/1/2006 12/31/2006 Year 3 Heart disease is a common and potentially lethal hazard for muscular dystrophy patients, especially those with Duchenne and Becker forms (DMD and BMD). Many studies have been performed to understand the etiology and clinical manifestation of the dystrophic heart disease. Yet, there is no cure. Gene therapy offers the hope of curing this devastating disease, but has been frustrated by the enormous size of the dystrophin gene. Recently a highly abbreviated micro-dystrophin gene was developed to treat the skeletal muscle disease in DMD. In this research project, researchers will evaluate the therapeutic potential of this same micro-dystrophin gene in the heart of the mdx mouse, a mouse model for DMD. The ultimate goal is to develop an effective gene therapy for heart disease in DMD/BMD patients. Christian Lorson, Ph.D. RG Analysis of SMN exon 7 function $95,274.00 $95,801.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 The SMN protein is truncated in SMA patients and is dysfunctional compared to the normal full-length protein produced in non-affected individuals. This proposal is designed to characterize the molecular differences between the truncated SMN protein and full-length SMN and identify factors that can be used to restore functionality to the truncated SMN protein. Monir Shababi, Ph.D. DG Development of SMN rAAV vectors $45,000.00 $45,000.00 $45,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 The investigators aim is to utilize therapeutic RNA molecules to restore the accurate splicing of the SMN2 pre-mRNA and, in turn, increase the level of the functional SMN protein to protect from SMA. The anti-sense RNA molecules and the bifunctional RNA molecules will be delivered into SMA patient-derived fibroblasts in a plasmid-based delivery system and selected for their efficiency to produce full-length SMN protein. The selected RNA molecules will be developed into rAAV vectors and delivered into patient fibroblasts and mature neurons of transgenic mice. Kansas City - Stowers Institute for Medical Research Olivier Pourquie, Ph.D. RG Role of atrophins in patterning/differentiating early muscle precursers $115,900.00 7/1/2005 6/30/2006 Year 3 Page 36 Of 91 Summary : Among the most promising treatments for muscular dystrophies are the cellular therapies involving the transfer of stem cells able to reconstitute the affected muscles. The Notch signaling pathway has been involved in the maintenance of the stem cell state of muscle precursors and thus the ability to control its regulation could be of great importance for such therapies. This project proposes to further the understanding of the regulation of the Notch pathway during early steps of myogenesis. St Louis - Washington University Didier Hodzic, Ph.D. RG Emery-Dreifuss muscular dystrophy: Dysconnection of the nuclear lamina-cytoskeleton? $114,187.00 $100,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 1 Year 2 The investigators recently discovered that lamin A/C (a building block of the nuclear lamina), Sun proteins (a family of inner nuclear membrane proteins) and nesprins (a family of outer nuclear membrane proteins) from a network that spans the nuclear envelope and pysically links the nucleoplasm to the cytoplasm. In mice lacking lamin A/C which constitute a model for Emery-Dreifuss muscular dystrophy, this network is "disrupted". They therefore, propose to study the biological role of this protein network and its possible involvement in other human diseases involving the mutation of lamin A/C. St. Louis - Washington University Anne Connolly, M.D. RG Role of complement 3 and B-cells in muscular dystrophy $92,261.00 Anne M. Connolly, M.D. RG Synergistic effects of steroids, ACE inhibitor, and exercise in mdx mice $109,126.00 $98,163.00 $99,764.00 Summary : 7/1/2005 6/30/2006 Year 3 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 This proposal will look at long-term effects including strength, fatigue, and amount of voluntary exercise in this well characterized mouse model. Paul Golumbek, M.D., Ph.D. DG Non-immune effects of steroid treatment on Mdx/SCID mice $41,238.00 $42,659.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 T-cells are key immune coordinator/killer cells, and B-cells make antibodies. Both T-cells and B-cells have been inferred to play important roles in the immune response to DMD muscle. Without these cells, Rag2-/-mdx mice are ideal for looking for the "other effects" of steroids. Jeffrey Milbrandt, M.D., Ph.D. RG Treatment of axonopathy in ALS by increased NAD synthesis and Sirt1 activation $100,000.00 $100,000.00 $100,000.00 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 Page 37 Of 91 Summary : The investigators have found that increased levels of an enzyme involved in cellular energy metabolism can protect against axonal degeneration. This protection requires an additional protein that is important for regulating lifespan. The investigators will determine whether axonal degeneration caused by defective mitochondria, powerplants of the cell that are frequently defective in neurological diseases, can be blocked by this pathway. The investigators will explore the therapeutic utility of activating this axonal protective pathway in a mouse model of ALS. NEW JERSEY Newark - University of Medicine and Dentistry of New Jersey Martha C. Nowycky, Ph.D. RG TRPC channels and calcium in Duchenne muscular dystrophy $103,171.00 Summary : 1/1/2006 12/31/2006 Year 3 DMD is characterized by muscle degeneration. Recent reports indicate that DMD cells are leaky to extracellular calcium and as a consequence resting calcium levels are abnormally high. Elevated calcium levels can lead to muscle deterioration as well as muscle death. In the last year, TRPC ion channels have been identified as a possible pathway for the increased calcium leakiness. Researchers will pursue the hypothesis that TRPC channels are misregulated in DMD muscle cells. Information about the properties and function of the calcium leak channels provides the basis for development of therapeutic pharmacological agents that can block TRPC channels and decrease muscle degeneration in Duchenne muscular dystrophy. South Plainfield - PTC Therapeutics, Inc. Langdon Miller, M.D. TRA C Summary : PTC124 treatment for Duchenne muscular dystrophy $476,540.00 1/1/2006 3/31/2006 Year 2 PTC124 is a new drug that allows the cellular protein production machinery to ignore abnormal stop signals, thereby restoring the production of full-length functional dystrophy. PTC124 has the potential fo offer a definitive therapy for DMD by overcoming the basic cause for the disease, and may thereby maintain muscle strength and extend patient survival. NEW MEXICO Albuquerque - University of New Mexico Richard Cripps, D.Phil. RG Transcriptional control of muscle remodeling in Drosophila $77,897.00 Summary : 7/1/2005 6/30/2006 Year 3 The aim of this research is to understand how genes work to control muscle formation and remodeling in the fruit fly. Investigators anticipate that the genes which function in this animal to make muscles are similar to those which function in higher animals including humans, and will help us identify how muscle formation sometimes does not occur properly. Page 38 Of 91 NEW YORK Bronx - Albert Einstein College of Medicine Mona Freidin, Ph.D. DG $45,000.00 $45,000.00 $45,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 Hanh Nguyen, Ph.D. RG Analysis of skeletrophin, a novel essential component of muscle differentiation $77,440.00 Summary : 7/1/2005 6/30/2006 Year 3 The goals of this project are to characterize the role of skeletrophin, a novel gene in the developmental pathway of skeletal myoblasts, and to uncover the mechanisms by which skeletrophin mediates its function in generating functional muscles. These studies will provide a better understanding of the normal development of founder myoblasts and critical cell fusion events occuring between these myoblasts and their cognate partners, the fusion-competent myoblasts. The results from these studies will provide important insights into a new essential gene which may have similar functions during vertebrate muscle development. Buffalo - State University of New York Luc Gosselin, Ph.D. RG Mechanisms of failed regeneration in dystrophic muscle $98,355.00 $98,728.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 The purpose of this proposal is to determine how inflammation promotes connective tissue accumulation (i.e., fibrosis) in dystrophic skeletal muscle, and to determine if the drugs Diclofenac and Enalapril are effective in preventing muscle fibrosis. Georgirene D. Vladutiu, Ph.D. RG Improved diagnosis of metabolic diseases among the statin myopathies $90,735.00 Summary : 7/1/2005 6/30/2006 Year 3 Investigators will determine the prevalence of underlying muscle disease in people who become symptomatic while taking cholesterol-lowering medications and develop cost-effective screening tests for the detection of high-risk individuals in order to take measures to prevent serious side effects. Ithaca - Cornell University Jun Liu, Ph.D. RG Functional studies of nuclear membrane proteins emerin and MAN1 in C. elegans $100,000.00 1/1/2006 12/31/2006 Year 2 Page 39 Of 91 Summary : Using the genetically tractable nematodie C. elegans, researchers have previously shown that emerin shares redundant and essential functions with another nuclear membrane protein MAN1. Investigators propose to further characterize the functions of emerin and MAN1 in C. elegans, and to identify factors that functionally interact with them. These studies will provide important insights into the molecular basis of EDMD, and help identify useful therapeutic targets for EDMD. New York - Columbia Presbyterian Medical Center Hiroshi Mitsumoto, M.D. EMG Restricted funds for the Eleanor and Lou Gehrig MDA/ALS Center $438,949.00 Summary : 4/1/2005 3/31/2006 Year 4 Ear-marked gift New York - Columbia University Salvatore DiMauro, M.D. RG Studies of human mitochondrial myopathies $100,000.00 Salvatore DiMauro, M.D. RG Glycogen and lipid storage myopathies $94,173.00 $94,173.00 $94,173.00 Summary : 7/1/2005 6/30/2006 Year 3 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 The investigators will study three hereditary metabolic myopathies. The first is a newly discovered glycogen storage disease due to the deficiency of 5'AMP-activated protein kinase (AMPK), which senses the energy status of the cell. The second is a newly recognized benign variant of a generalized lipid storage disease. The third disorder is due to the defect of coenzyme Q10 (CoQ10), a key component of the terminal pathway that truns fat into energy. Knowing the molecular genetic defect(s) in the infantile form of CoQ10 deficiency will allow prenatal diagnosis and preventive therapy by CoQ10 supplementation from birth. Robert Gilkerson, Ph.D. DG Mitochondrial DNA nucleoids: Organization and dynamic $45,000.00 $45,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 Investigators will determine how different types of mtDNA (i.e. normal and mutated) are distributed via the nucleoid by fusing two cell lines, each carrying a single type of mtDNA. Further, they will examine DNA-protein interactions involved in nucleoid maintenance and inheritance. Dmitry Goryunov, Ph.D. DG Mouse models of neurofilament light chain-linked Charcot-Marie-Tooth disease $40,909.00 $40,909.00 $40,909.00 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 Page 40 Of 91 Summary : Mutations in multiple genes have been linked to CMT. Among them is the gene encoding neurofilament light protein (NFL). The investigators intend to generate transgenic mice that express two NFL mutations that have been found in CMT patients, called P8R and Q333P. The investigators will analyze the nerve structure and function in these mice in order to detect features reminiscent of human CMT. These mice can then be used as a model for the testing of potential therapeutic treatments of the disease. Michio Hirano, M.D. RG Pathogenesis of mitochondrial myopathy due to thymidine kinase 2 deficiency $97,858.00 Summary : 1/1/2006 12/31/2006 Year 2 Thymidine kinase 2 (TK2) deficiency is a rare genetic muscle disease that usually begins in infancy and is fatal in childhood. Investigators propose to study muscle and cells from patients and a mouse model of this disease in order to understand why the TK2 deficiency causes severe myopathy. These studies may lead to therapy for this disease. Oliver Hobert, Ph.D. RG Characterization of a gene that suppresses aberrant motor axon overgrowth $110,000.00 $110,000.00 $110,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 The investigators have developed an animal model system that displays aberrant motor axon growth, a characteristic feature of neuromuscular disorders. The investigators propose to reveal the molecular identity of a genetic locus that is capable of suppressing the aberrant motor axon growth. Edward Laufer, Ph.D. RG Control of limb motor axon dorsal-ventral projection $67,519.00 Summary : 7/1/2005 6/30/2006 Year 3 Limb muscles are innervated by groups of motor axons that project from the spinal cord; the precise control of this process during development is necessary for coordinated muscular control after birth. This project takes advantage of chick and mouse mutants to define how motor axons entering the limb choose to appropriately project towards either dorsal or ventral limb muscles. Identifying the signals controlling the precise targeting of these axons can aid in designing regenerative therapies for neuromuscular diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. Chung-Ming Lin, Ph.D. DG Studies of muscular dystrophy in dystonia musculorum mice $45,000.00 Summary : 7/1/2005 6/30/2006 Year 3 Mutations of BPAG1 gene cause neuromuscular deficits in mouse mutant dystonia musculorum (dt). As dt mice can be used as a model of studying neuromuscular diseases, defining the function of BPAG1 in muscle is of tremendous value. Hence, investigators propose to study the muscle form of BPAG1 by various techniques in order to determine how its loss leads to muscle fragility. Hiroshi Mitsumoto, M.D. EMG Restricted funds for ALS research $438,949.00 4/1/2005 3/31/2006 Year 2 Page 41 Of 91 Hiroshi Mitsumoto, M.D. RG Genetic-environmental epidemiology in amyotrophic lateral sclerosis (ALS) $141,398.00 Hiroshi Mitsumoto, M.D. SG MDA/ALS Multidisciplinary Care Conference $15,000.00 Summary : 1/1/2006 12/31/2006 Year 3 2/1/2006 11/30/2006 Year 1 This conference is designed for neurologists, advanced practice nurses, rehabilitation therapists, nutritions, social workers and other health professionsl involved in the management of ALS. Participants will be provided with up to date information regarding ALS research and current clinical management practices releated to respiratory issues, symptom management, nutrition, communication, rehabilitation, caregiver support and end of life in ALS. Cecilia Ostlund, Ph.D. DG The role of A-type laminins in Emery-Dreifuss muscular dystrophy (EDMD) $45,000.00 $45,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 The muscle-specific nature of EDMD is intriguing, since both emerin and lamin A are present in virtually all cells. An explanation could be an interaction between these proteins and other proteins specific to, or particularly important in, muscle. The goal of this project is to identify proteins that bind to A-type lamins, to help understand the mechanism of this disease, a step towards finding a cure. Eric A. Schon, Ph.D. RG Mitochondrial redox sensing in cytochrome oxidase deficiency $96,987.00 $96,987.00 $96,987.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 Deficiencies of cytochrome c oxidase, a mitochondrial respiratory chain complex, cause a number fatal neuromuscular disorders. Among these are disorders due to mutations in SCO1 and SCO2, two related proteins requied for the assembly of the COX multisubunit complex. The investigators recently discovered that SCO has an unexpected function, namely it is apparently a molecule that can sense the amount of oxygen within mitochondria. They now propose to follow up on this finding, by finding "binding partners" for SCO, and by making a SCO mouse model in which oxygen sensing is compromised. Howard J. Worman, M.D. RG Abnormal Smad2/3-mediated signal transduction in nuclear envelopathies $111,566.00 Summary : 1/1/2006 12/31/2006 Year 3 Mutations in proteins of the nuclear envelope, the membranous structure that separates the genetic material from the rest of the cell, cause Emery-Dreifuss and other muscular dystrophies. It is not known how mutations in these peroteins, expressed in virtually all cells, cause muscle disease. Investigators have obtained preliminary results showing that nuclear envelope proteins may attenuate the effects of "hormone-like" factors that signal an inhibition of muscle development and regeneration. In this project, investigators will determine if mutations in nuclear envelope proteins lead to an abnormally increased activity of these "hormone-like" factors with inhibitory effects on muscle. If so, it could lead to the development of drugs acting on a well-characterized signaling pathway to treat muscular dystrophies. Page 42 Of 91 Stefanie Zanssen, M.D., Ph.D. PF Genetic control of mitochondrial proliferation $60,000.00 $60,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 1 Year 2 One of the most prominent features of mitochondrial diseases is the unregulated proliferation and accumulation of mitochondria containing mutated mitochondrial DNAs (mtDNAs), especially in skeletal and smooth muscle. It is almost certain that Mattie Stepanek, in whose memory this Fellowship Application is named and endowed, had a moypathy characterized by this unregulated proliferation of mutated mitochondria (called "ragged-red fibers", or RRFs), and that these RRFs contributed to his premature death. If we could interdict this process, we might be able to halt the progression of these devastating myopathies, but the genes regulating such proliferation are unknown. The investigators propose to characterize the candidate gene in a small region located on human chromosome 11q13. New York - Cornell University M. Flint Beal, M.D. RG Testing novel therapeutics in a transgenic mouse model of amyotrophic lateral sclerosis (ALS) $73,058.00 7/1/2005 6/30/2006 Year 2 $73,058.00 7/1/2006 6/30/2007 Year 3 M. Flint Beal, M.D. RG Targeting new therapeutics in a transgenic mouse model of ALS $82,042.00 $82,042.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 1 Year 2 The present studies are devoted to developing new effective treatments for ALS. The investigators will determine whether 2 agents, which block damage to mitochondria, exert therapeutic effects in a transgenic mouse model of ALS. They also intend to test a novel compound, which activities pathways, which protect against imflammation and oxidative damage. These studies have the promise of developing novel new thereapies to slow or halt the progression of ALS. Giovanni Manfredi, M.D., Ph.D. RG Bcl-2 and adenine nucleotide translocator in mitochondrial disorders $83,772.00 Summary : 1/1/2006 12/31/2006 Year 3 Mitochondria are the main source of energy in the cell. A large number of genetic defects cause loss of mitochondrial function and lack of energy that, ultimately, results in cell death and disease. Bcl-2 proteins are able to improve the mitochondrial dysfunction caused by mutations of the mitochondrial DNA. Researchers believe that this improvement is due to the exchange of high-energy molecules by the mitochondrial adenine nucleotide translocator (ANT). In addition, mutations in the ANT gene cause some forms of mitochondrial disease that affect muscle and heart. Thus, we want to understand the mechanisms underlying the interactions among Bcl-2, ANT, and mitochondrial disorders. These studies may provide novel insights on potential approaches to ameliorate these diseases. New York - Mount Sinai School of Medicine Dale Lange, M.D. EMG Restricted funds for neuromuscular research $100,400.00 4/1/2005 3/31/2006 Year 1 Page 43 Of 91 Summary : Giulio Pasinetti, M.D., Ph.D. RG The role of cyclooxygenase-2 inhibitors in a model of ALS neurodegeneration $87,698.00 Summary : 7/1/2005 6/30/2006 Year 3 Researcher's will generate a profile of protein biomarkers that represent the therapeutic benefit of cyclooxygenase in ALS and study these proteins as a function of the clinical and pathological progression of this disease. New York - New York University Brian Dynlacht, Ph.D. RG Deciphering Transcriptional Networks Involved in Muscle Development and Function $88,000.00 $88,000.00 $88,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 The investigators developed a novel approach that allows them to identify and understand the key regulatory proteins--transcription factors--and the target genes that they regulate, during the initial events of regeneration and damage. The investigators will investigate the changes that occur to the genome and the regulatory networks that promote muscle hypertrophy and respond to oxidative stress and damage. It is proposed that understanding these programs in muscle will begin to elucidate the alterations that occur in several skeletal muscle diseases. New York - Rockefeller University Zu-Lin Chen, M.D., Ph.D. RG Laminin gamma-1 in peripheral nerve myelination and muscular dystrophy $100,000.00 $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 Laminin abnormalities cause congenital muscular dystrophy. The patients have pathological changes in both nerves and muscle, and both changes are ciritical components of the disease. To investigate how laminin participates in nerve development, the researchers generated a mouse model in which the laminin gamma-1 gene is specifically disrupted in the peripheral nerve. These mice exhibit severe peripheral nerve pathological changes, muscular dystrophy, and hind leg paralysis. The researchers propose to use this mouse model to investigate the mechanism of laminin function in nerve development and explore the possibility of using laminin peptide and other reagents to promote nerve development. Rochester - University of Rochester James Cleland, M.B.Ch.B. RG Andersen-Tawil syndrome: Defining the clinical and genetic spectrum $30,000.00 $30,000.00 $30,000.00 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 Page 44 Of 91 Summary : Anderson-Tawil syndrome (ATS) is a periodic paralysis that is associated with serious heart-rhythm abnormalities. The underlying cause of this potentially fatal condition is only partly understood and there are no established treatments. The purpose of this study is to determine whether potassium supplements and/or acetazolamide (a diuretic) reduce the frequency and severity of muscle weakness and potentially life-threatening heart rhythm abnormalities in patients with ATS. Robert C. Griggs, M.D. SG From the Pipeline to the Patient: Translational and Experimental Research Strategies $10,000.00 Summary : 4/1/2006 8/31/2006 Year 1 This meeting will provide an informal setting that (1) promotes educational and scientific interactions; (2) develops novel treatments for neuromuscular disease and (3) develops collaborations between established and junior investigators. Richard T. Moxley, M.D. TRA C Summary : MD Cooperative Center Supplement - Rochester $499,999.00 1/1/2006 12/31/2006 Year 3 The MDA supplement supports three scientific projects, two investigating the causes of MMD and FSHD, respectively, and a third that will test a new drug in MMD. The grant also supports three core resources, including an imaging core. Rabi Tawil, M.D. RG A safety study of MYO-029 in adult muscular dystrophy $20,764.00 Summary : 7/1/2005 6/30/2006 Year 1 This funding is supplementing a trial being sponsored by Wyeth on MYO-029. Charles A. Thornton, M.D. RG Molecular pathogenesis of oculopharyngeal muscular dystrophy (OPMD) $100,000.00 $100,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 The goal of this project is to understand the disease process and develop treatments for oculopharyngeal muscular dystrophy. Syracuse - State University of New York Joseph W. Sanger, Ph.D. RG Titin and myosin in myofibril assembly: Insights into muscle diseases $99,037.00 $101,975.00 Jean M. Sanger, Ph.D. RG Z-band assembly and maintenance in skeletal muscle $90,000.00 $90,000.00 $90,000.00 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 Page 45 Of 91 Summary : Damage to muscle cells through disease or injury often results in Z-band abnormalities and then the loss of the normal array of the component thin and thick filaments in a sarcomere. The proposed experiments will help to determine how Z-bands are assembled and how new proteins enter existing Z-bands in renewal processes. An understanding of the process of normal Z-band assembly is needed if the investigators are to gain insights into the nature of Z-band abnormalities, so prevalent in a number of myopathies. This knowledge will permit the designing of a strategy to correct the conditions. NORTH CAROLINA Chapel Hill - Asklepios Biopharmaceutical Inc. R. Jude Samulski, Ph.D. TRA C Phase I/II Study of Mini-Dystrophin Gene in AAV Vector $48,000.00 $640,261.00 Summary : 4/1/2005 4/1/2005 3/31/2006 3/31/2006 Year 2 Year 2 The goal of this study is to carry out a double-blinded dose escalation Phase I/II gene therapy safety trial for Duchenne muscular dystrophy. A novel recombinant adeno-associated virus (AAV) vector carrying a functional mini-dystrophin gene will be utilized in these studies. Safety is the primary outcome measure of this trial. The long-term objective is to design, test, develop and market a gene therapy approach for the treatments of DMD. Chapel Hill - University of North Carolina Nikolay V. Dokholyan, Ph.D. RG Uncovering the origins of mutant SOD1 toxicity in familial ALS $110,819.00 Summary : 1/1/2006 12/31/2006 Year 3 To understand mutant-mediated SOD1 toxicity, investigators must uncover how the SOD1 physical properties - thermal stabilities of SOD1 monomers and naturally occurring dimers - are affected by mutations. It is challenging and time consuming to experimentally estimate the effect of a large number of these mutations. Investigators propose to computationally determine whether FALS associated SOD1 mutations (i) destabilize SOD1, (ii) increase SOD1 dimer dissociation rates, and/or (iii) alter SOD1 metallation. Each of these scenarios promotes SOD1 misfolding/aggregation, and aggregates, in turn, may be toxic. They also propose to employ newly developed computational tools to reconstruct the structure of SOD1 aggregates, a crucial step in the development of drugs that inhibit SOD1 aggregate formation. Da-Zhi Wang, Ph.D. RG Control of skeletal muscle differentiation and function by SRF and myocardin family of transcription factors $80,000.00 7/1/2005 6/30/2006 Year 3 This project is designed to study the molecular mechanisms of SRF and myocardin family of transcription factors that regulate skeletalmuscle determination and differentiation as well as the in vivo functions of these factors during skeletal muscle development. These studies are the important prerequisite to developing therapeutic strategies that correct or circumvent skeletal muscle dysfunction accompanying neuromusuclar disease. SRF and the myocardin family of transcription factors could become specific targets for therapeutic application. Furthermore, the transgenic gene targeted mice established from this study could serve as valuable animal models of human muscular disease. Summary : Page 46 Of 91 Charlotte - Carolinas Medical Center Qi Long Lu, Ph.D. RG Systemic delivery of antisense oligonucleotides for the treatment of DMD $120,000.00 Qi Long Lu, M.D. EMG Restricted funds for DMD research $96,000.00 Summary : 1/1/2006 12/31/2006 Year 2 4/1/2005 3/31/2006 Year 1 Durham - Duke University John R. Gilbert, Ph.D. RG Genetic and expression studies of non-chromosome 4 facioscapulohumeral muscular dystrophy (non-4q FSHD) $68,020.00 7/1/2005 6/30/2006 Year 2 $70,027.00 7/1/2006 6/30/2007 Year 3 FSHD is a common muscular dystrophy and the genetic etiology of neither the chromosome 4 nor non-chromosome 4 types has been identified. Investigators propose several experiments to further characterize the non-chromosome 4 type of FSHD by integrating new data from gene expression studies with existing data from genomic screens. Together, these data will allow a rational prioritization of candidate gene testing. Summary : Dwight Koeberl, M.D., Ph.D. RG Preclinical studies with AAV vectors in acid maltase deficiency (AMD) $94,845.00 Summary : 1/1/2006 12/31/2006 Year 3 In previous clinical trials of enzyme replacement therapy (ERT) in severe AMD, efficacy has been demonstrated by improved survival, heart function, and muscle strength. However, ERT requires weekly injections of acid maltase and very high-scale acid maltase production. Gene therapy could potentially correct AMD following a single administration of an AAV vector. Previously they demonstrated partial correction of AMD in mouse models, and will build upon that work in the proposed studies. Briefly, unique AAV vectors that are targeted to liver or muscle will produce enough acid maltase to correct AMD in the heart and skeletal muscle, essentially providing permanent ERT. These experiments could justify a clinical trial with AAV vectors in AMD. Marcy C. Speer, Ph.D. RG Genetic studies in unlinked muscular dystrophies $100,000.00 $100,000.00 $91,703.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 In this proposal, the investigators intend to study a variety of families that have been previously untractable for genetic studies because they are too small. New high density SNP panels have shown successfuly in a variety of diseases that they can identify regions of interest that were previously unfindable and thus not amenable to positional cloning approaches. Once regions of interest are identified, plans for indentifying the underlying genes will commence. Page 47 Of 91 Winston-Salem - Wake Forest University Osvaldo Delbono, M.D., Ph.D. RG IGF-1 regulation of calcium signaling in ALS $100,000.00 $100,000.00 $100,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 The main goal of this proposal is to determine whether the increased expression of targeted insulin-like growth factor-1 (IGF-1) to the central nervous system delays the fatal outcome of familial, and some cases, of sporadic Amyotrophic Later Sclerosis (ALS). In addition, the investigators will test the hypothesis that IGF-1 prevents the downregulation of the calcium signaling cascade - gene expression involved in ALS motor neuron apoptosis. OHIO Cincinnati - University of Cincinnati John Quinlan, M.D. RG Prevention and treatment of cardiomyopathy in mdx mice $100,000.00 Summary : 1/1/2005 6/30/2006 Year 3 Researchers will test four FDA-approved drugs in muscular dystrophy (mdx) mice in order to determine which drugs are likely to prevent heart failure from developing in boys with Duchenne and Becker dystrophy. Cleveland - Case Western Reserve University A. Gregory Matera, Ph.D. RG Gemin4 and spinal muscular atrophy (SMA) $84,503.00 $89,598.00 $91,265.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 Recently, the researchers have been studying the intracellular trafficking of both SMN and small RNAs. The Germin4 protein forms a complex with SMN and appears to be involved in the import of SMN and snRNAs into the nucleas, where the snRNAs ultimately function. Using mouse "knockout" strategies, they have disrupted the Germin4 gene. They plan to use this knockout mouse to determine whether Germin4 might be a genetic modifier of SMA. Cleveland - Cleveland Clinic Foundation Andrea Ladd, Ph.D. DG Developmental alternative splicing programs in normal and DM muscle $45,000.00 $45,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 The goal of this research is to investigate how alternative splicing is regulated during muscle development, what role these genes play in this regulation, and whether repression of these genes may be used to reverse the aberrant splicing associated with myotonic dystrophy and thus alleviate symptoms of the disease. Page 48 Of 91 Columbus - Children's Research Institute Paul Martin, Ph.D. RG UDP-Ga1NAc as a therapeutic in mdx mice $73,402.00 Summary : 1/1/2006 12/31/2006 Year 3 This grant will test a novel therapy for Duchenne muscular dystrophy in the mdx mouse model of the disease. This therapy involves delivery of a sugar nucleotide, UDP-Ga1NAc, that naturally occurs in mammalian cells. If found to be effective in mdx mice, such a therapy could be used in clinical trials for Duchenne muscular dystrophy. Jerry Mendell, M.D. TRA C Transfer of alpha-sarcoglycan gene to LGMD2D patients $60,000.00 $60,000.00 Jerry R. Mendell, M.D. EMG Restricted funds for gene therapy research $50,950.00 Summary : 10/1/2005 10/1/2006 9/30/2006 9/30/2007 Year 2 Year 3 4/1/2005 3/31/2006 Year 1 Columbus - Ohio State University Patrice Hamel, Ph.D. DG Functional dissection of a cytochrome c assembly machinery in mitochondria $45,000.00 Summary : 7/1/2005 6/30/2006 Year 3 The goal of this project is to decipher how c-type cytochomes, which are crucial protein molecules in the production of energy and cell death processes, are made in the mitochondria. OKLAHOMA Oklahoma City - University of Oklahoma Sanjay I. Bidichandani, Ph.D., MBBS RG DNA repair and GAA triplet-repeat instability in Friedreich's ataxia $100,000.00 $100,000.00 $95,818.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 Friedreich ataxia is caused by expansion of a GAA triplet-repeat sequence. The severity of disease correlates with the length of the GAA expansion. The investigators have detected significant variability in repeat length in cells from patients, including spontaneous reversions to the normal length. Here the investigators propose to use four different experimental systems, including bacteria, human cell lines, transgenic mice and drug treatment of cells grown in the lab, in order to determine the mechanism of the variability in GAA repeat length. The investigators hope the data will eventually lead to the development of novel strategies to reverse the expanded allele in patient cells. Page 49 Of 91 OREGON Eugene - University of Oregon J. Andrew Berglund, Ph.D. RG Understanding the RNA structure responsible for myotonic dystrophy $97,951.00 Summary : 7/1/2005 6/30/2006 Year 3 The development of an in vitro assay to study protein binding to the CUG triplet repeat RNA will potentially provide lead molecules for the design of therapeutic agents for DM. Also could lead to the development of drugs through rational drug design. Janis Weeks, Ph.D. RG A novel screen for muscle and motoneuron death and protection genes $82,869.00 Summary : 7/1/2005 6/30/2006 Year 2 This research seeks to identify new genes involved in the steroid-regulated protection or degeneration of muscles and motoneurons, utilizing a novel insect neuromuscular system. PENNSYLVANIA Danville - Geisinger Clinic Yiumo Chan, Ph.D. RG The assembly of the sarcolygcans and their role in muscular dystrophies $93,780.00 Summary : 1/1/2006 12/31/2006 Year 3 The purpose of this project is to understand the function of the sarcoglycans in muscle and their role in muscular dystrophy. Hershey - Pennsylvania State University James R. Connor, Ph.D. RG Genotyping analysis for Hfe mutations in amyotrophic lateral sclerosis $83,190.00 Summary : 7/1/2005 6/30/2006 Year 3 Investigators propose to: (i) perform a prospective genotyping analysis using blood samples, (ii) determine the effect of the Hfe mutation on age of onset and rate progression of ALS, and (iii) determine the cellular distribution at which the Hfe mutation may be influencing ALS (e.g. muscle versus motoneurons). Philadelphia - Children's Hospital of Philadelphia Carsten Bonnemann, M.D. RG Molecular mechanisms of dominant negative congenital muscular dystrophy type Ullrich (UCMD) $75,000.00 1/1/2006 12/31/2006 Year 2 $75,000.00 1/1/2007 12/31/2007 Year 3 Page 50 Of 91 Summary : We have found that dominant mutations may lead to the severe form of the disease, complicating diagnostic and therapeutic efforts. Investigators are proposing to clarify the molecular and genetic mechanisms in the collagen VI genes that lead to this disease, in particular as the dominant form is concerned, laying the foundations for effective diagnosis, counseling and the development of novel treatment options. David R. Lynch, M.D., Ph.D. PPG Clinical measures in Friedreich's ataxia (FA) $164,263.00 Summary : 7/1/2005 6/30/2006 Year 3 FA is a neurodegenerative disease leading to progressive loss of balance and coordination, and speech difficulty. Possible therapies based on antioxidants are being considered for clinical trials but at present no clinical measure exists for following patients with FRDA. Such clinical measures need to be validated in this patient population so that they can be utilized in brief trials of medications. Investigators will compare the ability of an FA scale based on quantitation of neurological exam components with simple performance measures of walking ability, coordination and visual function to design a scale for clinical evaluation of patients with FA. Philadelphia - Hahnemann University Terry Heiman-Patterson, M.D. EMG Restricted funds for support of the MDA/ALS Center of Hope $44,116.00 Summary : 4/1/2005 3/31/2006 Year 5 Philadelphia - Thomas Jefferson University Michael P. King, Ph.D. RG Correction of mtDNA mutations resulting in myopathies $98,512.00 $98,512.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 1 Year 2 Mitochondria are important for the function of the cells in our body. Mutations in the genetic material of mitochondria result in a variety of human diseases. The studies proposed here will investigate potential therapies for some human diseases resulting from mitochondrial DNA mutations. Philadelphia - University of Pennsylvania Sasha Bogdanovich, M.D. DG Myostatin blockade for improvement of limb-girdle muscular dystrophy phenotype $45,000.00 Summary : 1/1/2006 12/31/2006 Year 3 Investigators believe that antibody-mediated myostatin blockade, if developed adequately, has great potential as an easily administered pharmacological strategy for human patients with Duchenne muscular dystrophy and LGMD. Dennis E. Discher, Ph.D. RG Single molecule studies for muscular dystrophies $70,000.00 $69,836.00 $70,000.00 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 Page 51 Of 91 Summary : Dystrophin is a long and presumably extensible protein in normal muscle that leads, when absent or mutated, to Muscular Dystrophies. It is thought to have a central role in contractile force transmission, but there have been no measurements on how dystrophin responds to force. Understanding this would likely benefit both the design of mini-dystrophins being tested in gene therapy as well as the structure-stability effects of oligo-directed exon deletion. The investigators will measure this by single molecule methods using the atomic force microscope. The investigators will compare how dystrophins extend and even unfold to another long and presumably extensible protein, filamin-C, which is also involved in muscular dystrophies. Thomas Kadesch, Ph.D. RG The control of myoblast proliferation and differentiation by Notch $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 The normal age-related decline in the ability to regenerate nuscle is due, in part, to a decreased ability of satellite cells to signal through Notch. The same may be true for muscular dystrophies. Investigators propose to study the molecular consequences of Notch signaling in muscle cells in order to more fully understand the nature of the signals that control proliferation and differentiation. The longterm goal is to find a way to externally manipulate the pathway such that regenerative capacity is maintained. Stephen Kolb, M.D., Ph.D. DG Quantitative measurement of SMN complex proteins in SMA patients $45,000.00 $45,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 Investigators intend to develop robust, reproducible methods to measure the expression of SMN mRNA and protein from patient blood samples. They will determine exactly how baseline SMN expression varies in controls, carriers for the disease and SMA patients of varying severity. Finally, they will directly determine the sensitivity of these methods in patients receiving VPA, a candidate SMA therapeutic drug that is widely used in other patient populations. Hong Lin, Ph.D. DG Role of NF-L RNA-binding protein in protein aggregation and neurodegeneration in amyotrophic lateral sclerosis (ALS) $44,550.00 7/1/2005 6/30/2006 Year 2 $44,550.00 7/1/2006 6/30/2007 Year 3 This research proposal will seek to explore the role of p190RhoGEF in triggering aggregation if NF-L and mutant SOD1 proteins in motor neurons of mutant SOD1 transgenic mice, in cultured motor neurons and in neuronal cell lines. The study may provide important insights into pathogenetic mechanisms of motor neuron degeneration and identify potential targets for therapeutic intervention. Summary : Steven S. Scherer, M.D., Ph.D. RG Alterations in mutant protein Cx32 trafficking which cause Charcot-Marie-Tooth (CMT) disease $79,992.00 1/1/2006 12/31/2006 Year 2 $83,283.00 1/1/2007 12/31/2007 Year 3 Mutations in the human connexin-32 gene (Cx32-GJB1) cause the x-linked form of CMT, which affect about 1/2000 people. Investigators have devised simple and novel methods using a virus to transfect myelinating Schwann cells in vivo, which will enable them to evalute the trafficking and interactions of many different Cx32 mutants, bepassing the time and expense required for making transgenic animals that would otherwise have to be generated to perform the analyses proposed. Page 52 Of 91 Summary : H. Lee Sweeney, Ph.D. TRA C Summary : Preclinical studies to support clinical trials for muscular dystrophy $230,678.00 7/1/2005 6/30/2006 Year 3 Researchers are using mouse models of Duchenne muscular dystrophy and limb-girdle muscular dystrophy type 2c to evaluate either new drugs or new viral vectors that they want to bring rapidly to clinical trial. In the case of DMD, they are evaluating drugs that will allow patients with premature stop codons in dystrophin to begin to produce dystrophin in their muscles. For LGMD2C, they are testing different forms of adeno-associated viruses (AAV) that code for gamma-sarcoglycan in order to identify the virus that would be best for use in phase 1 human trials. J. Paul Taylor, M.D., Ph.D. RG Characterizing a Drosophila model of spinal bulbar muscular atrophy (SBMA) $98,534.00 $99,990.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 The genetic basis for SBMA is now known and has led to studies in cell culture and mice that have revealed impairments to several key cellular systems. This project will use an inducible model of SBMA in the fruitfly, Drosophila melanogaster. Since the relevant cellular systems are highly conserved and may be easily manipulated genetically, the fruitfly offers a powerful model system to address this issue. Erdem Tuzun, M.D. DG Effector roles of C1q, IL-6 and TNF-alpha in murine myasthenia gravis (MG) $45,000.00 Summary : 1/1/2006 12/31/2006 Year 3 MG is an autoimmune nerve-muscle junction disease. In MG, the transmission between nerve and muscle fails because of the loss of acetylcholine receptors (AChR) due to an immune attack. Anti-AChR antibodies and the complement cascade cause nerve-muscle junction destruction and this causes MG. Some cytokines are also known to be important for disease induction. Investigators are planning to investigate the significance of complement C1q, cytokines IL-6 and TNF-alpha in disease pathogenesis and the mechanisms by which they contribute to MG using the animal model in an effort to find possible future treatment strategies for MG. Robert Wilson, M.D., Ph.D. EMG Restricted funds for neuromuscular research $42,000.00 Summary : 4/1/2005 3/31/2006 Year 1 Pittsburgh - University of Pittsburgh Joseph C. Glorioso, Ph.D. TRA C Summary : MD Cooperative Center Supplement - Pittsburgh $500,000.00 1/1/2006 12/31/2006 Year 3 The MDA supplement supports four scientific projects encompassing several aspects of gene transfer for LGMD and DMD, as well as the exploration of early muscle development and stem cell-based therapies. The grant also supports two core resources including the production of gene therapy vectors. Page 53 Of 91 TENNESSEE Memphis - University of Tennessee Tulio Bertorini, M.D. EMG Restricted funds for neuromuscular research $2,500.00 Summary : 4/1/2005 3/31/2006 Year 2 Nashville - Vanderbilt University Peter Hedera, M.D. RG Molecular characterization of distal myopathy linked to chromosome 14q (MPD1) $53,117.00 Summary : 1/1/2006 12/31/2006 Year 3 Distal myopathy is a group of neurologic disorders affecting muscles, predominantly those in the feet and hands. Gradual degeneration of these muscles causes disabling weakness. Previous studies have shown that several genes can cause distal myopathy. One gene has been previously shown to be located on the chromosome 14. However, the gene responsible for this type of Distal myopathy, called MPD1, remains unknown. Researchers propose to identify a gene causing MPD1 and to characterize its role in the function of the skeletal muscles. Discovering and analyzing MPD1 gene will provide insight into the mechanism that causes this type of distal myopathy. Hopefully, understanding of the cause of MPD1 can ultimately advance our knowledge and ability to treat other myopathies. Jeffrey Myers, Ph.D. DG Folding of myelin proteins implicated in peripheral neuropathy $45,000.00 Summary : 1/1/2006 12/31/2006 Year 3 Mutations in the genes of two peripheral myelin proteins, PMP22 and PO, resulting in amino acid changes in the proteins, lead to seeral forms of peripheral neuropathy, including CMT disease. Proteins are produced as linear chains of amino acids, but must assume a specific structure (fold) in order to function. Changing the amino acid sequence may lead to problems in this folding process. Investigators will compare the folding properties of normal PO and PMP22 to those of disease-causing mutants. The understanding gained by the proposed research could lead to drugs designed to rescue or prevent folding defects. Hsiao-Huei Wu, Ph.D. DG The role of Jedi-1 and mEGF10 in peripheral nerve myelination-implications for Charcot-Marie-Tooth (CMT) $45,000.00 1/1/2006 12/31/2006 Year 1 $45,000.00 1/1/2007 12/31/2007 Year 2 $45,000.00 1/1/2008 12/31/2008 Year 3 Elucidating the molecular regulators of myelin formation is essential for determining the underlying causes of CMT and in guiding the design of therapeutic intervention stategies. This proposal is designed to determine whether Jedi-1 and mEGF10, two putative axon ensheathment-mediating proteins, are required in ensheathment and myelination of peripheral nerves. Summary : Page 54 Of 91 TEXAS Austin - University of Texas Ruth A. Hagerman, Ph.D. RG Effect of mutations in complex III on ubiquinone stability $66,355.00 Summary : 1/1/2005 6/30/2006 Year 2 One cause of muscular dystrophy lies in the inability of cellular mitochondria to produce sufficient energy. In some patients, the defect in energy production is believed to lie in the mitochondrial utilization of a required cellular compound, ubiquinone (coenzyme Q). This proposal investigates various mutations in the proteins that hold ubiquinone in place in the mitochondria, in order to understand the effect that altering the positioning of ubiquinone has on energy production. This research should lead to the development of more effective identification and treatment of patients with this type of muscular dystrophy. College Station - Texas A&M University Emily Wilson, Ph.D. RG Arterial remodeling in mouse models of muscular dystrophy $95,234.00 Summary : 1/1/2006 12/31/2006 Year 3 The goals of the current proposal are to better understand changes in blood vessel structure and function in mouse models of muscular dystrophy. The genes that are mutated in various forms of muscular dystrophy are also expressed in the smooth muscle cells that provide mechanical support to the vasculature and that are involved in regulating blood pressure and flow. Alterations in the structure, function and adaptations of arteries to perturbation in blood pressure may contribute to the pathologies of some forms of muscular dystrophy. Dallas - UT Southwestern Medical Center George N. DeMartino, Ph.D. RG Regulation of muscle protein degradation by the proteasome $92,296.00 $95,919.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 Despite the importance of protein degradation in health and disease, relatively little is known about the factors that control it or the molecular mechanisms by which it occurs. The purpose of this research is to determine how TNFalpha, a critical regulator of skeletal muscle protein degradation, controls the process via its effects on the ubiquitin-proteasome system. This work will provide important insights into how skeletal muscles atrophy. Jeffrey Elliott, M.D. EMG Restricted funds for ALS research $319,355.00 Summary : 4/1/2005 3/31/2006 Year 6 Page 55 Of 91 Jens Fielitz, M.D. DG Control of skeletal muscle regeneration by a novel small molecule $45,000.00 $45,000.00 $45,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 In this proposal, the investigators plan to elucidate the molecular mechanisms and regenerative capacity of PAMH in skeletal muscle and muscle-specific stem cells in order to find and develop muscle-specific compounds that can ultimately be developed into drugs to treat myopathies. Daniel J. Garry, M.D., Ph.D. RG Transcriptional regulation of myogenic progenitor cell populations $100,000.00 $100,000.00 $100,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 The investigators will examine the interaction of two transcription factors, Foxk1 and Sox15 and their role in the regulation of the myogenic progenitor cell population. These studies will enhance the understanding of the myogenic progenitor cell population and their role in muscle regeneration and have therapeutic applications for debilitating myopathies such as Duchenne muscular dystrophy. Ronald G. Haller, M.D. RG Exercise therapy for mitochondrial myopathies $130,104.00 Ronald Haller, M.D. EMG Restricted funds for neuromuscular research $33,380.00 Summary : 1/1/2006 12/31/2006 Year 3 4/1/2005 3/31/2006 Year 1 Osamu Nakagawa, M.D., Ph.D. RG Roles of MEF2-regulated kinase Stk23 in muscular dystrophy $65,000.00 Summary : 7/1/2005 6/30/2006 Year 3 Stk23 is a muscle-specific enzyme that modifies proteins relevant to muscular dystrophy. The mouse model expressing an excessive amount of Stk23 displays muscle abnormalities reminiscent of muscular dystrophy. This proposal seeks to elucidate the signficance of Stk23 in muscle diseases, using molecular biology and various mouse models. This research will provide insights into muscle biology and the etiology of muscular dystrophy. Eric N. Olson, Ph.D. RG Control of muscle growth by a novel small molecular $60,000.00 $60,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 The long-term goal of this project is to understand the biochemical mechanism of action of pyridine activator of muscle cell hypertrophy (PAMH) and to test its potential to enhance muscle growth and function during muscular diseases. Page 56 Of 91 Arie Struyk, M.D., Ph.D. RG A mouse model of hypokalemic periodic paralysis $100,000.00 $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 Hypokalemic Periodic Paralysis (HypoPP), is a heritable muscle disorder characterized by episodic attacks of skeletal muscle weakness. HypoPP is caused by mutations in one of two ion channel genes. The investigators propose to generate a mouse strain harboring a HypoPP mutation and use it as a resource to study the deranged physiology of HypoPP muscle. Galveston - University of Texas Tetsuo Ashizawa, M.D. RG Accelerated cellular senescence in myotonic dystrophy type 1 $75,740.00 Summary : 7/1/2005 6/30/2006 Year 2 Researchers intend to prove that the DM1 mutation increases cellular aging, and that selective therapies could be used to slow down the accelerated aging process. Premkumar Christadoss, M.D. RG Anti-IL6 antibody therapy for myasthenia gravis (MG) $110,000.00 $110,000.00 $110,000.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 Immune cells secrete a danger molecule called interleukin-6, which is very critical for the development and progression of myasthenia gravis, a neuromuscular disease. The investigators will treat myasthenia gravis in mice by depleting this danger molecule interleukin-6 by antibodies. The findings of this study will lead to the synthesis of antibody to human interleukin-6 molecule for the treatment of myasthenia gravis. Galveston - University of Texas Henry F. Epstein, M.D. RG The UNC-45 Myosin Chaperone in Muscle Dystrophy and Atrophy $91,022.00 $91,022.00 $91,022.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 When muscle atrophy and weakness develop as inmost of the MDA's diseases of interest, most of the lost protein is myosin. Increased production or stabilization of myosin may provide effective therapy of these diseases. The investigators wish to study the role of UNC-45 in these processes using cultured muscle cells and genetically altered laboratory mice. Galveston - University of Texas Medical Branch Premkumar Christadoss, M.D. RG New model of ocular myasthenia gravis in HLA transgenic mice $119,873.00 1/1/2006 12/31/2006 Year 3 Page 57 Of 91 Summary : A new mouse model of ocular myasthenia gravis (oMG) will be developed in humanized mice carrying human immune response genes. Investigators will characterize part of the acetylcholine receptor protein involved in the development of oMG. They will also characterize the lymphocyte subpopulation and molecules, which participate in oMG progression. This mouse model of oMG could be used as a pre-clinical model to identify specific therapeutic agents to treat oMG. Houston - Baylor College of Medicine Michael A. Barry, Ph.D. RG Development of metabolically biotinylated gene therapy vectors $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 This project will develop technologies towards the use of "smarter" gene therapy vectors that can seek out and target gene delivery to neuromuscular muscle cells in the body while reducing gene delivery into non-muscle cells. Aladin M. Boriek, Ph.D. RG Signal transduction in genetically altered dystrophic mice $75,000.00 Summary : 1/1/2006 12/31/2006 Year 3 Muscular dystrophy covers a diverse group of inherited disorders characterized by progressive muscle wasting. The mdx mouse is a model for Duchenne muscular dystrophy. Researchers propose to investigate the signal transduction pathways in the diaphragm muscle of the mdx mouse in response to mechanical stress. Understanding how signaling transduction pathways are being altered in dystrophic mice may help in the evaluation of gene therapies. Houston - Baylor College of Medicine Thomas A. Cooper, M.D. RG Splicing mis-regulation in the central nervous system in myotonic dystrophy $106,875.00 Summary : 1/1/2006 12/31/2006 Year 3 Researchers want to understand the changes that occur in the brain in myotonic dystrophy. An approach that has been successful in skeletal muscle will be applied to brain. Houston - Baylor College of Medicine Gabriella D'Arcangelo, Ph.D. RG Reelin signaling in Schwann cell development and function $100,000.00 Summary : 1/1/2006 12/31/2006 Year 3 Schwann cells regulate the survival and function of peripheral nerves. Genetic mutations causing loss of myelin or other proteins important for Schwann cell development result in neurological disorders such as Charcote-marie-Tooth (CMT) disease, which is characterized by nerve damage and muscle weakness. Researchers have previously identified Reelin, an extracellular protein essential for normal brain development, and elucidated its signaling mechanism. Recent studies led us to the discovery that this protein is also present in the peripheral nervous system and that it regulates its development and responsiveness to injury. Here they study the role of Reelin in Schwann cell survival and function in the hope of uncovering potential new targets for intervention in the treatment of peripheral neuropathies. Page 58 Of 91 Margaret A. Goodell, Ph.D. RG Reprogramming bone marrow cells to better regenerate muscle $100,000.00 $100,000.00 $100,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 The lab previously showed that bone marrow cells could become incorporated into regenerating skeletal muscle, such that the dystrophin protein became expressed in formerly dystrophin-negative cells. Here, the investigators will examine the efficiency of this process. The investigators will also attempt to enhance this conversion by a variety of strategies, with the hope that the investigators may be able to use bone marrow or bone marrow transplantation to treat some muscle-degenerative diseases. Yasuo Hamamori, M.D., Ph.D. RG Regulation of muscle differentiation by notch effectors $96,661.00 Summary : 7/1/2005 6/30/2006 Year 3 Muscular dystrophy has the loss of muscle mass due to muscle degradation, and the treatment will depend on growth of muscle fibers. One potential therapeutic approach is to promote growth of satellite cells that become myofibers. Notch signaling stimulates satellite cell growth. Therefore, growth of satellite cells could be greatly enhanced by activating Notch with drugs and gene therapy. Notch actions are mediated by effector proteins. However, Notch effectors in muscle are unknown. Researchers previously isolated such effector candidate genes, HERP. This study is designed to analyze HERP functions in muscle cells. Thus, knowledge from the study might ultimately contribute to development of new therapeutics for muscular dystrophy, based on satellite cell growth promotion. Susan L. Hamilton, Ph.D. RG Mouse models of central core disease $95,737.00 $99,364.00 Susan L. Hamilton, Ph.D. SG 2006 Muscle: Excitation/Contraction Coupling Gordon Conference $10,130.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 5/1/2006 10/31/2006 Year 1 This is the only conference dedicated to the study of skeletal muscle Ca2+ regulation and the muscle diseases that arise from or are impacted by alterations in Ca2+ homeostasis. G. Jackson Snipes, M.D., Ph.D. RG Protein degradation in Charcot-Marie-Tooth disease $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 The proposed studies will examine how disease-causing mutations affect quality control of protein synthesis and mechanisms of protein degradation in Schwann cells and how these mechanisms contribute to produce a neuropathy. They anticipate that identifying the most important mechanisms will suggest rational treatment strategies. Houston - Methodist Hospital Page 59 Of 91 Stanley H Appel, M.D. EMG Restricted funds for ALS research $30,930.00 Summary : 4/1/2005 3/31/2006 Year 4 Houston - Methodist Hospital Research Institute Stanley H. Appel, M.D. RG Immune mechanisms in amyotrophic lateral sclerosis (ALS) $110,000.00 $110,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 It is increasingly clear that motor neurons do not die by themselves in ALS. These studies should help define the potential toxic and/or protective properties of these cells surrounding motor neurons, and provide the scientific basis for minimizing cytotoxicity and enhancing cytoprotection in ALS. Houston - Texas A & M University Robert D. Wells, Ph.D. EMG Restricted funds for Friedreich's ataxia research $74,827.00 Summary : 4/1/2005 3/31/2006 Year 2 Houston - University of Houston Stuart E. Dryer, Ph.D. RG Generation of an animal model for a new form of myasthenia gravis (MG) $75,000.00 Summary : 1/1/2006 12/31/2006 Year 3 The autoimmune disease MG is in most patients caused by antibodies directed against the muscle acetylcholine receptor that disrupt the communication between nerve and muscle. However, in about 10-20% of human patients antibodies against a different muscle protein called muscle-specific kinase are found instead. To study this new form of the disease in more detail, they want to create an animal model by injecting purified protein into mice. This model will allow us and many other researchers to analyze the pathological changes induced by these antibodies. It will hlep to identify differences between this form and the main form and evaluate the effects of established and new drugs that are commonly used to control MG in human patients. Houston - University of Texas William Klein, Ph.D. RG Using myogenin to manipulate muscle stem cells $75,187.00 Summary : 1/1/2006 12/31/2006 Year 3 Stem cell therapy is emerging as an important intervention therapy for numerous skeletal muscle pathologies. However, without adequate knowledge of stem cell mechanisms, stem cells remain black boxes whose potential is largely untapped. This application seeks to better understand myogenin's role in skeletal muscle stem cells. Page 60 Of 91 Robert A. Schulz, Ph.D. RG Calcineurin function in muscle development $90,000.00 $90,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 The Drosophila model organism will be used to identify and characterize genes involved in muscle formation and function. Highly sensitive genetic approaches can be used with this experimental system, leading to discoveries that are likely unattainable when using most other animal species. Fundamental information acquired on genes that interact in promoting muscle growth and/or muscle fiber type should be of intellectual use in the development of therapies for specific neuromuscular diseases. Houston - University of Texas Health Center Vasanthi Jayaraman, Ph.D. RG High throughput screening for AMPA receptor antagonists for ALS $100,000.00 Summary : 1/1/2006 12/31/2006 Year 2 Glutamate toxicity mediated through a class of proteins called AMPA receptors is currently thought to be the major trigger for motor neuron death. Inhibitors of this protein have been consistently effective in animal models but not in humans mainly because of their low water solubility leading to their deposition in the liver resulting in necrosis. There is hence, a need for water soluble AMPA receptor inhibitors as drugs for ALS and investigators propose to address this need by screening for RNA ligands as inhibitors, since these are water soluble, using a high throughput screening assay developed in the lab. San Antonio - University of Texas Harry W. Jarrett, Ph.D. RG Muscular dystrophy and cell signaling $90,000.00 $90,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 Laminin binding to the complex of proteins that cause many muscular dystrophies has recently been shown to cause changes in the metabolism of muscle cells which determine whether they divide, mature, or die. These cell signaling pathways will be probed to discover if any of the drugs developed to alter this signaling are of potential benefit to patients. Holly Van Remmen, Ph.D. RG Alterations in mitochondrial function in the initiation and progression of ALS $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 To further delineate the role of oxidative stress in ALS, investigators will mutant SOD mice with mouse models that have decreased oxidative stress due to increased levels of the protective antioxidant enzymes, MnSOD, Catalase PHGpx and Thioredoxin. The results of this study will provide a better understanding of the role of mitochondria in ALS and potentially lead to new options for interventions and therapies aimed at preventing mitochondrial oxidative stress. Page 61 Of 91 UTAH Logan - Utah State University Brett A. Adams, Ph.D. RG Novel signaling proteins in motoneurons $70,000.00 Summary : 1/1/2005 6/30/2006 Year 2 Researchers will determine the basic properties and physiological functions of several recently-discovered signaling proteins in mammalian spinal motoneurons. Katarina Stroffekova, Ph.D. RG CaM as a calcium sensor of skeletal muscle DHPR and its implication in EC coupling $85,000.00 Summary : 1/1/2006 12/31/2006 Year 3 Skeletal muscle EC coupling requires mechanical coupling of two proteins, the DHPR and RyR1. The interactions between DHPRs and RyR1s are bi-directional and likely subject to regulation by a wife variety of modulators such as CaM, which affect either of the two proteins. Mutations in DHPR and RyR1 have been shown to cause the inherited human muscular diseases of HypoPP, MH and CCD. This proposal will provide new information about modulation of DHPR function and also EC coupling. Salt Lake City - University of Utah Kathleen Clark, Ph.D. DG A potential role for muscle LIM protein in limb girdle muscular dystrophy (LGMD) $45,000.00 $45,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 Telethonin, titin and muscle LIM protein (MLP) are thought to function together as a biomechanical sensor that detects changes in muscle activity. Investigators will determine the biological functions of this sensor by the analysis of one of its components, MLP. They will test the role of MLP as part of the sensor, and determine what changes MLP elicits in muscle. These experiments should greatly aid in determining the underlying cellular defects in LGMD type 2G and 2J. David J. Grunwald, Ph.D. RG Zebrafish models of congenital myopathies $90,000.00 $90,000.00 $90,000.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 This research program is aimed at developing models of congenital myopathies in the zebrafish. Modeling diseases in the zebrafish makes sense: i) embryonic muscle formation is well-studied in zebrafish. ii)all of zebrafish embryogenesis is completely accessible for analysis, iii) tools are available to test functions of genes, and iv) insights from work with zebrafish are highly applicable to understanding of human disease. Michael T. Howard, Ph.D. DG Restorative decoding of premature stop codon and frameshift mutations $45,000.00 1/1/2006 12/31/2006 Year 3 Page 62 Of 91 Summary : Approximately 10-15% of all cases of DMD are caused by premature stop codon or frameshift mutations within the dystrophin gene. Several strategies are proposed in this grant to correct these mutations by inducing the ribosome to either readthrough premature stop codon mutations, or shift reading frames at the site of frameshift mutations. Researchers have termed this approach "restorative decoding". By increasing the levels of mutant mRNA simultaneously with induction of restorative decoding, it should be possible to maximize expression of functional full length protein from mutant alleles to alleviate disease symptoms. Kathryn J. Swoboda, M.D. RG Refinement of outcome parameters for clinical trials in SMA $44,963.00 Summary : 7/1/2005 9/30/2006 Year 3 MUNE is a technique which allows us to make an estimate of the number of motor neurons in the spinal cord supplying a particular muscle. It is noninvasive, causes minimal discomfort and requires no voluntary participation, so that even infants and young children with SMA can be tested. Investigators propose to evalute MUNE in conjunction with other measures including SMN2 copy number, SMN protein and RNA levels, lean muscle mass as measured by DEXA scanning, and functional status. Such information will ensure the development of appropriate clinical trial design for assessing promising new therapies in SMA patients. VIRGINIA Charlottesville - University of Virginia Mani Mahadevan, M.D. RG Inducible transgenic mouse model of myotonic dystrophy type 1 (DM1) $109,000.00 $109,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 Investigators propose to develop a transgenic mouse model in which they control when and how much of the toxic RNA is made. This will provide a system in which to test out potential therapeutic strategies. Norfolk - Eastern Virginia Medical School Earl Godfrey, Ph.D. RG Role of nitric oxide synthase pathway in neuromuscular development $93,120.00 Summary : 7/1/2005 6/30/2006 Year 3 Investigators will study how nitric oxide synthese acts in forming nerve-muscle connections, and how it may increase utrophin, which could limit degeneration in muscular dystrophies. Page 63 Of 91 WASHINGTON Seattle - Fred Hutchinson Cancer Research Center Lisa Maves, Ph.D. DG Investigating interactions among MyoD, Pbx and Hox factors in skeletal myogenesis $45,000.00 $45,000.00 $45,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 The investigator proposes to determine how MyoD and Hox genes interact in muscle cells. Understanding the relationships between MyoD and Hox genes will provide important insight into the growth and maintenance of muscle cells and might allow the investigators to design better treatments for muscular dystrophies. Seattle - University of Washington Craig L. Bennett, Ph.D. RG CMT1C: possible defects in PMP22 regulation due to SIMPLE mutations $90,000.00 $90,000.00 $90,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 Evidence from the research suggests that SIMPLE plays a role in targeting proteins to the lysosome for degradation. The goal is to characterize SIMPLE's role in protein degradation in the peripheral nervous system and determine the mechanisms by which CMT1C mutations lead to pathology. Steven S. Carlson, Ph.D. RG Synaptic laminin and the postsynaptic membrane $80,337.00 $80,337.00 $80,337.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 Data suggests that a4b2g1 laminin links the calcium channel at the release site with an unidentified component at the detection site. Such a linkage would begin to explain the molecular mechanism by which nerve and muscle communicate to align these sites during synapse formation and maintenance. To test this hypothesis, the investigators propose to identify and characterize the muscle anchor proteins for the a4b2g1 laminin at the detection site. William A. Catterall, Ph.D. RG Calcium channel regulation in skeletal muscle $98,859.00 $100,000.00 $100,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 Forceful contractions of skeletal muscles are caused by high frequency discharges of the motor nerves. The investigators will study regulation of the calcium channels of normal and dystrophic muscle by rapid electrical stimulation and by hormonal pathways. This form of regulation is impaired in muscle cells that lack dystrophin, the defective gene in Duchenne muscular dystrophy, and may also involve calpain-3, the defective gene in limb-girdle muscular dystrophy. Failure of calcium channel regulation may damage muscle cells. The results will give new leads for therapeutic approaches to prevent damage of dystrophic cells. Page 64 Of 91 Jeffrey S. Chamberlain, Ph.D. TRA C MD Cooperative Center Supplement - Seattle $499,726.00 $242.00 Summary : 1/1/2006 1/1/2006 12/31/2006 12/31/2006 Year 3 Year 3 The MDA supplement supports four scientific projects. The first three relate to the development of gene transfer technology for DMD and the fourth explores the cause of MMD. The grant also supports four core resources including diagnostic and genetic counseling. Stanley Froehner, Ph.D. RG Identifying the genetic basis of a novel form of congenital muscular dystrophy $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 The sarcolemmal localization and the level of expresion of dystrobrevin and syntrophins in the muscle is markedly reduced or absent. Investigators have excluded mutations in the genes for these proteins. They have performed linkage analysis on a large consanguineous family with four affected children and have localized the gene to a region of chromosome 12. This research will identify the disease gene and its protein product in other human muscular dystrophies and in mouse models. Paul Gregorevic, Ph.D. DG Techniques for therapeutic gene delivery to cardiac and skeletal muscles $45,000.00 $45,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 Recently, it has been demonstrated that it is possible to deliver a gene throughout the muscles of mice using an engineered vector carrying the gene of interest, which is injected into the bloodstream. In this project, researchers will focus on improving the efficiency of gene delivery and use the best methods to treat mouse models of muscular dystrophy. Stephen Hauschka, Ph.D. RG Therapeutic regulatory gene cassettes for diaphragm muscle $100,000.00 $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 This proposal seeks to optimize the transcriptional activity of regulatory gene cassettes that express therapeutic proteins within respiratory muscle fibers. These cassettes can then be used by other investigators for vector-and cell-mediated therapy strategies designed for treating these and other neuromuscular diseases. Albert La Spada, M.D., Ph.D. RG Modeling motor neuron degeneration in spinal bulbar muscular atrophy (SBMA) $104,553.00 Summary : 1/1/2006 12/31/2006 Year 3 SBMA is an adult onset neuromuscular disorder affecting only men. Investigators wish to understand why motor neurons are dying in this disease. By developng a mouse that accurately recapitulates the full neurological spectrum of SBMA, investigators will be able to determine the earliest steps in the process of motor neuron degeneration in SBMA and apply this information to the development of therapies. Page 65 Of 91 Hannele Ruohola-Baker, Ph.D. RG Drosophila as a model for muscular dystrophy: A molecular-genetic analysis of dystroglycan-dystrophin complex $100,000.00 1/1/2006 12/31/2006 Year 1 $100,000.00 1/1/2007 12/31/2007 Year 2 $100,000.00 1/1/2008 12/31/2008 Year 3 The researchers have developed a Drosophila model for studying muscular dystrophies. Behavioral studies showed that both Dg and Dys mutants in flies have decreased ability to move and shortened lifespan. Importantly, the mutants also show age-dependent muscle and brain degeneration. The researchers will now use this Drosophila model for muscular Dystrophy to screen for modifiers that can suppress or enhance the muscle phenotype to obtain new components that regulate the Dys-DG complex. Summary : Seattle - University of Washington Patrick Weydt, M.D. DG VEGF gene delivery strategies for motor neuron disease $45,000.00 $45,000.00 $45,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 VEGF-replacement therapy has yielded encouraging successes in transgenic animal models. However, VEGF also has effects on many other tissues, e.g. tumor growth. Therefore, targeting of VEGF to the motor neurons may be mandatory to fully realize its therapeutic potential. The investigators propose to generate 2nd generation viral vectors and then to test if VEGF delivery to motor neurons or muscle can successfully treat mice with ALS and SBMA, while limiting untoward off-target effects. Page 66 Of 91 WISCONSIN Madison - University of Wisconsin Elizabeth Craig, Ph.D. RG Friedreich's ataxia: The biological function of frataxin $94,075.00 $94,075.00 $94,075.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 Although the frataxin gene was identified 8 years ago, a great deal of controversy exists as to frataxin's normal cellular function. Based on the belief that a basic understanding of the biological function of frataxin will aid in the design of effective treatment of the disease, the investigators propose to carry out a combined genetic and biochemical analysis to determine frataxin's mechanism of action in cells. James M. Ervasti, Ph.D. RG TAT-utrophin as a protein therapy for dystrophinopathy $120,000.00 $90,000.00 $90,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 There is presently no cure or effective treatment that can alleviate the devastating progression of Duchenne muscular dystrophy. The proposed studies will investigate a novel protein-based therapy that may stop or slow the progression of Duchenne muscular dystrophy until more permanent or curative strategies can be implemented. Jon A. Wolff, M.D. RG Intravascular injection of naked plasmid DNA into the mdx mouse model for Duchenne muscular dystrophy (DMD) $90,000.00 7/1/2005 6/30/2006 Year 2 $90,000.00 7/1/2006 6/30/2007 Year 3 Investigators have promising preliminary results that show that a gene within a plasmid can be delivered via a peripheral vein into more than 10% of the muscle cells throughout the limbs of mice, rats and monkeys. The proposed mouse studies will help us plan for possible human clinical gene therapy trials for DMD. Summary : Australia Page 67 Of 91 Melbourne - University of Melbourne Gordon Lynch, Ph.D. RG Growth factor therapy for improving muscle function in muscular dystrophy $84,843.00 Summary : 7/1/2005 6/30/2006 Year 3 Muscle wasting and weakness are symptoms of neuromuscular disorders, including Duchenne muscular dystrophy. This project investigates the potential for growth factor (IGF-I and/or IL-15) administration to ameliorat emuscle wasting and improve function in muscular dystrophy. The aim is to develop a treatment that will provide an immediate improvement in the quality of life for muscular dystrophy patients. David Thorburn, Ph.D. RG Finding the pathogenic mechanisms by which different genes cause mitochondrial complex I deficiency $91,842.00 1/1/2006 12/31/2006 Year 3 Muscle and brain "burn" fuels (sugar, fat and protein) in small power plants called mitochondria. Over 500 children born each year in the US have inherited disorders of mitochondrial energy generation, causing disease ranging from infant death to later-onset neuromuscular disease. Investigators are focusing on the most common of these disorders, Complex I deficiency. Complex I requires 45 separate components to be assembled together in order to work properly. It appears that in most patients the problem is not in the components themselves but factors required to put them together. Investigators are using a range of methods to identify the location and identity of the genes encoding these factors. They believe this will allow to devise better strategies for diagnosis, prevention and ultimately treatment. Summary : Page 68 Of 91 Nedlands - University of Western Australia Manfred W. Beilharz, Ph.D. RG Peripheral tolerance, regulatory T cells and myoblast transfer therapy $100,000.00 $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 The major problem facing Myoblast Transfer Therapy (MTT) is the immune response directed against the transplanted myoblasts. Tolerisation protocols based on graduated pretreatments of recipients with donor tissue have been successful in transplants other than MTT. Such peripheral tolerance is often mediated by regulatory T cells which have recently shown to be be present in skeletal muscle. The central themes of this proposal are to develop a tolerisation protocol for MTT which could be directly transferred to human therapeutic use and may permit long-term graft survival without the need for sustained immunosuppression treatment. Nigel G. Laing, Ph.D. RG Can cardiac actin ameliorate skeletal actin congenital myopathies? $76,647.00 $82,850.00 $90,732.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 A significant proportion of congenital myopathies are caused by defective skeletal muscle actin genes. The investigators propose that an alternative gene, cardiac actin, could be used as a treatment for the skeletal muscle-actin myopathies. They will use mouse models to investigate whether cardiac actin can completely replace absent skeletal actin, and furthermore overcome mutant skeletal actin. Parkville - Murdoch Children's Research Center Joseph Sarsero, Ph.D. EMG Restricted funds for FA research $20,000.00 Summary : 4/1/2005 3/31/2006 Year 1 Page 69 Of 91 Parkville - Murdoch Childrens Research Institute Shireen R. Lamande, Ph.D. RG Functional consequences of collagen VI mutations in Bethlem myopathy and Ullrich congenital muscular dystrophy $78,862.00 1/1/2006 12/31/2006 Year 1 $82,903.00 1/1/2007 12/31/2007 Year 2 $87,244.00 1/1/2008 12/31/2008 Year 3 Mutations in the extracellular matrix protein collagen VI cause Bethlem myopathy and Ullrich congenital muscular dystrophy, but we don't yet understand why the mutations cause muscle disease. This project aims to define the important structural role that collagen VI plays in muscle. Not all patients with Bethlem myopathy and Ullrich congenital muscular dystrophy have collagen VI mutations and the studies aim to identify the underlying cause of the muscle disease in these patients. Summary : Joseph Sarsero, PhD RG Novel approaches to the therapy of Friedreich's ataxia $100,000.00 Summary : 1/1/2006 12/31/2006 Year 3 Novel cellular and animal models will be developed to facilitate the discovery of drugs that can restore frataxin to therapeutic levels in Friedreich's ataxia. Perth - University of Western Australia Stephen D. Wilton, Ph.D. RG Reducing the severity of DMD by redirecting pre-mRNA splicing $108,864.00 Summary : 1/1/2006 12/31/2006 Year 3 Nucleic acid drugs can redirect processing of a DMD dystrophin gene transcript so that the mutation is by-passed and the induced BMD-like mRNA will reduce the severity of the disease. Randwick - University of New South Wales Des Richardson, B.Sc., M.Sc., Ph.D., D.Sc. RG The role of iron in Friedreich s ataxia and the use of iron chelation therapy $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 Investigators have designed lipid-soluble chelators that can enter the mitochondrion to bind Fe and these new drugs will be tested to prevent disease progression in the KO mice. Sydney - Children's Hospital at Westmead Page 70 Of 91 Sandra Cooper, Ph.D. DG The role of dysferlin in the pathogenesis of limb girdle muscular dystrophy $44,952.00 Summary : 7/1/2005 6/30/2006 Year 3 Dysferlin deficiency causes muscular dystrophy. Investigators will study dysferlin in skeletal muscle, to better understand why muscle damage occurs and to identify possible approaches to therapy. Sydney - Victor Chang Cardiac Research Inst. Peter Currie, Ph.D. RG Characterisation of zebrafish dystrophin mutants $70,000.00 Summary : 7/1/2005 6/30/2006 Year 3 To understand how mutation in the dystrophin gene leads to muscle weakness, investigators will study zebrafish that lack dystrophin protein, and identify genes that modulate the dystrophic phenotype. Toowoomba - University of Southern Queensland Andrew Hoey, Ph.D. RG Cardiac dysfunction in Duchenne muscular dystrophy (DMD) $70,475.00 Summary : 7/1/2005 6/30/2006 Year 3 This project will examine two major mechanisms through which cardiac function can be enhanced so as to reduce the progression or development of heart failure. The first approach is to regulate the neural and hormonal influences on the heart while the second approach will aim to bypass the genetic lesion and restore synthesis of the missing dystrophin protein in cardiac muscle. The benefits on cardiac and skeletal muscle function and integrity will be examined to further ascertain the role that degeneration of cardiac performance plays in muscle deterioration. Sydney - University of New South Wales Stewart I. Head, Ph.D. RG CNS dysfunction in Duchenne muscular dystrophy $80,000.00 $77,810.00 $77,810.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 The investigators propose to utilize a brain slice preparation to investigate this dystrophinopathy, focusing on the GABAA inhibitory synapses on cerebellar Purkinje cells. The investigators work could pave the way for using a combination therapy of benzodiazepines, barbiturates and "the dietary supplement" creatine in order to eliminate some of these distressing CNS-mediated behavioral and cognitive deficits common in boys with DMD. Belgium Page 71 Of 91 Antwerpen - University of Antwerp Vincent Timmerman, Ph.D. RG Molecular genetic and functional analysis of HSP22/HSP27 mutations in relation to motor neuropathies $100,000.00 7/1/2005 6/30/2006 Year 1 $100,000.00 7/1/2006 6/30/2007 Year 2 $100,000.00 7/1/2007 6/30/2008 Year 3 Investigators aim to perform a molecular genetic and functional study of two small heat shock protein genes in relation to distal hereditary motor neuropathies (distal HMN) in order to identify the mechanism through which these mutant genes induce a dominantly inherited axonopathy. Summary : Brussels - Universite Libre de Bruxelles Massimo Pandolfo, M.D. EMG Restricted funds for the support of Friedreich's ataxia research $34,000.00 Summary : 4/1/2005 3/31/2006 Year 6 Leuven - VIB Peter Carmeliet, Ph.D., M.D. RG Therapeutic potential of VEGF for amyotrophic lateral sclerosis (ALS) $118,000.00 Summary : 1/1/2006 12/31/2006 Year 3 Accumulating evidence indicates that reduced VEGF levels negatively influence ALS both in humans and in animal models of ALS. This project investigates in preclinical mouse and rat models of ALS, whether and how VEGF can be used to prevent or attenuate neurodegeneration and neuromuscular disease. Canada Page 72 Of 91 London - University of Western Ontario Christen Shoesmith, BSc, MD CRT G Clinical Research Training $74,200.00 $69,910.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 1 Year 2 The Clinical Research Training Grant is designed to provide promising young physicians the research training opportunities that are needed to become productive clinical investigators in neuromuscular diseases. Grantees will receive training in the diagnosis and management of adults and children with neuromuscular diseases, complete formal coursework in clinical research methodologies, and complete a clinical research project during the two years of fellowship training. Michael Strong, M.D, FRCPC RG The regulation of microglial activation in amyotrophic lateral sclerosis (ALS) $86,782.00 $89,702.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 The Researchers are proposing that the nature of the motor neuron injury is a critical determinant in whether this microglial response is neuroprotective or neurotoxic, and that this delicate balance between neuroprotection and neurotoxicity is disturbed in ALS. In these experiments, they will determine whether the nature of the motor neuron interaction with microglial cells, following neuronal injury, can be modified to shift the balance in favor of neuroprotection. Page 73 Of 91 Montreal - Hopital Notre-Dame-CHUM Bernard Brais, M.D., Ph.D. RG Cloning and characterization of the mutated gene responsible for a new form of recessive LGMD $60,000.00 7/1/2005 6/30/2006 Year 1 $60,000.00 7/1/2006 6/30/2007 Year 2 $60,000.00 7/1/2007 6/30/2008 Year 3 The investigators have recruited a group of 17 individuals from 11 different French-Canadian families affected by a new recessive form of LGMD associated with quadriceps atrophy and muscle pains. A genome-wide scan uncovered linkage to a chromosomal region not previously associated with a muscular dystrophy. This application proposes to clinically and genetically characterize this new recessive form of LGMD. The investigators are convinced of the ability to recruit cases of this condition living in the USA and in other countries. The identification of the mutated gene will allow a better definition of this new form of LGMD and the investigators hope it helps to design new therapeutic approaches. Summary : Montreal - McGill University Michael Sinnreich, M.D., Ph.D. RG A study of the modular flexibility of dysferlin-application to therapeutic strategies $75,000.00 $75,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 1 Year 2 The proposed research project is designed to develop molecular therapeutic strategies for a common form of Limb Girdle muscular dystrophy caused by dysferlin deficiency. In this genetic disease a protein responsible for repairing exercise induced muscle membrane tears, dysferlin, is lacking. This results in muscle fiber damage and leads to muscular dystrophy. Montreal - McGill University Brendan J. Battersby, Ph.D. DG New animal model for mitochondrial diseases $44,990.00 $44,990.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 Deficiencies in cytochrome c oxidase lead to a heterogeneous collection of human diseases that affect primarily the heart, skeletal muscle, and the nervous system. The objective of this project is to investigate the molecular genetic basis for differential tissue susceptibility to cytochrome c oxidase dysfunction in zebrafish, a model organism used in biomedical research. Heather Durham, Ph.D. RG Mechanisms of motor neuron vulnerability to disease $86,185.00 $88,715.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 This research project will investigate how mutant proteins responsible for familial motor neuron diseases alter the interaction between two important normal functions that must occur in motor neurons: receiving information through excitation of receptor proteins by the neurotransmitter, glutamate, and disposal of both normal and damaged proteins through the proteasome. Page 74 Of 91 George Karpati, M.D. RG Substantial increase of extrasynaptic utrophin in mdx muscle fibers by upregulation of utrophin transcription using zinc $95,700.00 1/1/2006 12/31/2006 Year 1 $93,280.00 1/1/2007 12/31/2007 Year 2 $94,980.00 1/1/2008 12/31/2008 Year 3 In Duchenne muscular dystrophy (DMD), there is progressive destruction of muscle fibers due to a genetically determined deficiency of an essential protein (dystrophin) localized to the surface membrane of muscle fibers. Several forms of molecular (gene) therapy are being investigated in animal models including increasing the amount of an analogue of dystrophin, utrophin whose gene is intact in DMD. The investigators propose a promising method of substantially augmenting utrophin throughout the surface membrane in muscle fibers of the mouse model of DMD. They anticipate that this method will prove to be safe and effective for eventual use in clinical trials of DMD patients. Summary : Josephine Nalbantoglu, Ph.D. RG Use of histone deacetylase inhibitors to improve gene transfer to dystrophic muscle $90,464.00 $90,310.00 $92,950.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 The investigators are proposing a novel approach to render mature muscle more susceptible to adenovirus-mediated gene transfer. They foresee that pre-treatment of muscle with agents called histone deacetlase (HDAC) inhibitors would be required for a short period of time only, just to increase viral uptake. Some of these HDAC inhibitors have had long-term usage in humans. Therefore, this approach would be applicable to human dystrophies. Basil Petrof, M.D. RG Plasmid-mediated delivery of therapeutic genes in muscular dystrophy $88,588.00 $88,588.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 These studies are aimed at making intravascular delivery of plasmid DNA a safe and effective method of gene therapy for patients with Duchenne and limb-girdle muscular dystrophies. Studies will be performed in dystrophic animals to help guide future trials of this approach in patients. Eric A. Shoubridge, Ph.D. RG Assembly of cytochrome c oxidase in mitochondrial encephalomyopathy $88,554.00 $88,554.00 $88,554.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 The enzymes responsible for energy production are large protein complexes composed of many subunits. The proper coordination and assembly of these components is essential to deliver the energy required for muscle work. The investigators are investigating the role of two different proteins which, when mutated, result in loss of activity of one of the enzyme complexes in skeletal muscle and nerve, due to a failure of complex assembly, and fatal neuromuscular disease. Montreal - Montreal General Hospital Page 75 Of 91 Guy Rouleau, M.D., Ph.D. RG Identification and characterization of the ALS3 gene $100,000.00 Summary : 1/1/2006 12/31/2006 Year 2 Investigators are examining the sequence of the entire 4 mega-base pair region from the disease bearing allele of an affected individual. When all of the patient's DNA sequence variations in this region are know, they will identify which variant is the causative mutation. This will be done by testing for the variation's absence in control individuals and by searching for other mutations in the same gene from our panel of sporadic and familial ALS samples. A thorough characterization of the causative gene will ensue. Montreal - University of Montreal Bernard Brais, M.D., Ph.D. RG Cloning and characterization of the mutated gene responsible for a new form of congenital muscular dystrophy (CMD) with hyperlaxity $80,000.00 1/1/2006 12/31/2006 Year 1 $80,000.00 1/1/2007 12/31/2007 Year 2 $80,000.00 1/1/2008 12/31/2008 Year 3 The investigators have recruited a group of 14 individuals from 11 different French-Canadian families affected by a new recessive form of Congenital Muscular Dystrophy (CMD) associated with joint hyperlaxity. They have mapped the gene to an original chromosomal region. This application proposes to characterize this new recessive form of CMD. They have already recruited cases of this condition that are not of French-Canadian background. The identification of the mutated gene will allow a better definition of this new form of CMD, help diagnosis and genetic counseling for this disease, shed light on how the mutations lead to the muscular dystrophy and they hope to help design new therapeutic approaches. Summary : Guy A. Rouleau, M.D., Ph.D. RG Molecular investigations for an OPMD therapy $80,000.00 $80,000.00 $80,000.00 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 Guy Rouleau, M.D., Ph.D., FRCPC RG Screening genes critical for the development of motor neurons in ALS patients $100,000.00 $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 Recently, a group of researchers have identified a set of 30 genes specifically expressed in a subset of motorneurons. Identifying mutations in these genes will have a significant impact on our understanding of the pathogenic mechanisms in ALS as well as provide new insights into potential treatment strategies and therapeutic targets. Page 76 Of 91 Ottawa - Children's Hospital of Eastern Ontario Robert G. Korneluk, Ph.D. RG Therapeutic potential of apoptosis suppression for myotonic dystrophy (DM) $101,200.00 Summary : 1/1/2006 12/31/2006 Year 3 DM is a very common genetic neuromuscular disease that causes significant health problems in a wide age range. Approaches to the treatment of this disease has advanced slowly, but, a new concept has emerged recently that holds great promise. Cells that are damaged by a diverse range of factors undergo a form of cellular suicide that is known as apoptosis. Investigators have shown that by repressing apoptosis, the lifetime of damaged cells can be extended and their function preserved. They have discovered a family of genes known as the inhibitors of apoptosis (IAPs), which perform this important function of preventing apoptotic cell death. The goal now is to use these genes to rescue the damage caused by DM and other neuromuscular disorders. Alex MacKenzie, M.D., Ph.D. RG Compound testing in organotypic cultures of spinal muscular atrophy (SMA) mouse model spinal cords $77,000.00 7/1/2005 6/30/2006 Year 2 Researchers have identified compounds that stimulate the production of SMN protein by the SMN2. The use of animal models to test all of these compounds would be costly and timely. Researchers are proposing the use of whole spinal cord cultures in order to identify the drugs with the most potential for SMA therapeutics and study their effect. Summary : Ottawa - Ottawa Health Research Institute F. Jeffrey Dilworth, Ph.D. RG Proteomic approach to defining the role of different muscle regulatory factors in myogenesis $80,000.00 1/1/2006 12/31/2006 Year 1 $80,000.00 1/1/2007 12/31/2007 Year 2 MyoD, Myf5, MRF4 and myogenin are thought to act as "molecular switches" that turn on genes that are expressed in muscle. However, very little is known about the individual role of each of these proteins in establishing muscle. Using an innovative new proteomics technology, the investigators plan to define the function of these proteins in muscle by identifying factors that associate specifically with each one. Understanding the mechanism by which each of these "switches" functions will facilitate the development of novel therapies for muscular dystrophy patients. Summary : Rashmi Kothary, Ph.D. RG The role of sodium channel 8a in skeletal and cardiac muscle function $100,000.00 Summary : 7/1/2005 6/30/2006 Year 3 Neuromuscular disorders are a heterogeneous group of diseases that lead to progressive muscle atrophy, weakness, degeneration, loss of movement, and often to early death in affected patients. Identification of protein networks whose expression or activities are altered as a common theme in the many neuromuscular disorders is an important step prior to designing therapies that might be applicable for the treatment of muscle atrophy in general. With that in mind, the latter half of this proposal dealing with molecular profiling of partially (the dmu mouse) or completely (experimentally) denervated skeletal muscle will allow us to identify potential targets for therapeutic intervention in the many disease states that lead to muscle atrophy. Page 77 Of 91 Lynn A. Megeney, Ph.D. RG Characterizing the role of the TC10/JNK1 atrophic pathway in dystrophic muscle $100,000.00 $100,000.00 Lynn Megeney, Ph.D. RG The role of caspase 3 activity in muscle differentiation and disease $100,000.00 $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 Observations in the laboratory have shown that the proteins responsible for muscle cell death/apoptosis are also absolutely required for the normal maturation of healthy muscle cells. In this grant application the investigators propose to continue their studies of how cell death proteins regulate muscle development and maturation, as it will help to establish when and where it is appropriate to block the activity of these factors without disrupting or limiting normal function. Michael Rudnicki, Ph.D. RG Molecular regulation of satellite cell function $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 In this application, investigators outline a research porposal to further investigate the molecular mechanisms that regulate the function of satellite cells during muscle regeneration. The research program will identify the sequences that control Pax7 expression in satellite cells, investigate the role played by Wnt-signaling in regulating Pax7 expression, and investigate the function of different Wnt proteins in muscle regeneration. The proposed studies will provide novel insights into the biology of muscle regeneration that will potentially lead to new types of therapeutic intervention. Ottawa - University of Ottawa Stephen H. Gee, Ph.D. RG The role of diacylglycerol kinase-zeta and syntrophins in myoblast fusion $84,020.00 Summary : 1/1/2006 12/31/2006 Year 3 The transplantation of cultured muscle precursor cells (myoblasts) into host skeletal muscles is a promising treatment for Duchenne muscular dystrophy (DMD), however several technical hurdles must be overcome before clinical benefits can be realized. One is limited fusion of donor myoblasts with host muscle fibers. The proposed studies will elucidate the molecular events underlying myoblast fusion and may provide a therapeutic target with which to enhance fusion and improve therapies aimed at restoring dystrophin to muscles of DMD patients. Bernard Jasmin, Ph.D. RG Role of calcineurin signalling in the regulation of utrophin in skeletal muscle $124,700.00 Summary : 1/1/2006 12/31/2006 Year 3 One possible approach to counteract the effects of DMD consists in up-regulating the levels of a protein normally expressed in dystrophic muscle which could then functionally compensate for the lack of dystrophin. An ideal candidate for such a role is utrophin. Therefore, it becomes essential to understand the mechanisms regulating the synaptic expression of utrophin with the aim of pharmacologically inducing its expression in extrasynaptic compartments of DMD muscle fibers. Page 78 Of 91 Luc Sabourin, Ph.D. RG Role of SLK in myoblast migration $98,709.00 $98,709.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 Investigators have recently isolated a novel protein kinase, termed SLK, involved in the control of cellular reorganization. The proposed experiments will focus on understanding the molecular mechanisms that regulate myoblast migration using in vitro and in vivo approaches. Dissection of the regulatory mechanisms that govern cellular reorganization and cell migration will contribute significantly to the design of more efficient myoblast transfer. Catherine Tsilfidis, Ph.D. RG Dedifferentiation of mammalian muscle following treatment with newt regeneration extract $100,000.00 $100,000.00 $100,000.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 The primary aim of this proposal is to identify regulatory factors controlling the onset of dedifferentiation in mammalian muscle cells following treatment with newt regeneration extract. The knowledge obtained from these studies could lead to therapies aimed at enhancing regenerative capability in humans. Quebec - Laval University Francois Berthod, Ph.D. RG Development of a tissue-engineered model of spinal cord to study amyotrophic lateral sclerosis (ALS) $75,240.00 7/1/2005 6/30/2006 Year 2 $80,240.00 7/1/2006 6/30/2007 Year 3 A model of reconstructed spinal cord will permit the study of various combinations of cells overexpressing the mutant and wild type human SOD1, in order to determine which non-neuronal cell type could induce or participate in MN death and the mechanism responsible. Summary : Ste-Foy - Laval University Jack Puymirat, M.D., Ph.D. RG Stratagems in vitro for a gene therapy for myotonic dystrophy $34,892.00 Summary : 7/1/2005 6/30/2006 Year 3 This proposal outlines an ordered series of experiments aimed at testing a myotonic dystrophy gene therapy based on the specific targeting of the mutant DMPK transcripts. Page 79 Of 91 Toronto - Hospital For Sick Children Christopher E. Pearson, Ph.D. RG DNA replication, protein-DNA-interactions and CTG instability at the DM1 locus in DM1 cells $100,000.00 1/1/2006 12/31/2006 Year 1 $100,000.00 1/1/2007 12/31/2007 Year 2 $100,000.00 1/1/2008 12/31/2008 Year 3 The investigators long-term goal is to prevent or treat DM1 at the DNA level - by inhibiting or reversing CTG expansions. Using DM1 patient cells, in which we have demonstrated active CTG instability, we will identify DNA and protein-elements that "drive" this mutation. These elements are potential targets for therapeutic treatment of DM1. They will attempt to modulate repeat instability in DM1 patient cells by modulating levels of an identified protein. The ability to genetically modulate the DM1 mutation may offer treatment for affected families. Summary : Toronto - University of Toronto Anthony Gramolini, Ph.D. DG Generation and characterization of transgenic mouse models of central core disease (CCD) $44,550.00 1/1/2006 12/31/2006 Year 3 CCD is a skeletal muscle disease characterized by weakness. Muscle biopsies of CCD patients reveal the presence of a central "core" in the muscle that produces less energy and muscle force. Mutations in RyR1, a channel protein that releases calcium into muscle cells triggering muscle contraction, are responsible for CCD. This channel is either "leaky" or "uncoupled" in CCD patients. Researchers propose to create CCD mouse models and use these mice to learn about the disease process and to test possible therapeutic approaches. Summary : Vancouver - University of British Columbia Fabio Rossi, M.D., Ph.D. RG Identification and engineering of circulating myogenic progenitors $90,000.00 $90,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 Researchers have recently identified the origin of circulating cells with muscle regenerating potential. Here, researchers plan to capitalize on this experience to explore the mechanisms underlying this phenomenon and investigate strategies aimed at increasing the efficiency of muscle regeneration to a therapeutically relevant level. Page 80 Of 91 Winnipeg - University of Manitoba Judy Anderson, Ph.D. RG Combating fibrosis in mdx mouse dystrophy by halofuginone--a novel gene therapy for DMD $100,000.00 7/1/2005 6/30/2006 Year 1 $100,000.00 7/1/2006 6/30/2007 Year 2 Investigators discovered the clinical potential of halofuginone as a novel anti-fibrotic drug that can reduce and prevent pathological fibrosis. If halofuginone is effective, then treatment and prevention of fibrosis in DMD and other neuromuscular diseases are achievable. Summary : Chile Santiago - Catholic University of Chile Enrique Brandan, Ph.D. RG DMD fibrosis: Role of CTGF, LRP and proteoglycans $53,306.00 $50,602.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 The main goal of this project is to elucidate the biological role of CTGF, LRP and proteoglycans on skeletal muscle formation, fibrosis and disease. This project will provide important basic information on the mechanisms underlying fibrosis formation in the skeletal muscle and muscle diseases and would permit in a near future to design and/or purify possible target molecules that interfere with fibrosis. England Oxford - University of Oxford Kay E. Davies, MA, D.Phil. RG Increased utrophin expression in therapy of DMD $106,495.00 Summary : 1/1/2006 12/31/2006 Year 3 The long term research objective is to develop an effective therapy for DMD by increasing the amount of utrophin in muscle cells. France Page 81 Of 91 Gif sur Yvette Cedex - CNRS Sabine De La Porte, Ph.D. RG Up-regulation of utrophin gene via the nitric oxide (NO) and the histone deacetylase (HDACs) pathways $34,973.00 1/1/2006 12/31/2006 Year 1 $28,665.00 1/1/2007 12/31/2007 Year 2 The investigator has focused the attention on the NO pathway in an attempt to reactivate the expression of utrophin, the alternative approach proposed to treat Duchenne and Becker dystrophies. As their results open the way to a potential treatment, they propse to develop a thrapeutic molecule and to explore the molecular mechanisms involved in the observed effects. Summary : Paris - UPMC Hopital Pitie-Salpetriere David A. Sassoon, Ph.D. RG Functional analysis of a potential regulator of muscle stem cells $90,000.00 $90,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 In this proposal, investigators will examine how PW1 may function in stem cell behavior, identify other genes in this pathway, and lastly construct a mouse model from which they can more easily examine these cell in vivo and purify them. Germany Essen - University Hospital of Essen Helge Amthor, M.D. DG Evaluating the adverse effects of myostatin loss on normal and dystrophic skeletal muscle $44,961.00 $44,961.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 This proposal aims to further investigate the structural changes in muscle of different animal models that lack Myostatin. It will be analyzed whether loss of Myostatin will result in abnormalities in muscle of mdx mouse. Expected results will predict adverse effects of Myostatin blockade in muscular dystrophy patients. Hannover - Medizinische Hochschule Hannover Christoph M. Fahlke, M.D. RG Modification of CIC-1 function by cytoplasmic domains in normal and myotonic muscle $99,192.00 1/1/2006 12/31/2006 Year 3 Page 82 Of 91 Summary : Myotonia congenita is an inherited condition characterized by muscle stiffness upon forceful movement. The life-long muscle stiffness can be quite disabling, and the current treatment is largely ineffective and poorly tolerated by many patients. This research intends to characterize the role of a cytoplasmic channel segment that modifies normal and pathological C1C-1 gating. This might allow to develop components that bind outside of the pore and restore aberrant C1C-1 gating as a possible novel therapeutic paradigm for treating myotonia. Greece Athens - Hellenic Pasteur Institute Socrates Tzartos, Ph.D. RG Autoantibody depletion and down-regulation in myasthenia gravis (MG) $99,880.00 $98,560.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 Myasthenia gravis is caused by autoantibodies which destroy the acetylcholine receptor at the neuromuscular junction. The Researchers aim to selectively remove these autoantibodies from patients' blood using receptor-containing absorption columns and to down-regulate the anti-receptor antibody-producing cells to stop levels increasing again. This is expected to achieve remission in myasthenic patients. Athens - Hellenic Pasteur Institute Socrates Tzartos, Ph.D. RG Functional characterization of autoantibody subgroups in myasthenia gravis (MG) $101,200.00 $101,200.00 $101,200.00 Summary : 1/1/2006 1/1/2007 1/1/2008 12/31/2006 12/31/2007 12/31/2008 Year 1 Year 2 Year 3 Myasthenia gravis is caused by antibodies which destroy acetylcholine receptor, a key-player molecule in the neuromuscular junction. Current knowledge regarding the anti-receptor antibodies has been derived mainly from indirect studies and several issues remain obscure. The aim here is to directly specify the fine characteristics of the anti-receptor antibodies, search for antibody groups of high pathogenic potential and elucidate the mechanism reported to enhance receptor synthesis under autoimmune attack conditions, leading to new approaches for novel therapeutics. Israel Page 83 Of 91 Jerusalem - Hebrew University Lili Anglister, Ph.D. RG Regulation of neuromuscular components in mdx mice - an animal model of Duchenne muscular dystrophy $72,694.00 1/1/2006 12/31/2006 Year 1 Dystophin deficiency in mutant muscles resulted not only in damage to muscle fibers but also in abnormalities in the juncton where the muscle activity inititates. The regulation of acetylcholine receptor and cholinesterase properties is critical to the proper functioning of these junctions, and pathological alterations in their properties could result in impaired muscle function. The investigators propose to examine the regulation of the receptors and the esterase in mdx mutant muscles. The studies are aimed at finding the factors that will produce heathly nmjs in mdx and, potentially DMD muscles. Summary : Millet Treinin, Ph.D. RG Identification and characterization of genes needed for nAChR mutation $61,534.00 Summary : 1/1/2006 12/31/2006 Year 3 This work aims at characterization of the mechanisms of acetylcholine receptor biogenesis, a key process in regulating muscle excitation. Rehovot - Weizmann Institute of Science David Yaffe, Ph.D. RG The DMD gene products in mammals and drosophila: Functional implications $83,310.00 $83,310.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 Investigators intend to extend their research on the human DMD gene products and investigate the function of the DMD gene homologue in the fruitfly drosophila. Studies in drosophila have led to the understanding of the function and evolution of many genes involved in human development and genetic diseases. Emphasis will be made on the function of the non-muscle products and their involvement in cognitive impairments. Tel-Aviv - Open University of Israel Miriam Souroujon, Ph.D. RG Immunotherapies for experimental myasthenia $79,217.00 $81,246.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 The Researchers plan to: 1) improve the ability to affect severe MG by combining this antigen-specific treatment with modulation of cytokines, costimulatory signaling or with IVIg treatment: 2) identify by DNA microarrays new molecules involved in MG pathology that may serve as drug targets; 3) establish an experimental model for seronegative MG. They believe that these approaches could be adopted and employed for the treatment of human MG. Italy Page 84 Of 91 Milan - Istituto Nazionale Neurologico Besta Elena I. Rugarli, M.D. RG Towards a therapy for hereditary spastic paraplegia due to paraplegin deficiency $65,560.00 Summary : 7/1/2005 6/30/2006 Year 3 Hereditary spastic paraplegia is characterized by weakness and rigidity of the lower limbs and has no effective cure. Researchers propose to use a mouse model to investigate its cause and develop new therapies. Monterotondo Scalo - Dulbecco Telethon Institute Livio Pellizzoni, Ph.D. RG Characterization of SMN interactions in the mouse spinal cord $49,600.00 Summary : 1/1/2006 12/31/2006 Year 3 Reduced levels of SMN cause spinal muscular atrophy (SMA). Investigators will characterize SMN interactions in the mouse spinal cord to search for the cause of the specific degeneration of motor neurons. Rome - Dulbecco Telethon Institute Pier Lorenzo Puri, M.D., Ph.D. RG Deacetylase inhibitors as a pharmacological tool for muscular dystrophies $90,000.00 $90,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 The potential of deacetylase inhibitors to counter muscle degeneration by enforcing follistatin production in dystrophic muscle might be a remarkable evidence of the benefit that can be achieved from targeting downstream effects of a gene defect, without addressing the primary defect. Rome - University of Rome Antonio Musaro, Ph.D. RG Study of the molecular and functional interplay between muscle and nerve in a mouse model of ALS $73,700.00 7/1/2005 6/30/2006 Year 1 $73,700.00 7/1/2006 6/30/2007 Year 2 $73,700.00 7/1/2007 6/30/2008 Year 3 ALS is considered a motor neuron disease. However, in light of recent experimental evidences it is clear that the accumulation of SOD1 mutants in postnatal motoneurons does not cause motoneuron pathology or motoneuron disease. The innovative aspects of this project are to disclose the role exerted by the untested skeletal muscle system on the pathogenesis of ALS and to define the molecular connection between muscle and nerve regulating tissue remodeling. Summary : Page 85 Of 91 Milan - Istituto Scientifico San Raffaele Giulio Cossu, M.D. RG Isolation, in vitro expansion and characterization of human mesoangioblasts for the cell $99,000.00 $102,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 Investigators plan to isolate human mesoangioblasts from normal and dystrophic muscle, develop methods to expand them in vitro, characterize their phenotype and myogenic potential and finally deliver them through intra-arterial injection in SCID/mdx mice. Dystrophic cells will be transduced in vitro with lentiviral vectors expressing micro-dystrophin. The success of this protocol should set the conditions for a future clinical trial in patients. Mexico Mexico City - CINVESTAV-IPN Bulmaro Cisneros, Ph.D. RG Molecular mechanism of the inhibition of neuronal differentiation induced by the DM expanded CTG repeats $27,200.00 1/1/2006 12/31/2006 Year 3 Researchers propose to identify the genes and events in the neuronal differentiation pathway that are affected by the CTG expanded mutation. Understanding the basis of the neuronal alterations of congenital DM patients is an essential first step in the development of a cure. Summary : Netherlands Leiden - Leiden University Silvere Van der Maarel, Ph.D. RG Comparative analysis of 4q-linked FSHD, non-4q-linked FSHD, and ICF syndrome $94,929.00 $100,875.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 Patients with ICF syndrome do not present with muscular dystrophy, though showing a similar modification of D4Z4 as FSHD patients. Researchers expect that this study will lead to the identification of the genetic defect in unexplained FSHD, and through comparison of these different classes of disease, a better understanding of the disease mechanism of FSHD by identifying functional domains within D4Z4. Portugal Page 86 Of 91 Lisboa - University of Lisboa Mario do Carmo-Fonseca, M.D., Ph.D. RG Profiling alternative splicing in muscular dystrophies $100,000.00 Summary : 1/1/2006 12/31/2006 Year 3 The goal of this research is to search for proteins that may be malfunctioning in dystrophic muscles due to errors in splicing regulation. These will constitute novel targets for the development of potential drugs for the treatment of this group of diseases. Singapore Singapore - National Cancer Centre Mac Mengfatt Ho, D.Phil RG Functional proteomic analysis of dysferlinopathy and dysferlin-mediated membrane repair $72,572.00 $76,145.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 The proposed experiments in this study aim to delineate the mechanism of dysferlin-mediated membrane repair and thereby provide insight into the pathogenesis of diseases like LGMD 2B and Miyoshi myopathy. They will use proteomic approaches and the mouse models of dysferlinopathy that were generated in the lab for this study. Spain Barcelona - Center for Genomic Regulation Pura Munoz Canoves, Ph.D. RG Role of the plasminogen activation system in mdx dystrophinopathy $100,000.00 Summary : 1/1/2006 12/31/2006 Year 3 There are no efficient treatments for Duchenne muscular dystrophy (DMD). The identification of plasminogen activation system components, which could improve the therapeutic approaches to DMD, would constitute an important finding and an attractive option for therapeutic intervention. In particular, this project will clearly demonstrate whether removal of fibrin has a positive effect in mdx muscle regeneration, and whether it may constitute an alternative for human DMD treatment. Sweden Page 87 Of 91 Lund - Lund University Madeleine Durbeej-Hjalt, Ph.D. RG Laminin alpha1 chain and congenital muscular dystrophy $70,735.00 $66,335.00 $66,335.00 Summary : 7/1/2005 7/1/2006 7/1/2007 6/30/2006 6/30/2007 6/30/2008 Year 1 Year 2 Year 3 To develop a therapeutic strategy for humans, the investigators will introduce laminin alpha1 chain to laminin alpha2 chain deficient muscle by viral vectors. The investigators will also investigate whether laminin alpha1 chain can prevent the development of peripheral nerve defects. Thus, improvement of laminin alpha2 chain deficiency by laminin alpha1 chain may serve as a paradigm for gene therapy in patients. Stockholm - Karolinska Institute Nils-Goran Larsson, M.D., Ph.D. RG Mechanisms of pathology in a mouse model for mitochondrial myopathy $79,970.00 $79,970.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 The Researchers will study mechanisms underlying the impaired muscle function in mitochondrial myopathy using a novel mouse model developed in the laboratory. The Netherlands Leiden - Leiden University Judith C. T. van Deutekom, Ph.D. RG Antisense therapy in different Duchenne muscular dystrophy (DMD) mouse models $100,000.00 Summary : 7/1/2005 6/30/2006 Year 3 DMD is caused by mutations in the DMD gene that disrupt its genetic code such that the synthesis of the dystrophin protein is aborted prematurely. Due to the consequent dystrophin deficiency patients suffer from a progressive and lethal muscle weakness. Researchers have recently demonstrated the therapeutic potential of small synthetic "antisense" molecules to restore the disrupted genetic code and induce dystrophin synthesis in cultured muscle cells from DMD patients. In this project, they aim at further optimizing this antisense strategy towards clinical applications. They will focus on developing the safest and most efficient delivery of the antisense molecules to muscle tissue in vivo, using different mouse models. UK Page 88 Of 91 Dundee - University of Dundee Miguel Maroto, Ph.D. DG Role of notch signaling in patterning/differentiation of early muscle precursors $45,000.00 $45,000.00 Summary : 7/1/2005 7/1/2006 6/30/2006 6/30/2007 Year 2 Year 3 The Notch signaling pathway seems to be involved in controlling the expansion of myogenic progenitor cells during satellite stem cell activation and thus, increasing our knowledge concerning its mechanisms of regulation could be of great relevance for such therapies. This project proposes to further characterize the role of the Notch signaling pathway in early muscle patterning and differentiation. Nottingham - University of Nottingham Jane E. Hewitt, Ph.D. RG Characterization and functional analysis of the mouse homologue of the FSHD associated repeat D4Z4 $82,148.00 7/1/2005 6/30/2006 Year 1 $87,453.00 7/1/2006 6/30/2007 Year 2 $93,828.00 7/1/2007 6/30/2008 Year 3 The investigators have recently found that mice have sequences that are similar to D4Z4 and that these are copied into RNA. This finding suggests that humans D4Z4 could code for a protein. The investigators now wish to investigate the function of this mouse sequence, as the investigators believe this will help lead to an understanding of the function(s) of the human D4Z4 repeat and determine its role in FSHD. Summary : United Kingdom London - King's College Hospital Michael Rose, M.D. RG US Validation of a neuromuscular disease quality of life measure $53,946.00 Summary : 1/1/2005 6/30/2006 Year 3 Investigators wish to further develop a quality of life measure that can be used as a sensitive and reliable measure of the benefit of any treatment, taking into account its benefits and its side effects. This particular quality of life measure would be tailored to those with various muscle diseases and would be flexible enough to take account of individual life styles. It has been designed with major input from patients themselves. It could be used in clinical trials or in muscle clinics. In financially limited health service organizations the arguments for the provision of any type of treatment would be strengthened, were that treatment shown to have a major impact on the quality of life of those with muscle disease. Page 89 Of 91 London - University College London Linda Greensmith, Ph.D. RG Treatment of ALS with Arimoclomol, a novel inducer of heat shock proteins $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 Arimoclomol belongs to a new category of molecules that up-regulate the expression of heat shock proteins. In the proposed study, investigators would like to investigate the mechanism of action of these novel molecules and characterize the heat shock response in motor neurons, in order to optimize human clinical trials of this compound and possibly identify other potential novel therapeutic targets. Nottingham - University of Nottingham J David Brook, Ph.D. RG The role and interactions of muscleblind proteins in myotonic dystrophy $100,000.00 $100,000.00 Summary : 1/1/2006 1/1/2007 12/31/2006 12/31/2007 Year 2 Year 3 Investigators have identified the mutation underlying DM but they do not understand how this mutation causes the condition. Recently three proteins, called muscleblind proteins have been identified which play a critical role in DM. The experiments they wish to perform involve producing mice and zebrafish which lack the muscleblind proteins so that they can test whether this causes DM-like symptoms in both types of animals. These experiments will address basic questions about the normal role of muscleblind proteins and their contribution to DM. Oswestry - RJAH Hospital Glenn Morris, D.Phil. TRA C A monoclonal antibody resource for genetic neuromuscular diseases $99,429.00 $104,579.00 Summary : 10/1/2005 10/1/2006 9/30/2006 9/30/2007 Year 2 Year 3 A collection of over 150 "exon-specific" antibodies against dystrophin is, and will continue to be, especially useful interantionally in trials of potential therapies for Duchenne muscular dystrophy. Very popular antibodies have also been produced for research, diagnosis and drug evaluation in spinal muscular atrophy, Emery-Dreifuss muscular dystrophy and myotonic dystrophy. This project will ensure that these antibodies will continue to be available to resarchers for the foreseeable future and will also add to and refine the library. USA Page 90 Of 91 Chicago - Children's Memorial Institute for Ed. & Research Christine DiDonato, Ph.D. RG Gene therapy for animal models of spinal muscular atrophy (SMA) $94,668.00 Summary : 7/1/2005 6/30/2006 Year 3 Investigators will use mouse models of the human disease SMA, to investigate the potential of re-introducing the corrective gene, survival motor neuron (SMN) to ameliorate the pathological effects of the disease. Page 91 Of 91