Activity

American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards Stimulus Award Tracking UNC Tomorrow legend: GR = Global Readiness, AC = Access to HE, K12 = Public Education, ET = Economic Transformation, HE = Health, EV = Environment, OE = Outreach and Engagement Status Amount Requested Amount Awarded Prelim. Notice UNCT Code Date Submitted/A warded Campus PI Prop. Award Sponsor Title NCSU Threadgill, David $293,630 $0 X GR, AC, HE, OE National Institutes of Health NCSU Schaff, Jennifer $499,800 $0 X GR, AC, National Institutes ET, HE, OE of Health Summary Begin Date End Date CFDA# SPS # The College of Agriculture and Life Sciences at North Caorlina State University seeks to obtain a Leica LMD7000 fluorescent microscope equipped for laser microdisection (LMD) and image quantification to support molecular analyses of biological specimens from whole organisms at the cellular level. The LMD7000 provides the highest cutting precision of any LMD and allows realtime cutting the a ?move and cut? setting. When a high-energy laser pulse hits the tissue, a fast reaction limited to the focus of the laser light called ?cold ablation? takes place. This process is very fast, and surrounding tissue is not impaired or heated. Single laser pulses, strung together, form the cutting line of the system. Only Leica uses high-precision optics to steer the laser beam along the desired cut line on the tissue, greatly improving cutting precision. Importantly, the Leica LMD7000 is the first LMD system that integrates these Acquisition of a Fluorescent contradicting approaches within one system. By controlling the repetition rate, the user can Microscope Equipped For Laser adjust the laser according to the specimen and make narrow, powerful, and fast cuts with a Capture Microdissection and single system. This overcomes many limitations of previous systems that use fixed laser Quantitative Morphology Analysis strengths. The UV offset corrects the focus of the UV laser with respect to the focus of the 4/1/2010 3/31/2011 93.389 2009-1874 Summary/Abstract: We propose to purchase an Illumina Genomic Analyzer IIX sequencing platform. The equipment brings deep-read sequencing technology to North Carolina State Acquisition of Next-Gen sequencing University (NCSU), which is needed for continued research competitiveness and to train the at NCSU next generation of students in modern biomedical genomic research. The equipment will be 4/1/2010 3/31/2011 93.389 2009-1909 3/30/2009 4/2/2009 NCSU Sykes, Wanda D. $300,000 $0 X Northeast Workforce Development Board GR, AC, (NC) (US Dept. of ET, HE, OE Commerce) WIA Workforce Readiness NCSU Loboa, Elizabeth G. $200,000 $0 X HE, OE Virginia Commonwealth Naturally Derived Biomaterials for University (National Stable Propagation of Human Institutes of Health) Pluripotent Cells Summer workforce development program for youth ages 16-24 in a 10 county region This application addresses broad Challenge Area (11) Stem Cells and the specific challenge topic of ?11-EB-106 Technologies for Expanding Stem Cells and Producing Engineered Tissue?. The long-term goal of this project is the development of propagation systems and controlled microenvironments for generation of stable populations of human pluripotent stem cells (hPSCs) that not only maintain their undifferentiated state but also their genomic integrity. The consequences of a propagation system that generates a genomically unstable hPSC can be devastating. When hPSC lines are either intentionally selected for specific phenotypes or genotypes, these cells could also be undergoing unintended selection for altered karyotype. Engineering cell phenotypes and function based on dynamic cell-cell, cell-surface and adjacent microenvironment interactions will be critical to generation of stable hPSCs. The specific hypothesis is that human fibroblast-derived extracellular matrix (hECM) in hyaluronic acid (HA)based ?fall-apart? hydrogels promote stable expansion of hPSCs in suspension culture. We base that hypothesis on the observations that (a) enzymatic passaging of cells using trypsin or collagenase leads to hPSCs exhibiting abnormal karyotype (b) hECM promotes stable expansion of hPSCs in feeder-free settings and (c) ?fall-apart? hydrogels utilize a convenient 4/1/2009 8/31/2009 17.259 2009-1911 4/2/2009 9/30/2009 9/29/2011 93.701 2009-1930 4/6/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Denton, Brian $233,892 $0 X GR, AC, HE, OE Mayo Foundation (National Institutes of Health) NCSU Franzen, Stefan $290,300 $0 X Duke University (National Institutes ET, HE, OE of Health) NCSU Zeng, ZhaoBang $32,990 $0 X Duke University Medical Center GR, AC, (National Institutes ET, HE, OE of Health) NCSU Zeng, ZhaoBang $68,920 $0 X Duke University Medical Center GR, AC, (National Institutes ET, HE, OE of Health) Diabetes, a leading cause of morbidity and mortality, is projected to increase dramatically over the coming decades. Medication treatment guidelines must be designed to simultaneously control multiple risk factors such as cholesterol, blood pressure, and glucose levels. Imperfect adherence to medication presents a serious barrier to successful implementation of theoretically optimal treatment guidelines. This grant will study optimal medication initiation for Type 2 diabetes in older patients with a focus on how uncertainty in the degree of adherence and the resulting medication effects influence optimal treatment guidelines. We will also investigate how competing risks from other comorbidities influence Development of Medication the optimal treatment guideline. We will evaluate whether medication prioritization changes Algorithms for Complex Elderly for older patients and how such changes depend on the degree of adherence and presence of Patients comorbidities. Combination chemotherapy is a mainstay of treatment for blood cancers, but often has significant side effects and is not curative, likely because treatment fails to eradicate the root cause of disease, the leukemic stem cell. In traditional combination chemotherapy regimens, patients are exposed to maximum tolerated doses of each drug. Laboratory data, however, indicate that effectiveness could be maintained with less toxicity if drugs could be administered in amounts found to optimally inhibit growth of leukemic cells in culture (drug synergy). However, it is currently not feasible clinically to deliver drug combinations in precise concentrations and ratios. Furthermore, cancer drugs typically attack both tumor and normal dividing cells, and tumor cells can survive by actively pumping out the drug. To address these issues, a novel drug delivery technology has been devised based on a common plant virus found in the soil. This virus has several unique drug-delivery properties: a) it occurs naturally, is non-toxic, does not infect human cells and can be modified in many ways to enhance Nanoparticle-Targeted specificity for tumor cells, b) drugs are easily loaded and don?t leak out; c) there is a Combination Chemotherapy For mechanism for release of drug cargo once inside the tumor cell; d) encapsulated drugs cannot AML Stem Cells be easily pumped out, and e) the virus can deliver drugs directly to the cell nucleus, where In this RC1 application we are proposing to carry out metabolomic profiling of unique plasma samples to be obtained from participants in the LiTMUS study to address the following specific aims are: A.1.Primary Aim: To identify metabolomic signatures predictive of Li+OPT effectiveness and specific side effects. A.1.1.Hypothesis 1: Plasma levels of candidate metabolites capturing the overall state of intermediary, anabolic and other biosynthetic metabolic pathways differ significantly between patients classified as remitted and tolerating lithium well based on improvement on Clinical Global Impression-BP severity scale (CGI-BP-S) and fewer Necessary Clinical Adjustments (NCAs) over the course of 6 months. A.1.2.Hypothesis 2: Development of side effects such as anti-thyroid antibodies and perturbations in kidney function are linked to specific Metabolomic signatures emerging from different levels of metabolites in patients having or not these side effects. A.1.2.Hypothesis 3: To identify biomarkers predictive of Lithium response by comparing the baseline and two Pharmacometabolomics of Lithium weeks plasma metabolomic profile of in a subset of patients available from the Li+OPT and Response in Bipolar Disorder OPT groups. A.2. Secondary Aim: To identify potential metabolomic signatures of depression, Alzheimer?s disease (AD) is a major public health and there is an urgent need to validate biomarkers relevant to early detection and disease progression. AD is accompanied by neurochemical alterations in multiple systems such as beta-amyloid, tau, inflammation, oxidative stress, neurotransmitters, energetics, and cellular lipds. Metabolomics, the study of metabolism at the global or ?-omics? level, is a new but rapidly growing field that has been earmarked as an important area to develop under the NIH roadmap initiative. In this collaboration between Duke and the University of Pennsylvania ADRC, we plan to use complementary and targeted metabolomics technologies to capture biochemical changes in CSF of a well characterized cohort of 160 subjects (40 AD patients, 40 MCI, 40 controls, 40 neurologic controls). This cohort is unique since it has already been recruited and studied at the UPenn using other biomarkers such as CSF amyloid-beta and tau, MRI volumetrics, FDG PET scans, and neurocognitive testing. Hence, there is high confidence that the study will be Metabolomic Markers of Preclinical completed in 2 years. Specifically we will test hypotheses that CSF metabolomic signatures can and Early Alzheimer's Disease separate AD and MCI subjects from controls, and can predict cognitive decline over a 2 year 10/1/2009 9/30/2011 93.701 2009-1988 4/13/2009 9/30/2009 9/29/2011 93.701 2009-1998 4/14/2009 9/30/2009 9/29/2011 93.701 2009-2004 4/14/2009 9/30/2009 9/29/2011 93.701 2009-2009 4/15/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Zeng, ZhaoBang $76,434 $0 X NCSU Lila, Mary Ann $196,001 $0 X NCSU Sannes, Philip L. $225,720 $0 X Statins are the largest single class of drugs prescribed for CVD prevention, with over 120 million prescriptions and over $13 billion in sales in 2003. Statins are HMG CoA reductase inhibitors, and the primary clinical rationale for the use of statins is to reduce the level of LDLcholesterol and, thereby, to reduce CVD risk. This effect is due in large part to increased LDL and IDL clearance as a result of the upregulation of LDL receptors. Multiple intervention trials with statin drugs have demonstrated a remarkable degree of consistency in their ability to reduce risk for both CVD and stroke by an average of approximately 1/4 to 1/3. Nevertheless, in all of these trials, residual CVD risk remains high (60-75%), and potential drug-related toxicity, while infrequent, is a significant concern ? i.e., there is large individual variation in the drug response phenotype after statin therapy. Complicating our understanding of past trials Duke University and future clinical trials, the most widely accepted immediate surrogate endpoints for Medical Center cardiovascular disease trials, LDL cholesterol and HDL cholesterol, have recently failed to GR, AC, (National Institutes Metabolomic Signatures as predict clinical benefit following drug intervention. The application of a biomarker to predict ET, HE, OE of Health) Predictors of Statin Response treatment response to statins therefore represents a major opportunity for translational The Lila Lab team will take primary responsibility for the activity-guided fractionation, dereplication, and structural characterization of bioactive compound leads with activity against malaria and other infective disease targets. As such, the Lila Lab team will work in close coordination with partnering laboratories responsible for in vitro screening of phytochemical mixtures and isolated compounds (U South Florida for antimalarial screening, USFQ for antileishmanial screening, and Rutgers University for other lead compounds screening), The Lab will accomplish activity-guided fractionation of prioritized extracts from Central Asia, using a customized preparatory HPLC protocol established in our laboratory. The HPLC effluent will be analyzed using LC MS, and mass analysis will be performed using quadrupole ion trap and time-of-flight (TOF) analyzer. Libraries of plant natural product chemistry obtained both commercially and in our databases will be used to dereplicate the phytochemical leads. For complete structural characterization of high priority leads, once Rutgers University Novel Antimalarial and dereplication process has been completed and the novelty of the structure is determined, we GR, AC, (National Institutes Antiinfective Pharmacological will utilize a comprehensive, state of the art NMR suite (400-950 MHz) available in the Core ET, HE, OE of Health) Leads from Plants Laboratory of the NCRC. As resident faculty on the campus, our laboratory team has The pathogenesis of fibrotic lung disease involves the inability of proliferating alveolar type II cells (AT2) to differentiate effectively into type I (AT1) cells, leading to faulty epithelial repair, irreversible damage, loss of function, and fibrosis. The mechanisms that normally control this process are not fully understood, so potential regulatory molecules or pathways that may be altered in fibrotic pulmonary diseases have not been elucidated. We propose that the key to normal alveolar cell differentiation is the relative sulfation of the extracellular matrix (ECM) microenvironment underlying alveolar cell types. This in turn controls expression of two important differentiation factors: a member of the forkhead (Fox) family of transcription factors and specific wingless (Wnt) signaling pathways. These factors act in conjunction with expression and signaling of transforming growth factor � (TGF�), which enhances Wnt signaling targets, to collectively drive the cell differentiation process and establish stable alveolar phenotypes. In this proposal, we will show that following proliferative events National Institutes Alveolar Basement Membrane/Cell associated with re-epithelialization in the alveolus, there is a critical, dynamic balance HE, OE of Health Interactions in the Lung between alveolar epithelial cells and their ECM microenvironment. This is significantly 9/30/2009 9/29/2011 93.701 2009-2020 4/15/2009 10/1/2009 9/30/2011 93.701 2009-2029 4/16/2009 4/1/1992 3/31/2014 93.838 1991-1541 4/16/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Zeng, ZhaoBang $27,492 $0 X NCSU Sherry, Barbara $101,072 $0 X The current application is specifically designed to build additional capabilities within the "Metabolomics Network for Drug Response Phenotype" to enable integration of metabolomics and pharmacogenomics data to achieve a deeper understanding of mechanisms implicated in drug-response variation towards a more personalized approach to therapy. Metabolomics is the study of metabolism at the "global" level and involves studies of the "metabolome", the entire repertoire of small molecules present in cells and/or tissues. The identities, concentrations and fluxes of these compounds represent the final product of interactions among gene sequence, gene expression, protein expression and the cellular environment, an "environment" that in the clinical setting includes drug exposure. We believe that the inclusion of Metabolomic data as an additional, and highly informative "intermediate phenotype" might significantly enhance our ability to understand and predict individual Duke University variation in response to therapeutic agents. In this supplemental application we propose to Medical Center add informatics and pathway analysis capabilities that can accelerate significantly the effort of GR, AC, (National Institutes Metabolomics Network For Drug the network creating and retaining jobs in-line with the Recovery Act Funds for Administrative ET, HE, OE of Health) Response Phenotype Supplements (NOT-OD-09-056). Additionally we propose to develop standards that can Viral myocarditis affects >5% of the human population, usually with no clinical signs. However in infants it is often fatal, and in young adults it can progress to a chronic disease requiring heart transplantation. Investigations proposed here may provide new avenues for therapeutic National Institutes The Cardiac Interferon Response to intervention. Funds will be used to employ one technician and purchase supplies, consistent ET, HE, OE of Health Reovirus Infection with the goals of the ARRA. 12/14/2008 6/30/2011 93.701 2009-1978 4/16/2009 7/1/2004 4/30/2010 93.701 2004-0472 4/17/2009 NCSU Henderson, Wesley $575,804 $0 X NCSU Eggleston, David B. $285,382 $0 X Electrochemical double layer capacitors (EDLCs), or supercapacitors, store energy through ionic interactions with charged, high specific surface area (SSA) electrodes. They can complement or replace batteries when high power delivery or uptake is needed. The primary limitation of EDLCs is their relatively low energy density. The goal is to optimize EDLC energy density without comprising power delivery, device lifetime, etc. Energy density can be improved through optimization of the properties of the electrode-electrolyte double layer SISGR: The Influence of Electrolyte and/or increasing operating voltage. For high SSA carbon electrode EDLCs, the double layer Structure and Electrode properties are determined by the morphology of the electrode (e.g., surface area and pore Morphology on the Performance of size) and the physical interactions between the electrode and electrolyte. The operating Ionic-Liquid Based Supercapacitors: voltage is largely determined by the electrochemical stability of the electrolyte. A molecularUniversity of Utah A Combined Experimental and level understanding of bulk electrolyte and electrode-electrolyte interactions is therefore GR, EV (US Dept. of Energy) Simulation Study necessary and will be undertaken for further improvements in properties and performance. Populations of eastern oysters in North Carolina have reached historic lows, and the NC DMF is building new oyster reefs in Pamlico Sound to be used as unfished, broodstock reserves for oyster restoration (Street et al. 2005). Little is known about oyster population dynamics within each reserve, the potential for reserves to persist as a network of distinct subpopulations connected by larval dispersal (i.e., a metapopulation), or the ability of reserves to seed other areas in Pamlico Sound with oyster larvae. North Carolina State University will team with the North Carolina Coastal Federation and North Carolina Division of Marine Fisheries to (1) assess North Carolina the ecological performance of this restoration effort, and (2) quantify the impact of this Coastal Federation restoration effort on species of concern that use oyster reefs as essential fish habitat. The NC (National Oceanic & Division of Marine Fisheries will (3) quantify the amount of oyster acres restored. A related Atmospheric study led by Brian Efland and Jack Thigpen, both recreational fishing specialists with NC Sea Administration Ecological Performance Measures Grant, will (4) quantify changes in recreational angling use in Pamlico Sound as a function of (NOAA) - National of Large-Scale, Sub-Tidal Oyster this oyster restoration effort. The proposed oyster restoration effort will help to stabilize the ET, HE, OE Ocean Service) Restoration oyster metapopulation in Pamlico Sound by presumably increasing overall larval output and 11/1/2009 10/31/2012 81.049 2009-2062 4/20/2009 5/1/2009 12/31/2010 11.463 2009-2077 4/22/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Jones, Melissa G. $655,281 $0 X NCSU Gould, Fred L. $99,965 $0 X NCSU Wallace, Andrew Daniel $90,802 $0 X This proposed research will address the Challenge Area (02) Bioethic and the Challenge Topic: 02-OD(OSP)-101* Unique Ethical Issues Posed by Emerging Technologies. This study will document the ethical perceptions of freshmen, seniors, graduate students, and researchers in Biomedical Engineering, Pharmacology, Materials Science, and Chemistry. Measurements will be made of perceptions of risks, benefits, regulations, and critical reasoning (reflective judgment). The field of nanomedical technology has emerged from interdisciplinary research teams with a speed that has never been experienced before in modern science. Advancements in nanoscale science and medicine have resulted in part because of new tools and techniques that allow for specific and targeted manipulation of materials at the molecular and atomic levels. Nanotechnology?s use in health care may present unique social and ethical issues that have never been considered before. Furthermore, the ability to directly intervene Ethics of Nanomedical in human health with constructed nanoscale materials raises new questions about risks, Technologies: Perceptual benefits, and safety regulations. Most new nanotechnology advancements have resulted from National Institutes Differences Across Domains and teams of researchers from distinct fields of study who have traditionally worked within HE, OE of Health Degrees of Expertise separate communities of practice. We know little about how researchers within these Our proposal titled "Population genetics of transgenes in insect vectors" enabled us to move ahead with developing a comprehensive modeling framework that can be used by both theoretical and empirical researchers in determining autocidal and strain replacement approaches that are most likely to successfully suppress specific insect-borne diseases in specific regions. We designed our models to encompass a range of detail and goals. The initial models that we developed were very general and examined basic genetic strategies. We used results of these initial models to further examine the concepts of genetic pest management and to make these concepts accessible to a broad scientific audience. A set of intermediate complexity models that include age and spatial structure of the insect vector species have recently been completed. The most biologically rich model was developed to fit the biology of Aedes aegypti, the principal vector of dengue virus (DV). Our proposal specifically stated that we would 1) develop computer simulation models that were accessible to empirical researchers in vector biology and others interested in this area of work. 2) use outputs of our GR, AC, National Institutes Population Genetics of Transgenes models to determine which biological parameters had strong effects on model outputs and ET, HE, OE of Health in Insect Vectors required more accurate parameter estimation. 3) develop novel gene drive strategies. We Aberrant DNA promoter methylation, an emerging hallmark of cancer, is affected by environmental exposure and alters gene expression without changing DNA sequence. Changes in DNA methylation, therefore, appear to constitute an important link between environmental exposure and disease risk. For the particular case of pesticides, we have previously shown in an Inuit population, a highly pesticides-exposed population, that higher plasma levels of pesticide were associated with DNA methylation aberrations. We also demonstrated that treatment of human blood cells in vitro with pesticides increased methylation of the RASSF1A promoter. RASSF1A is a tumor suppressor gene. The ultimate goal of my research is to increase our understanding between pesticide exposure and cancer risk. Based upon the hypothesis that pesticides increase cancer risk in man by altering DNA methylation, the specific aims of this research are to: 1) Determine whether pesticide exposure alters DNA methylation in blood cell DNA, 2) Examine whether pesticide exposed cancer cases have DNA Northwestern methylation patterns similar to those seen in high pesticide exposed individuals, 3) Investigate University (National DNA Methylation Alterations in whether pesticides can directly affect the methylation of specific genes. This research is HE, OE Institutes of Health) Response to Pesticide Exposures important and timely. With our increasing reliance upon pesticides, their untoward effects will The goal of this project is to measure the impact of an established, research-based, reform introductory electromagnetism curriculum on student problem solving. We will measure quantitative problem solving ability both on exam problems given in the classroom, and problems given in a more formal experimental setting. Data will be analyzed based on coding student work, for correctness, use of physics principles, and appearance of common errors. 10/1/2009 9/30/2011 93.701 2009-2087 4/22/2009 12/1/2003 5/31/2010 93.701 2003-1335 4/23/2009 10/1/2009 9/30/2010 93.701 2009-2092 4/23/2009 NCSU Kohlmyer, Matthew A $34,364 $0 X ET Georgia Institute of Technology Measuring the Impact on Problem (National Institutes Solving of a Cognitive Scienceof Health) Based Physics Curriculum University of California - San Diego (National Drug Therapy in Rhodopsin Institutes of Health) Transgenic Pigs 9/30/2009 9/29/2011 93.701 2009-2095 4/23/2009 NCSU Petters, Robert M. $73,010 $0 X HE, OE New therapies will be tested on rhodopsin transgenic pigs. These pigs are a model of retinitis pigmentosa. Delay of symptoms may indicate a potential treatment that could be applied to humans. 9/30/2009 9/29/2010 93.701 2009-2096 4/23/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Lu, Wenbin $244,933 $0 X HE, OE One of the crucial issues in designing randomized controlled clinical trials is to calculate sample size needed in the study. Survival models, such as the proportional hazards (PH) model and competing risk model, are used widely in disease studies. However, the existing method and software for the sample size calculation in survival analysis only considering the treatment efficacy. To our knowledge, there is no existing method and software can provide the power and sample size calculation of the PH model with time varying predictor with or without competing risk. In order to fill in this gap, we are going to develop a method for the power and sample size calculation in the PH model with time varying predictor. The method will be extended to the competing risk model. Furthermore, the user friendly software will be developed during this grant period with complete user manual. Therefore, the proposed method provide a useful tool for investigators to explore the optimal sample size accounting for various dynamic association between the time varying predictor and the user friendly University of South Sample Size Methods and Software software solves the computational issue in the power and sample size calculation in the Carolina (National in Survival Trials For Obesity proposed methods. Thus the researchers and practitioners can apply the proposed method in Institutes of Health) Diseases their study very easily. This project will use Pro-Bubbles to enhance the use of ultrasonic imaging for the treatment of prostate cancer. To accomplish these aims we will: 1) Conduct ultrasound studies to determine power output requirements for activating ?pro-bubbles into bubbles; 2) Optimize University of Pro-Bubbles For Ultrasound acoustic parameters required for radiation force assisted localization and marginalization of Arizona (National Imaging and Treatment of Prostate pro-bubbles; and 3) image activated pro-bubbles in vivo to determine scattering capabilities Institutes of Health) Cancer and sensitivity to imaging utilizing optimized ligands, pro-bubbles, and ultrasound. 9/30/2009 9/29/2011 93.701 2009-2097 4/23/2009 NCSU Dayton, Paul A. $399,026 $0 X HE, OE 9/30/2009 9/29/2011 93.701 2009-2101 4/23/2009 NCSU Henderson, Wesley $636,179 $0 X GR, EV Electrochemical double layer capacitors (EDLCs), or supercapacitors, store energy through ionic interactions with charged, high specific surface area (SSA) electrodes. They can complement or replace batteries when high power delivery or uptake is needed. The primary limitation of EDLCs is their relatively low energy density. The goal is to optimize EDLC energy density without comprising power delivery, device lifetime, etc. Energy density can be improved through optimization of the properties of the electrode-electrolyte double layer SISGR: The Influence of Electrolyte and/or increasing operating voltage. For high SSA carbon electrode EDLCs, the double layer Structure and Electrode properties are determined by the morphology of the electrode (e.g., surface area and pore Morphology on the Performance of size) and the physical interactions between the electrode and electrolyte. The operating Ionic-Liquid Based Supercapacitors: voltage is largely determined by the electrochemical stability of the electrolyte. A molecularUniversity of Utah A Combined Experimental and level understanding of bulk electrolyte and electrode-electrolyte interactions is therefore (US Dept. of Energy) Simulation Study necessary and will be undertaken for further improvements in properties and performance. The goal of this project is to measure the impact of introducing computational modeling in an introductory science. We will make comparative quantitative measurements on large numbers of students in introductory physics courses with and without computation to address whether the use of computational modeling changes the way students think about complex problems, and how student proficiency with computation impacts problem solving. Data from student inclass work and from student work in more formal experimental setting will be analyzed to determine the frequency of application of computational methods. 11/1/2009 10/31/2012 81.049 2009-2062 4/27/2009 NCSU Kohlmyer, Matthew A $34,364 $0 X ET Georgia Institute of Technology (National Institutes of Health) Measuring the Impact of Computational Modeling on Scientific Thinking in an Introductory STEM Course 9/30/2009 9/29/2011 93.701 2009-2132 4/28/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Kleinstreuer, Clement $473,748 $0 X NCSU Clark, Allan C. $312,339 $0 X NCSU Marcellin-Little, Denis J. $581,200 $0 X The incidence of asthma, especially among children, has dramatically increased in the United States over the past 30 years, with annual health care cost exceeding $16 billion. Relying on a new targeting methodology for inhaled drug-aerosols (Kleinstreuer-Seelecke, US patent pending), optimal asthma-drug delivery to severely inflamed lung sites of children is proposed. Collaborators on the proposed work include PI Prof. Mark Witten (Pediatrics Laboratory, UA, Tucson, AZ), Dr. Roni Grad (Pediatric Pulmonary Division, UA), and Prof. S. Hyun (Medical Image Conversion, Mercer University). The specific aims are as follows: (i) Develop a realistic and accurate simulation model and validate the computational air-particle dynamic data with experimental observations using three representative lung casts made from deceased 5-10 year-old children, i.e., the oral-tracheobronchial airways down to Generation 9. A 99mTc-DTPA Experimental/Computational radioactive tracer will be administered to various particle deposition areas under normal and Analyses For a Rudimentary Smart pathological inhalation conditions. These studies will provide a predictive computer simulation University of Inhaler Device For Targeted Drug- model and addresses the problem of subject variability. (ii) For optimally targeted air-particle GR, AC, Arizona (National Aerosol Delivery Focusing on release as well as particle transport and deposition, two sequential tasks are necessary: (a) ET, HE, OE Institutes of Health) Asthmatic Children prediction of the controlled air-particle conditions and optimal release parameters, employing The mechanisms that lead to the activation of procaspases play central roles in the regulation of apoptosis and inflammation. For all procaspases, formation of a dimer is a critical event in processing because the active sites of the enzyme are comprised of loops contributed by both monomers of the dimer. However, a fundamental difference exists in the caspase subfamilies regarding dimerization and maturation, and this difference is a key aspect for regulating apoptosis. Several inflammatory and initiator procaspases exist as inactive monomers in the cell, but the proteins have relatively high enzymatic activity upon dimerization. For those caspases, chain cleavage simply stabilizes the active site. In contrast, the executioner procaspase-3 is a stable dimer, but it has very little enzymatic activity. In this case, maturation is dependent on cleavage by the initiator procaspases. Our long-term goals are to understand how dimerization, activation and enzymatic activity are coupled for procaspases. Overall, we want to determine why procaspases-1 and -8 are monomers, but yet the active sites form National Institutes Dimerization Mechanisms of Two properly upon dimerization. In contrast, we want to determine why the stable dimer of HE, OE of Health Procaspase Subfamilies procaspase-3 is not active. We hypothesize that the procaspase dimer exists in two primary Nanomaterials are promising materials for biomedical applications due to the exceptional properties they exhibit, and this is particularly true for the use of carbon nanotubes (CNTs) as prospective reinforcing elements in biomaterials. However, the uncertainty regarding the cytotoxicity and genotoxicity of CNTs has hindered progress in their use for biomedical applications. This research aims to reveal that CNTs when introduced into living organisms through biodegradable medical devices are nontoxic resulting in no or negligible short term or projected long term effects. These findings will subsequently validate CNTs safe utilization and compatibility for several orthopedic applications. The specific aims of the proposed research include 1) Histological assessment of the effect of CNTs-based biomaterials on animals? connective tissue, epithelial tissue, and major organs (i.e liver, spleen, kidney), 2) Assessment of the cytotoxic effects of CNTs-based biomaterials, and 3) In vivo characterization and Texas Tech Short Term & Predictive Long Term documentation of the degradation behavior of CNTs-based biomaterials as a function of their University (National Response of Residual location in the body. Most studies so far have reported on basic findings conducted in vitro. ET, HE, OE Institutes of Health) Nanomaterials in Living Organisms However, the in vivo animal testing being suggested in this research will provide a more 10/1/2009 9/30/2011 93.701 2009-2135 4/28/2009 7/1/2002 12/31/2014 93.859 2002-0368 4/28/2009 9/1/2009 8/31/2011 93.701 2009-2137 4/28/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Petters, Robert M. $643,724 $0 X GR, AC, National Institutes ET, HE, OE of Health NCSU Bottomley, Laura J $561,153 $0 X HE, OE National Institutes of Health This application addresses broad Challenge Area (05) Comparative Effectiveness Research and Specific Challenge Topic, 05-EY-101: Treatment of Age Related Macular Degeneration and Diabetic Eye Diseases and Disorders. Diseases that exhibit retinal degeneration, such as age related macular degeneration (aMD), have common themes of photoreceptor (rod and cone) cell death. Sparing or delaying photoreceptor cell death is the main goal of treatment for age related macular degeneration and other retinal degenerative diseases. This application will test one such intervention for its ability to slow the progression of photoreceptor cell death in animal models of macular degeneration and retinitis pigmentosa (RP). These animal models will serve as examples for the broader application in retinal diseases such as aMD. Testing of animal models is key for the ultimate application in people. Transgenic pigs exhibiting an inherited juvenile form of macular degeneration (Stargardt-like macular dystrophy-3: STGD-3) and those exhibiting a form of RP will be treated with a nutritional supplement, the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). DHA is a polyunsaturated fatty acid (PUFA) that is a major component of cell membranes in the retina. DHA and Retinal Degeneration PUFAs are decreased in diseases such as STGD-3 and RP that have common features of retinal K-12 schools across the nation are implementing or considering implementing various curricula that use engineering. From high school curricula that are fairly comprehensive (i.e. Project Lead the Way) to textbooks intended for middle or high school courses (i.e. Survey of Engineering from Great Lakes Press) to elementary school after school clubs based on activities from engineering societies and more comprehensive sets of activities (i.e. Engineering is Elementary from the Museum of Science, Boston), enthusiam for engineering in K-12 is increasing. These curricular activites have different foci from increasing technological literacy to encouraging students to pursue engineering. Although those of us who are engineers are enthusiatic about this trend, to date, there is only cursory assessment data available to indicate the efficacy of any of these approaches to meeting their respective goals. Consequently, there is no guarantee that the overall affect on the fields of engineering won?t be negative, if these activities become nothing more than an educational ?fad.? Solid research Do Engineering Curricula Improve on the abililty of engineering curricula to support solid student learning is needed. This Science and Mathematics Learning proposal describes a project designed to comprehensively assess student learning with an in Elementary School Students? elementary school curriculum (Engineering is Elementary) and a comprehensive Membrane proteins are important constituents of biological cells and currently constitute over 50% of drug targets aimed at treating a broad spectrum of diseases including cancer, schizophrenia, ulcers, HIV, and many others. Here, new solid-state Nuclear Magnetic Resonance (NMR) methodology will be developed for structure determination of membrane proteins, which will yield an atomic-resolution drug screening method for membrane proteins in their native physiological environment. Issues relating to decision-making competence are of increasing interest in the field of gerontology as the average lifespan increases, along with the number of older individuals who are faced with important life decisions having to do with health care, finances, end-of-life care, and housing. One focus of research in this realm is the assessment of the ability to both comprehend and make decisions in people who may be experiencing initial stages of dementia or whose health problems are in danger of impairing their mental abilities. It is also critical, however, that we understand how judgment and decision-making processes in healthy older adults are affected by factors associated with aging. Changes in our society have resulted in these individuals being faced with increasingly complex choices in a wide-variety of domains with important implications for physical and financial well-being, and continued independence. It is also the case that as families become more widely dispersed and the rate of technological change accelerates, older adults may be faced with making decisions without adequate social and knowledge-based supports. Finally, older adults are increasingly and disproportionately targeted for marketing scams. Thus, it is important to understand the 9/30/2009 9/29/2011 93.701 2009-2138 4/28/2009 9/1/2009 8/31/2011 93.701 2009-2139 4/28/2009 NCSU Nevzorov, Alexander A. $560,398 $0 X ET National Institutes of Health Membrane Protein Structures and Ligand-Induced Conformations By Solid-State NMR 9/30/2009 9/29/2011 93.701 2009-2140 4/28/2009 NCSU Hess, Thomas M. $350,075 $0 X National Institutes ET, HE, OE of Health Social Cognition and Aging 1/1/2009 12/31/2013 93.701 2008-2455 4/28/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Riviere, Jim E. $999,982 $0 X HE, OE National Institutes of Health NCSU Hernandez, Raquel $447,000 $0 X GR, AC, HE, OE National Institutes of Health NCSU Clark, Allan C. $496,631 $0 X GR, AC, HE, OE National Institutes of Health QUANTITATION AND OPTIMIZATION OF DRUG AND NANOTHERAPEUTICS DELIVERY INTO SKIN This application addresses broad Challenge Area (15) Translational Science, 15-AR-106: Transdermal Drug Delivery. The goal of this research is to identify and quantitate those physicochemical properties of small molecules and nanomedicines that result in significant skin penetration while not being appreciably absorbed into the blood circulation. We have identified the knowledge gap and opportunity in drug delivery for skin targeting of small molecules and nanomedicines. Conventional transdermal drug delivery research focuses on systemic absorption, yet systemic delivery is not required for many skin diseases including skin cancer (melanoma, squamous and basal cell carcinoma) and other chronic diseases. At present, there is no quantitative approach for skin targeted delivery of small drugs and nanomedicines. We have developed a quantitative structure permeability relationship (QSPeR) for quantitative assessment of diverse chemicals in complex chemical mixtures, which is Quantitation and Optimization of applicable to transdermal delivery from realistic clinical formulations. Our approach is based Drug and Nanotherapeutics on using an isolated perfused skin model previously validated for predicting human drug Delivery into Skin delivery. This model contains all biological functions of viable skin, making it superior to This application addresses broad challenge area (03) Biomarker Discovery and Validation. Challenge topic 03-AI-101 -- Identification, characterization and evaluation of novel pathogen or host targets that may lead to the development of antimicrobials with broad spectrum activity. It is the goal of this research to identify virus components which are essential for replication of arthropod bourne viruses (Arboviruses) in mammalian cells but not insect cells. This research will identify targets for production of vaccines and antiviral agents against many of the 600-700 known agents in this class. Among these agents are dengue fever, West Nile Fever, Chikungunya Fever Yellow Fever and many forms of viral encephalitis. This will be done by random mutagenesis of the RNA of the model alphavirus Sindbis. Mutations produced will be screened for ability to grow in mammalian and insect cells. Those which replicate efficiently in insect but not mammalian cells will be further characterized by identifying the mutated genes by complementation with a set of well characterized temperature sensitive (TS) New Targets for Production of mutants. The identified gene will be sequenced to determine changes in sequence and the Arbovirus Vaccines and Antivirals nature of any amino acid changes. The suspected mutation will be reproduced in the wild type Cancer cells typically have gained the ability to circumvent apoptosis, so the proteins in the apoptotic cascades have become ideal targets for cancer therapy. Learning to selectively manipulate the level of apoptosis is expected to provide new therapeutic strategies for the treatment of cancer. As a proof of this principle, upstream components of the cascades have been shown to be effective targets, but the therapy is most efficient only when combined to target multiple proteins. Importantly, current cancer therapeutics activate caspase-3, albeit indirectly. We have established that procaspase-3, the executioner of cell death, is a viable target for therapy by showing that the activated zymogen is highly efficient in inducing apoptosis in mammalian cells. One advantage of directly activating procaspase-3 is that the polypeptide chain is not cleaved, which may circumvent the endogenous inhibitor XIAP. In addition, procaspase-3 is the terminal protease in apoptosis, so it is unlikely that cells need to be sensitized in combined therapies. Once procaspase-3 is activated, the cell dies rapidly by Crystallographic Studies of apoptosis. Under normal conditions, procaspase-3 has very little enzymatic activity until the Constitutively Active Procaspase-3 polypeptide chain is cleaved by initiator caspases, but structural data are lacking to explain the 10/1/2009 9/30/2011 93.701 2009-2147 4/28/2009 10/1/2009 9/30/2011 93.701 2009-2149 4/28/2009 10/1/2009 9/30/2011 93.701 2009-2152 4/28/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Berube, David M. $671,950 $0 X HE National Institutes of Health Emerging Technologies, Societal Implications, and Publics NCSU Berube, David M. $745,718 $0 X HE, OE National Institutes of Health Environmental Public Health, Organizational Trust, and Public Communities This project uses a series of data gathering and testing activities to separate unique issues associated with biotechnology, tissue engineering, nanomedicine, and synthetic biology from common issues associated with all technologies. Stakeholders involved in these four fields have significant differences in their levels of understanding. While it may not be necessary for public communities to have to same level of technical expertise as technical communities, a baseline must be set for meaningful dialogues. As such we have designed a project that moves step by step through a fact and opinion gathering process beginning with experts in research communities to experts in regulation and media to a broad set of stakeholders known as the public. This call creates some challenges. For example, the emergent nature of these technologies may present special ethical concerns. As technologies converge and new applications surface the ethical issues can evolve. Nanomedicine raises ethical concerns regarding monitoring that takes privacy interest to another level. At other times, we see a natural progression of ethical issues, such as how biotechnology through synthetic biology impacts human hubris challenging religious beliefs. Another challenge involves how to affect NIH - 09-ES-101 Building trust between researchers and communities through capacity building in Environmental Public Health - Environmental Public Health, Organizational Trust and Public Communities. Given the complexity of the environmental public health and the high levels of uncertainty associated with it, deference to researchers as experts is a default. However, if experts are to entertain high levels of efficacy demands correspondingly high levels of organizational trust. Researchers function as individuals and as a research community. They seldom communicate directly with public communities. When they speak to the media, regulators and policy makers, they speak for their field hence they function as communities or organizations more than as individuals per se. Indeed, the public perceives them as speaking as a community. Trust in communities and organizations by individuals and other communities or organizations while sharing some similarity to interpersonal and relational trust remains a distinct area of scholarship. Understanding how to best capture, maintain, or increase trust capacity between research and public communities demands a different set of exercises and activities than one would undertake during a team-building workshop at a corporate retreat. As such we offer a project with a series of building blocks. The Post Doctoral Associate supported by the Administrative Supplement will will work with the graduate student currently funded on the project to optimize acoustic parameters for activation of stealth agents; and will then will lead the integration of the custom ultrasound transducer designed as part of this project with the Visualsonics ultrasound system. This will require fabricating electronics, software programming, testing, and calibration. The Post Doctoral Associate will also be the lead person on the animal imaging studies to evaluate in vivo performance of the improved ultrasound molecular imaging technology by using conventional rodent models of angiogenesis. The objective of this proposed research is to develop a novel surface-enhanced Raman scattering (SERS) system based on plasmonics-active nanowire biochips for biomedical diagnostics, more specifically for early diagnosis of cancers (breast cancer, prostate cancer, and colon cancer). The introduction of molecular gene signatures in these types of cancers provides important prognostic and predictive information, and holds promise for individualized molecular therapy of these patients. In this project we propose wafer-scale development of molecular sentinels-on-chip for detection of several unlabeled candidate gene biomarkers known to play a critical role in the different cancers mentioned above. We propose the reproducible development of plasmonics-active substrates having controlled sub5 nm gap between metal-coated nanowire structures over an entire 6-inch wafer from which the SERS biochips will be obtained. Our methodology employs a hybrid approach integrating a top-down technique using deep UV lithography with a bottom-up method based on controlled epitaxial growth of silicon germanium on silicon nanostructures to form diamond-shaped nanowire structures that are coated with a metallic layer to form a plasmonics-active substrate. This unique methodology provides the scaling process for bridging the gap between 1/1/2010 12/31/2011 93.701 2009-2159 4/29/2009 1/1/2010 12/31/2011 93.701 2009-2160 4/29/2009 NCSU Dayton, Paul A. $148,970 $0 X HE, OE Columbia University Immune-Shielded, Ultrasound(National Institutes Stimulated Contrast Agents for of Health) Molecular Imaging 9/30/2008 12/31/2012 93701 2008-1247 4/29/2009 NCSU Misra, Veena $150,000 $0 X Duke University Plasmonics-active Nanowire GR, AC, (National Institutes Structures on Chip Platforms for ET, HE, OE of Health) Biomedical Diagnostics 9/1/2009 8/31/2011 93.701 2009-2161 4/29/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Bonner, James C $962,797 $0 X GR, AC, National Institutes ET, HE, OE of Health The Challenge of Determining Whether Carbon Nanotubes Represent the Next Asbestos Rapid advances in nanotechnology will be accompanied by the exposure of millions of individuals to products containing nanomaterials. Carbon Nanotubes (CNTs) are engineered nanomaterials designed for multiple uses (electronics, engineering, medicine), but have properties similar to asbestos, a fiber that is linked with the development of pulmonary fibrosis (tissue scarring) and mesothelioma (a rare cancer on the pleural surface of the lung). We found that mice which inhaled CNTs have increased platelet-derived growth factor (PDGF) and monocyte chemotactic protein-1 (MCP-1), two important mediators of fibrosis and pleural disease. We also found that CNTs activate the tumor suppressor p53, which is implicated in mesothelioma. The broad challenge area addressed is ?13: Smart Biomaterials ? Theranostics?. The specific challenge area is ?Methods to evaluate the health and safety of nanomaterials: 13-ES-101?. The challenge to our laboratory is to determine whether CNTs inhaled into the lungs of mice cause pathologic effects similar to asbestos fibers and to explore the mechanisms through which CNTs activate specific cell signaling events linked to the progression of fibrosis and/or cancer. The specific hypothesis to be tested in this proposal is that CNTs activate growth factor and chemokine signaling pathways that act coordinately 10/1/2009 9/30/2011 93.701 2009-2162 4/29/2009 NCSU Kleinstreuer, Clement $912,364 $0 X GR, AC, National Institutes ET, HE, OE of Health NCSU Bedair, Salah M. $2,130,842 $0 X GR, AC, ET, HE, OE US Dept. of Energy NCSU Mente, Peter L. $1,000,000 $0 X HE, OE National Institutes of Health The flip side to all the useful applications of nanotechnology is that toxic nanomaterial is being inhaled during nanoparticle generation, micro-device fabrication, material handling and product use. The proposed work involves support from experts in experimental toxicology, pulmonary radiology, petascale computing science, and biomedical/mechanical engineering. Computational Evaluation of The anticipated results link realistic ambient nanoparticle concentrations with inhaled Inhaled Nanomaterial Deposition in deposition data sets, which are of interest to toxicologists, epidemiologists, health-care Subject-specific Lung Airways providers and federal regulators alike. The concepts of hot carriers and carrier multiplication (CM) in quantum dot (QD) structures have been demonstrated using spectroscopic techniques. However for photovoltaic applications, collecting these carriers is a major challenge and was not yet demonstrated. When QD are configured to allow charge extraction (type I interfaces), new non-radiative recombination channels are opened that arise from charge delocalization and increased surface trapping and recombination sites. Also, the time scales for charge separation and charge transport should be fast compared to carrier cooling and carrier recombination. Our approach addresses the above challenges by using well-developed lattice matched epitaxial heterostructures incorporating both type I and type II band line up interfaces for fast carrier extraction. III-V compounds offer the required flexibilities to address these issues and allow optical absorption to take place in the QD only. Our experience with Atomic Layer Epitaxy Extraction of Hot and Multiple (ALE) will allow more effective passivation of these QDs. We will focus our investigation on Exciton Generated Carriers in InAs QDs because the band mass of holes is significantly higher than that of electrons, thus Quantum Dot Structures. enhancing the phonon bottleneck and allowing low minimum photon energy for CM. Joint degenerative diseases such as osteoarthritis (OA) can be severely debilitating conditions. The end stages of this disease process are fairly well documented but, the early degenerative changes are poorly understood and biomarkers that indicate the initiation of the disease and severity of the disease are unknown. While most cases of joint degeneration are idiopathic in nature, joint injury is a known predisposing factor. Joint degenerative diseases involve all of the joint tissues, bone, cartilage and synovium; however, the articular cartilage is the most significantly affected tissue and tends to see the most damage. Cartilage degeneration is likely to be a very complex process involving the chondrocytes that are responsible for the maintenance and health of the tissue and the extracellular matrix that controls the mechanical environment for the cells and allows for the transmittal of loads and smooth motion of the Identification of Potential joint. The response to injury will require changes in the chondrocyte phenotype as the cells Biomarkers Associated With respond and adapt to the new and changing environment post injury. Understanding the Persistent Cartilage Damage After chondrocyte phenotypic changes that occur post injury are a first step in unraveling the an In Vitro Impact Injury changing cell processes. Because of the long time frame over which OA develops transient 10/1/2009 9/30/2011 93.701 2009-2163 4/29/2009 11/1/2009 10/31/2012 81.049 2009-2165 4/29/2009 10/1/2009 9/30/2011 93.701 2009-2168 4/29/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Cavanagh, John $997,778 $0 X GR, AC, National Institutes ET, HE, OE of Health NCSU Tsuji, Jun N. $83,140 $0 X National Institutes ET, HE, OE of Health The overall research goal of our multi-disciplinary research team at North Carolina State University is to define novel microbial targets to overcome antibiotic resistance. This approach allows us to define alternative therapeutic approaches that will work synergistically with conventional antibiotics to control and eliminate multi-drug resistant infections. The two applications that we focus on are: 1) control of bacterial biofilm development/maintenance and 2) suppression of antibiotic resistance genes. The reason for focusing on these two aspects of bacterial behavior is straightforward. First, 3 in 4 bacterial infections are biofilmbased. Bacteria within a biofilm are known to be upwards of 1000-fold more resistant to antibiotics and are inherently insensitive to the host immune response. Thus, bacteria in a biofilm represent a significant hurdle for antibiotic treatment. Second, the dissemination of antibiotic resistance genes amongst diverse pathogenic bacteria coupled with the dearth of new antibiotics that have been introduced by the biomedical community has led to a situation Isolation of Novel Targets to in which many microbial infections are multi-drug resistant and extremely difficult/impossible Remediate Vibrio Infections to treat. We have developed a lead compound that will inhibit and disperse biofilms across This project took longer time than that of originally expected due to two major reasons. First, hiring all qualified personnels took 2 years because this is a new investigator?s project. Second, The project leads an unexpected and physiologically important finding as described below. Therefore, the project requires additional support. The original specific aims are; 1) to determine the role of TAK1 in TGF-b signaling; 2) to isolate and characterize scaffold/regulatroy molecules associated with TAK1; 3) To create and characterize mice with a skin specific deletion of TAK1. We have completed Aim 1 and have determined the roles of several TAK1 binding proteins (Aim2); however, characterization of TAB1 and TAB2, which are constitutive binding partners of TAK1, are currently in progress. Results in Aim 1 and Aim 2 indicated that TAK1 is an essential signaling molecule to induce inflammatory responses. However, to our suppress, we discovered that TAK1 deletion causes skin inflammation in Aim 3. TAK1 is essential not for inducing but for preventing inflammation in an in vivo setting. This unexpected finding raised questions that have to be addressed in Aim 3 more than we TAK1 Regulation of TGF-beta and IL- originally anticipated. We are currently attempting to define the molecular mechanism by 1 Signaling which TAK1-deficiency causes inflammation. We have found that TAK1 is essential for reactive This is to increase the subcontract to NCSU in order to obtain a Bio-Rad Bio-Plex 200 system to run cytokine and adipokine analyses on the Collaborative Cross mice as part of the Systems Genetics Reource Consortium. It is apparent that MARCKS protein is a major signaling molecule in a variety of cellular functions. In the lung, MARCKS serves as a crossbridge between stimulation at the cell surface and subsequent secretion of mucin from epithelial secretory cells. MARCKS also can serve as a mediator of leukocyte degranulation as well as leukocyte migration, suggesting it also has an important role in inflammation. One of the key findings of the previous funding period is that it appears to be the N-terminus of MARCKS that is involved in these functions, as a peptide identical to the MARCKS N-terminus has potent effects on these parameters when cells are treated with it. The studies in the next funding period will now investigate and further nail down the exact molecular mechanism(s) by which MARCKS interacts with other cellular proteins in each of these cell types in order to carry out its function. We will use some new imaging techniques as well as develop new methods to assay for secretion and epithelial function. We plan to use proteomic approaches to identify novel proteins associated with mucin granule membranes and investigate their interactions with MARCKS during the secretory process. We also plan to expand our collaborations with investigators at Duke 9/30/2009 9/29/2011 93.701 2009-2178 4/29/2009 3/1/2004 3/31/2014 93.701 2003-1966 4/29/2009 NCSU Threadgill, David $66,298 $0 X GR, AC, HE, OE UNC - UNC Chapel Hill (National Systems Genetics Research Institutes of Health) Consortium 10/1/2008 8/31/2012 93.701 2009-0725 4/29/2009 NCSU Adler, Kenneth B. $28,425 $0 X HE, OE National Institutes of Health Mechanism of Oxident-Induced Respiratory Mucin Secretion 4/1/1987 2/28/2014 93.213 1987-1036 4/29/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Hall, Carol K. $350,000 $0 X NCSU Goshe, Michael B. $999,653 $0 X NCSU Anholt, Robert R. $720,232 $0 X The aim of this work is to design theranostic liposomes for targeting solid tumors that can be programmed to simultaneously release a chemotherapeutic agent (doxorubicin) and an imaging agent. The goal is to maximize the therapeutic index (killing efficacy) per delivered drug, thus administering lower drug doses to the patient, and reducing toxicities. Concurrent release of radioactive imaging agents will allow physicians to monitor the effectiveness of the treatment and the spread of metastatic cells. These goals will be accomplished through a combined experimental and theoretical approach which optimizes the design of liposomes formed by combining two different functionalized lipids. The first lipid, DSPS will be functionalized with PEG tethered to an antibody that targets PSMA on the surface of cancer cells. The second lipid, 21PC, will be functionalized with a fusion peptide that promotes fusion Polytechnic with the endosomal membrane. At normal pH, the two different lipids will be uniformly Institute of NYU Design of Multifunctional Doubly- distributed across the liposome surface with the PEG tails hiding the fusion antibodies because GR, AC, (National Institutes Fusogenic Liposomes For DSPC is negatively charged at these conditions. At low pH, which is characteristic of the tumor ET, HE, OE of Health) Theranostic Applications vasculature, the liposome membrane will phase separate into two domains because DSPC The ability to identify and characterize protein interactions has a broad impact in all areas of health-related research, and thus methods related to their identification and characterization are important for understanding disease pathogenesis. By elucidating how proteins interact, a fundamental understanding of their biochemical properties begin to emerge, which can lead to a better understanding of the underlying mechanisms of protein function. Although NMR or x-ray crystallography provide the gold standard for high resolution structural detail, these techniques do not easily lend themselves to the study protein dynamics in dilute aqueous solutions and are not amenable to the study of large macromolecular complexes comprised of many proteins isolated from cells or clinical samples. The overall research goal of our multidisciplinary research team is to develop a new mass spectrometry approach termed XID-MS. XID-MS: A Novel Integrated Mass This method integrates recent advances in chemical crosslinking (CXL) reagents, ion mobility Spectrometry Approach to mass spectrometry (IMMS), and data-independent acquisition (DIA) mass spectrometry (MS) Structurally Characterize Protein analysis. This XID-MS approach utilizes unique gas phase-based separations and selective lowNational Institutes Oligomerization and Megaenergy fragmentation events to enable protein components within mega-macromolecular ET, HE, OE of Health Macromolecular Complexes complexes (> 200 proteins) to be quantitatively identified while simultaneously providing Environmental toxins, such as the herbicide paraquat, cause neuronal cell death through oxidative stress. Locomotor impairments are sensitive indicators of neurodegeneration. A longstanding challenge in environmental health science is to assess the effects of environmental chemicals such as pesticides or herbicides on genetic risk for neurodegenerative diseases as manifest through locomotor dysfunction (e.g. Parkinson?s disease). Studies on genotype by environment interactions require a model system in which both the genetic background and the rearing environment can be controlled precisely. The fruit fly, Drosophila melanogaster, provides such a model. In this application we propose to capitalize on natural variation in inbred wild-derived strains of Drosophila to construct genome-wide networks of covariant transcripts that are associated with a range of locomotor phenotypes, including spontaneous activity, startle-induced locomotion, and gravitaxis, under control conditions and after chronic exposure to paraquat at a concentration that is not acutely lethal, but shortens lifespan. In addition we propose to associate DNA sequence variants in 192 inbred wild-derived GR, AC, National Institutes Oxidative Stress and Neurogenetic Drosophila lines with fully sequenced genomes with variation in these behavioral phenotypes HE, OE of Health Networks in Drosophila under control conditions and after paraquat exposure. The combined information from these 10/1/2009 9/30/2011 93.395 2009-2182 4/29/2009 10/1/2009 9/30/2011 93.701 2009-2186 4/29/2009 10/1/2009 9/30/2011 93.701 2009-2191 4/29/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Schanz, Stephen $463,359 $0 X HE, OE National Institutes of Health Impact of Intellectual Property Issues on Human Genome Diagnostic Patents NCSU Harrysson, Ola L. $847,573 $0 X HE, OE National Institutes of Health Translational Research For Osseointegrated Prosthetics NCSU Zeng, ZhaoBang $553,032 $0 X GR, AC, National Institutes ET, HE, OE of Health Statistical Methods For Analyzing the Genetic Architecture of Complex Traits A thorough analysis, for a defined four year period, will be undertaken to review opinions from the U.S. Patent Board of Interferences & Appeals, the United Sates Court of Appeals for the Federal Circuit, and the United Sates Supreme Court to determine the extent to which groups or clusters of patents (commonly referred to as patent thickets) applicable to human genome discoveries have been discussed and/or issued. Additional reviews, for the same time period, will be undertaken to search law reviews and journals to ascertain emerging or prevalent intellectual property principles used in human genome patent efforts together with the identification of obstacles or barriers anticipated to encumber the utilization of such patent discoveries in the medical diagnosis, treatment or research on behalf of patients. The objectives of the planned research are to gauge intellectual property barriers to widespread use of beneficial genome discoveries and to anticipate new constructs or legal principles likely to arise as genome-related technology accelerates and is more widely used in medicine. Specifically, research will examine the extent to which patent thickets have been used in the patent issuance process. The cost-effective adoption of new technologies and advances is Osseointegrated prosthetics can potentially replace the external prosthetics currently used by most amputees. Instead of having a loose socket that is fit over the stump the osseointegrated prosthetics are attached to the bone in the stump surgically and a part of the implant is breaking the skin barrier. A prosthetic limb can then be attached to the implant once the bone has grown into the implant and providing a stable fixation. The osseointegrated prosthetics can resolve many of the current issues with the external prosthetics and provide a better solution for patients that would like to live an active life style despite their handicap. Osseointegrated prosthetics have been design, fabricated and implanted by the research team at NCSU using animals with amputated limbs with great success. The proposed research project is aimed at laying the way for translating the technology into the human medicine. A collaborative effort has been initiated with orthopedic surgeons at Duke Medical Center and the Rehabilitation group at the Durham VA Medical Center. The proposed research will develop custom osseointegrated prosthetics for 10 human amputees and mock surgeries will be performed using leg replicas. Throughout the project the quality control and implant The general long-term objective of this project is to develop theories and statistical methods to characterize and analyze the genetic architecture of quantitative traits and to learn the genetic and evolutionary bases of quantitative trait variation within and between natural and experimental populations. The specific goals of the current application are: (1) Use a score statistics based re-sampling method to assess the relevant criterion for model selection under multiple interval mapping for mapping multiple QTL. Develop and assess a procedure to analyze QTL epistasis under multiple interval mapping. (2) Extend MIM to multiple traits in multiple environments and populations (MT-MIM) to combine data for QTL analysis, to study genetic basis of trait correlations and genotype by environment interaction. Specific research includes formulation and implementation of efficient model selection procedures, assessing appropriate model selection criterion, implementation of procedures for testing a number of biologically interesting hypotheses, such as pleiotropy vs. close linkage. (3) Further develop and update QTL Cartographer and Windows QTL Cartographer. This includes adding new features to the software, constantly updating functions, features and interface of the software; and maintaining the interaction with users. The new features include various 1/1/2010 12/31/2011 93.701 2009-2195 4/29/2009 10/1/2009 9/30/2011 93.701 2009-2218 4/29/2009 9/30/2009 9/29/2011 93.701 2009-2197 4/29/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Lila, Mary Ann $978,564 $0 X GR, HE, EV, OE National Institutes of Health This proposal is in direct response to Challenge Area (12): Science Technology Engineering and Mathematics Education (STEM), RFA 12-OD-105 Identification of practices that overcome equity issues in STEM learning. Encouraging diversity within the population of students interested in STEM careers. Efficacy and effectiveness of specific approaches that aim to increase diversity in the STEM workforce. This project plan introduces and evaluates a novel toolkit and program designed to capture and sustain the interest and enthusiasm for science and discovery of students in Alaska Native or American Indian communities. In this program, local teachers (and their students) are provided with straightforward, logical and illustrative field deployable portable assays known as Screens to Nature (STN) technology, and thoroughly coached on the use of these renewable and extremely safe to use testkits to investigate the biological activity of indigenous plants, fungi, microbes and marine organisms in their communities. The inventive STN portfolio is designed to help students recognize the unique In-Field Biodiscovery Framework a bioactive (human health protective) properties of the local natural resources, to put the Catalyst for Science Education and students in direct charge of making novel discoveries taking advantage of the scientific Validation of Traditional Knowledge method, and to validate the traditional ecological knowledge of the community elders through 10/1/2009 9/30/2011 93.701 2009-2201 4/29/2009 NCSU Lester, James C. $999,064 $0 X NCSU Yingling, Yaroslava $321,800 $0 X NCSU Agris, Paul F. $990,071 $0 X Despite the great promise offered by game-based learning environments for middle school science education, realizing its potential poses significant empirical challenges. In this project we will conduct a controlled study to evaluate the effectiveness of an intelligent game-based learning environment, Crystal Island, which leverages both commercial game technologies and Crystal Island: Evaluating an the inferential capabilities of intelligent tutoring systems. The effectiveness of specific features Intelligent Game-Based Learning of the Crystal Island intelligent game-based learning environment will be tested in a controlled National Institutes Environment For Eighth Grade study with a population of eighth grade students. The subject matter focus will be the ET of Health Microbiology standard eighth grade microbiology curriculum. Telomerase is the ribonucleoprotein complex responsible for synthesizing telomeric DNA at the ends of chromosomes, thereby extending the proliferating capacity of the cell and minimizing genomic instability. Approximately 90% of human cancers involve reactivation of telomerase; thus, making telomerase an attractive target for cancer therapy, diagnosis, and prognosis. Human telomerase is composed of an RNA (hTR), a reverse transcriptase protein, and additional protein subunits. The hTR contains four conserved domains: (1) the pseudoknot domain which provides the template and enhances repeat amplification processivity, (2) the CR4/CR5 domain which supports the catalytic activity, (3) the H/ACA and (4) the CR7 domains which are involved in localization, accumulation, and 3?? end processing. Very little is known structurally about the telomerase complex, yet this knowledge and an understanding of the molecular interactions between its RNA and protein components are essential to understand its function and mechanism. The long term goal of this project is to understand structureThree Dimensional Structure function relationships in human telomerase with a special attention to the regulation of National Institutes Prediction and Analysis of telomerase activity, since telomerase inhibitors could be broadly effective cancer ET, HE, OE of Health Telomerase RNA therapeutics. Toward this goal, we propose to conduct structural, thermodynamic, and Some 30 million people are infected with human immunodeficiency virus. Existing anti-virals target HIV protein functions. But, HIV is capable of mounting significant resistance to drug intervention that targets proteins. Antiretroviral resistance develops when viral replication continues in the presence of the selective pressure of drug exposure, especially when the drugs are directed against the same or similar protein targets. Unfortunately, vaccine development has been problematic. Novel targets for intervention are sought in which the development of resistance will be difficult. The proposed approach changes the focus from that on HIV proteins alone to the distinctive chemistry and structures of a unique target of opportunity, HIV?s recruitment of the human tRNALys as the primer of reverse transcription. All retroviruses use a host cell tRNA species as the primer for reverse transcription. HIV?s steadfast dedication to the host tRNALys3 species as the primer validates the human tRNA National Institute of recruitment by viral proteins as a possible target of intervention. This is a target that may GR, AC, Allergy and HIV Infection: Early Events and New preclude drug resistance because of the central role of the tRNA in viral replication and in host ET, HE, OE Infectious Diseases Targets of Intervention cell translation. The HIV proteins polymerase, Gag and nucleocapsid and the human lysyl-tRNA 10/1/2009 9/30/2011 93.701 2009-2206 4/29/2009 9/30/2009 9/29/2011 93.701 2009-2208 4/29/2009 9/1/2009 8/31/2011 93.701 2009-2212 4/29/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Threadgill, David $991,543 $0 X GR, AC, National Institutes ET, HE, OE of Health Revolutionizing Preclinical Detection of Risk Factors For Idiosyncratic Drug-Induced Liver Injury Drug-induced liver injury (DILI) is the major adverse drug event that leads to regulatory actions on drugs, including failure to approve, restricted indications, and withdrawal from the marketplace. The most problematic form of DILI is ?idiosyncratic?, meaning the drug is safe for the vast majority of treated patients while causing catastrophic liver injury in the rare susceptible patient. A variety of data suggests that genetic factors may largely underlie susceptibility, and there are now two gene banks established from patients who have experienced DILI: The Severe Adverse Events Consortium (SAEC) and the Drug Induced Liver Injury Network (DILIN) Genome-wide association studies and testing of specific hypotheses based on drug metabolism and transport have met with limited success to date. What is needed is an unbiased mechanism to generate specific hypotheses that can be tested in these gene banks. We believe that a newly available mouse genetics resource, the Collaborative Cross, may facilitate identification of rare alleles that contribute to idiosyncratic DILI. We hypothesize that drugs capable of causing idiosyncratic DILI in patients will produce DILI in a subset of the Collaborative Cross strains allowing detection of genes and pathways that underlie DILI susceptibility in human patients. The proposed studies will test this hypothesis 9/30/2009 9/29/2011 93.701 2009-2213 4/29/2009 NCSU Haugh, Jason M. $975,163 $0 X NCSU Agris, Paul F. $957,291 $0 X NCSU Monteiro, Nancy A. $999,423 $0 X We propose herein a collaborative program between our two research groups with the overarching goal of developing novel intracellular biosensors with prescribed properties for live-cell imaging. The proposed project combines expertise in protein engineering (co-PI Rao), live-cell imaging (PI Haugh), and quantitative cell biology (both labs). Our overall approach will be to employ directed evolution of an ensemble of small (~ 10 kDa) protein scaffolds for recognition of specific protein and lipid targets with relatively modest binding affinity (KD ~ National Institutes Novel Protein Biosensors For 0.1?10 �M); whereas most protein engineering efforts to date have sought tight, persistent ET, HE, OE of Health Imaging Intracellular Dynamics binders, those properties are entirely undesirable for intracellular biosensors. Bacterial drug resistance is an increasingly significant threat to the successful treatment of infectious diseases. As antibiotic resistance continues to evolve, some pathogens that were once considered routine to treat are developing, or have developed, resistance to almost every antibacterial agent currently available. Furthermore, because infections caused by resistant pathogens are associated with higher morbidity and mortality than those caused by susceptible pathogens, the global impact of increasing resistance is a major concern. Given the frequency with which gram-positive bacteria [Bacillus, Bifidobacterium, Corynebacterium, Clostridium, (vancomycin-resistant) Enterococcus (VRE), Erysipelothrix, Listeria, Nocardia, (multi-resistant) Staphylococcus aureus (MRSA), Streptococcus] are responsible for serious nosocomial infections, it is no surprise that the emergence of resistance among these organisms to existing antibiotics has become a serious medical issue in hospital settings, and National Institute of Characterization and Evaluation of now emerging as community acquired resistance. Only two new classes of antibiotics have GR, AC, Allergy and Novel Targets of Intervention in been developed and brought to market in decades. Corporate and academic researchers in HE, OE Infectious Diseases Gram Positive Pathogens the field of antibacterial drugs, and antibiotic resistance have traditionally looked toward The extent of dermal absorption after topical exposure to manufactured nanomaterials under different conditions is unknown. The focus of this research is to assess the effect of species, vehicle and skin barrier damage on the dermal absorption or penetration of topically applied model nanomaterials. Recent data suggests that specific vehicles may enhance nanomaterial absorption in human skin. These studies will utilize carbon fullerenes and silver nanoparticles, and cadmium selenide nanocrystals (quantum dots-QD) in human, rodent and porcine skin using in vitro flow-through diffusion cell systems. The hypotheses to be tested are: I. Species differences in anatomy and biochemistry will affect dermal disposition of nanomaterials, specifically in the characteristics of the rate-limiting penetration barrier. II. Vehicle effects that are primary determinants of chemical partitioning will also affect nanomaterials movement into skin and must be controlled to make rational interpretation across different studies. III. Effects of Species, Vehicle and Skin Alterations in skin function, such as would occur with UV irradiation (sunburn) or barrier National Institutes Damage on Dermal Penetration of disruption to the stratum corneum, will modify nanomaterials penetration. These studies will HE, OE of Health Nanomaterial define those properties of skin that modulate nanomaterial absorption. All nanoparticles will 1/1/2010 12/31/2011 93.701 2009-2215 4/29/2009 10/1/2009 9/30/2011 93.701 2009-2217 4/29/2009 10/1/2009 9/30/2011 93.701 2009-2221 4/29/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Kleinstreuer, Clement $737,660 $0 X GR, AC, National Institutes ET, HE, OE of Health NCSU Tsuji, Yoshiaki $936,491 $0 X GR, AC, National Institutes ET, HE, OE of Health A large proportion of cancer patients develop also uncontrolled liver tumors which are then the actual cause of death. Traditional treatment options of liver tumors range from surgery (within early stages), via chemotherapy, to whole-body radiation. The latter two are associated with severe side-effects. Furthermore, as effective as chemotherapy agents and anti-angiogenic drugs may be, more than 50% of patients with solid tumors experience full resistance to chemotherapy. Exclusively localized radiation via Y90-microspheres of unresectable liver malignancies would be an effective and safe form of treatment. This could be accomplished on a patient-specific basis with a smart micro-catheter which will allow for Patient-specific optimally targeted delivery of radioactive microspheres. Steady 3-D fluid-particle dynamics Computational/Clinical Particlesimulations (Kleinstreuer 2006) have demonstrated that the new methodology of optimal Hemodynamics and Micro-Catheter targeting lung tumors (Kleinstreuer et al., 2008) also works in principle for targeting liver Analyses for Targeted Delivery of tumors (Kennedy et al., 2009a, b). However, the rheology of blood-microsphere dynamics, the Radioactive Microspheres onto presence of a (well-designed) micro-catheter, the internal microfluidics of the novel catheter Liver Tumors and its positioning in the hepatic artery for optimal microsphere release have to be ABSTRACT This application addresses broad challenge area (01) Behavior, Behavioral Change, and Prevention and specific Challenge Topic, 01-CA-102: The Role of Nutrition in Cancer Biology. Iron is an indispensable element in a variety of cellular functions including cell proliferation. Cancer cells typically have increased iron requirements due to their high growth and proliferation rates. In fact, cancer cells take advantage of higher availability of intracellular iron for their rapid cell proliferation. However, little is known about the mechanism through which cancer cells create the higher availability of iron. Is there a particular gene involved in determining iron availability in cancer cells? We have recently found that ATF1 transcription factor shows upregulation of transferrin receptor 1 and downregulation of ferritin H, resulting in higher iron transport and lower iron storage. Increased ATF1 expression is responsible for enhanced growth potential of some cancer cells including lymphomas and metastatic melanoma cells. Furthermore, chromosomal translocation t(12;22)(q13;12) results in the Regulation of Iron Transport and fusion of the Ewings sarcoma oncogene (EWS) to ATF1 (EWS/ATF1) that functions through the Storage by Oncogenes ATF1 DNA binding domain and causes clear cell sarcoma and malignant melanoma of soft 10/1/2009 9/30/2011 93.701 2009-2222 4/29/2009 10/1/2009 9/30/2011 93.701 2009-2224 4/29/2009 NCSU Dutta, Rudra $548,167 $0 X HE National Institutes of Health Recognizing patterns in complex data produced by diagnostic tests and other healthcare processes is a common problem. It is especially challenging when the problem is not only one of recognition but of discovering the pattern in the first place - and indeed of detecting if a pattern to match a given desired decision exists in the data, for example when a new diagnostic method is being investigated for suitability as replacement of an existing one. Automated machine learning paradigms such as artificial life class of algorithms have been suggested as suitable for this type of application, but such tools do not handle distributed learning well. We hypothesize that a general automated learning system which consists of a A Distributed General Automated perceptron learning machine replicated at diverse locations can be programmed to exchange Learning and Knowledge learning data over a computer network, and serve as a powerful information technological Generation Tool For Diagnostic and tool for the development of new diagnostic methods. We propose research to design and Other Healthcare Data build such a system, and develop algorithms for the distributed learning ability. 10/1/2009 9/30/2011 93.701 2009-2231 4/30/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Ashwell, Melissa Schuster $59,600 $0 X GR, AC, HE, OE South Dakota State Discovery of Oxidative Stress University (National Biomarkers in a Pig Model of Institutes of Health) Artherosclerosis Presently, early oxidative stress response biomarkers are not available and we have no way of knowing whether an individual is under oxidative stress, which is a risk factor for development of some diseases, including atherosclerosis. Mouse and rat models have answered many questions about the biology of the oxidative stress response and will continue to be valuable resources for researchers investigating redox imbalances. Rodent models, however, may not be the best model system for discovering oxidative stress response biomarkers in humans. Atherosclerosis does not lead to a myocardial infarction in mice. Also, the tunica media of the mouse has less smooth muscle cells than humans, allowing atherosclerotic lesions to cross the internal elastic lamina in these mice models. The pig is biologically more similar to humans than the rodent; for example, the lipoprotein profile of the pig is more similar to humans and pigs and humans have higher amounts of cholesterol than mice. Therefore, the pig has natural advantages over the mouse as a biomedical model for human disease. Our experimental design should capture early biomarkers associated with oxidative stress and atherosclerosis. Oxidative stress biomarkers discovered by our study will be useful to researchers studying diseases associated with an oxidative stress response. We anticipate that some biomarkers we This project will evaluate the utility of current peer review practices in radiation oncology, with the aim of using this information to develop tools that support moving peer-review from a retrospective to a prospective activity. The traditional peer-review quality assurance (QA) methodologies used in complex radiation oncology have been based on physical, ?traditionalpaper? medicals record and physical film radiographs. As radiation oncology evolves toward an entirely digital system (electronic medical records and digital images) the traditional QA methods need to be re-evaluated. The need to refine our QA procedures is imperative as evolving radiation techniques become increasingly complex, thereby increasing the risk of medical errors. The goal of this project is improve patient and community health by decreasing medical errors in clinical radiation oncology. Elucidation of the structural events occurring within viruses as infection takes place is a major goal of molecular and structural biology. The overarching goal of this research is to investigate the structural changes in Sindbis virus which occur during the process of cell infection in a series of Small Angle Neutron Scattering and X-ray crystallography experiments. Small-angle neutron scattering with contrast variation is a powerful tool to gain molecular level structural information of large, nested, multi-density, and spherical systems such as virus particles in solution. Used in combination of contrast variation techniques, small angle neutron scattering makes it possible to highlight different structural elements, thereby understanding the assembly of the whole particle. It is the objective of this work to reproduce in vitro pH driven conformational changes in Sindbis virus particles to mimic and characterize the structural rearrangements that occur upon activation and infection process. X-ray crystallography will be used to acquire complementary atomic level information of the fusion peptide. Sindbis virus is a member of the Arbovirus group, a group of structurally unique infectious agents that are transmitted by blood-sucking insects and produce some of the most devastating infectious Nearly all cellular functions are governed by proteins which mediate their biological specificity by high affinity three-dimensional recognition. Thus, characterizing how proteins interact is fundamental to understanding their biochemical properties as well as aberrant protein function and manifestations of disease. Although many methods are available to study protein interactions, most techniques are limited by some type of analytical restriction which precludes the analysis of certain protein classes or higher order complexes. The overall research goal of our multi-disciplinary research team is to develop a new approach using insolution chemical crosslinking and quantitative mass spectrometry analysis to characterize protein complexes and macromolecular assemblies in their native environment. This will involve synthesizing a series of chemical crosslinking reagents containing a specially designed linker region that can be selectively fragmented upon collision-induced dissociation (CID) and be used to provide enhanced detection of modified proteins and complexes using liquid chromatography-tandem mass spectrometry (LC/MS/MS) analysis that cannot be achieved with traditional crosslinking reagents. The modular design of these reagents will permit the 9/30/2009 9/29/2011 93.701 2009-2232 4/30/2009 NCSU Mazur, Lukasz M $194,859 $0 X HE Development of a Simple PeerUNC - UNC Chapel Review Tracking Tool to Improve Hill (National Patient Safety in Clinical Radiation Institutes of Health) Oncology 10/1/2009 9/30/2011 93.701 2009-2235 4/30/2009 NCSU Meilleur, Flora $933,371 $0 X GR, AC, National Institutes ET, HE, OE of Health Analysis of the Structure and Function of a Model Alphavirus By Neutron Scattering and X-Ray Crystallography 10/1/2009 9/30/2011 93.701 2009-2236 4/30/2009 NCSU Goshe, Michael B. $550,148 $0 X GR, AC, National Institutes ET, HE, OE of Health Novel Chemical CID-Crosslinking Reagents and Methods to Study Biological Interactions of Proteins Using LC/MS/MS Analysis 10/1/2009 9/30/2011 93.701 2009-2237 4/30/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Tonkonogy, Susan L. $53,000 $0 X HE, OE NCSU Li, Zhilin $178,800 $0 X HE, OE NCSU MontoyaWeiss, Mitzi M. $438,834 $0 X GR, AC, HE, OE UNC - UNC Chapel Hill (National Center for Gastrointestinal Biology Institutes of Health) and Disease This request is for funds to purchase an autoclave. Molecular recognition is central to biology, forming the foundation for precise hormonal control of distant organs, immune targeting of nonself proteins, the specificity of enzymatic catalysis, and exogenous control of biological systems. Many medications and biological probes act by binding and usually inhibiting a specific macromolecular target. Indeed, the discovery of a ligand that binds a targeted protein with high affinity is a major goal in the earlystage drug discovery. However, discovering a small molecule that binds a specific protein tightly, while retaining favorable pharmacological properties, can be a major challenge. In this proposal, we intend to address one specific issue to overcome this challenge: how to accurately describe the interactions with high enough efficiency to positively impact the prediction of protein-ligand binding. Specifically, we propose the following. Aim 1: We propose University of to develop a continuum polarizable force field for general organic molecules, based on the California - Irvine recently developed continuum polarization framework for proteins for more accurate (National Institutes High Accuracy Energy Models for treatment of polar interactions. Aim 2: We propose to develop a high accuracy finiteof Health) Molecular Recognition difference Poisson-Boltzmann solver that allows coarse grid spacing to be used for high The proposed project will develop and surgically evaluate a novel device that will allow safe, rapid and complete LAA occlusion through the use of shape memory alloy (SMA) tendons. An estimated 2.3 million Americans have been diagnosed with atrial fibrillation (AF). Risk of embolic stroke, resulting from increased production of thrombi in the LAA, is one of the most severe potential outcomes of the arrhythmia. Occlusion or elimination of the LAA alleviates stroke risk by preventing the release of thrombi from the appendage. The proposed device will provide long LAA occlusion in the following settings: cardiac surgeries, minimally invasive (thoracoscopic) epicardial ablation, as well as stand-alone LAA occlusion procedures. Perhaps its greatest impact will be realized by patients with lone AF due to current procedural risks and invasiveness of surgery. A reduction in complications (tissue bleeding, tearing) and increased long-term reliability of closure, provided by the clip, could dramatically increase the number of Virtual Environment to Develop a patients prescribed for AF treatment, resulting in fewer occurrences of stroke throughout the National Institutes Device for Left Atrial Appendage AF patient population. The device will be the first LAA occlusion method employing suction of Health Occlusion and the first to use SMA tendons. Use of SMA tendons will pave the way for other devices The Lila Lab will be responsible for preparing exogenously 14C labeled bioactive fractions and subfractions (primarily isoflavone-rich fractions from kudzu and from red clover) for the metabolic tracking studies. The postdoctoral research associate will work with a Senior Research Associate to rigorously characterize the structural chemistry of labeled fractions that will be administered in vivo. As appropriate, analysis of metabolites in the animal serum and tissue will be subsequently examined. NCSU will employ St. thermophilus as a cloning and expression host for the Alanyl-Glutamine (Ala-Glu) rich peptides in an effort to orally deliver maximum amounts of the these peptides, in vivo. NCSU will identify the optimum bile sensitive strain of St. thermophilus for cloning and expression of these peptides. NCSU will make the genetic constructs, both plasmid and chromosomal based. The genes for the peptides will be synthesized using optimal codon usage for St. thermophilus. Expression of the peptides will be examined and steps taken to maximize expression using strong constitutive and inducible promoters. Lastly, strains selected as cloning and expression hosts will be examined for bile induced release of the peptides from intracellular locations. These constructs will be sent to University of Virginia for evaluation of efficacy in their models. NCSU will make genetic modifications, as needed throughout the study, in order to optimize expression and delivery of the peptides to the gastrointestinal tract. 12/1/2007 11/30/2010 93.866 2008-1740 4/30/2009 9/30/2009 8/30/2011 93.701 2009-2259 4/30/2009 10/1/2009 9/30/2011 93.701 2009-2265 5/1/2009 NCSU Lila, Mary Ann $50,000 $0 X Purdue University (National Institutes Botanical Center For Age-Related ET, HE, OE of Health) Diseases 7/1/2009 93.701, 6/30/2011 93 2009-2274 5/1/2009 NCSU Klaenhammer, Todd R. $226,097 $0 X University of Tailored Probiotic Delivery of Virginia (National Glutamine-rich Peptides for ET, HE, OE Institutes of Health) Intestinal Repair. 9/30/2009 9/29/2011 93.701 2009-2276 5/1/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU King, Martin W. $960,555 $0 X GR, AC, HE, OE National Institutes of Health Application of Advanced Fiber Technologies for Emgineering Hollow Renal Tissues The team of urologists at Wake Forest University have made great strides in using natural decellualar matrices (ECM's) for the repair of tubular urethra, bladder or ureter tissues. While this approach has yielded positive results, it cannot work equally well with every patient, because the natural biological matrix is non-uniform and does not provide a consistent and uniform size, shape and structural integrity to the scaffold and its tissue construct. Martin King and his team at NCSU have experience using collagen and synthetic resorbable polymers to prepare uniform and consistent porous elastomeric fiber based scaffolds. They use a number of fiber spinning and textile fabrication techniques, such as melt spinning, electrospinning, weaving, knitting and braiding. In this project they plan to combine tubular webs of electrospun nanofibers with knitted and woven pile structures made from synthetic resorbable polymers, collagen and/or elastin. However, first it will be necessary to melt or wet spin continuous filaments of nanofiber yarns using a biconstituent fiber spinning process. These yarns can then be used to knit and weave appropriate pile fabrics with a large enough surface area to regenerate tubular urethral structures. The WFIRM team will then implant the 9/30/2009 9/29/2011 93.701 2009-2285 5/5/2009 NCSU King, Martin W. $170,105 $0 X NCSU Weisel, Deborah L. $592,967 $0 X The role of Martin King and his team at NCSU is to fabricate, sterilize and provide tissue engineering scaffolds that will serve as an extracellular matrix (ECM) for growing pancreatic islets in experimental quantities. The NCSU team has experience in preparing highly porous and bioresorbable fiber based scaffolds made from different synthetic resorbable polymers as well as collagen using a number of fiber spinning and textile fabrication techniques, such as melt spinning, electrospinning, weaving, knitting and braiding. In this project they plan to combine electrospun nanofiber webs, knitted or woven pile stuctures with a bioactive surface coating of collagen and/or laminin. However, first it will be necessary to melt or wet spin continuous filaments of nanofiber yarns using a biconstituent fiber spinning process. These yarns can then be used to knit and weave appropriate pile fabrics with a large enough surface UNC - UNC Chapel area, suitable for pancreatic islet culture. The UNC-CH team will then implant the derived GR, AC, Hill (National Progenitor Cell Differentiation and tissue constructs in an animal model so as to be able to evaluate their cell viability and HE, OE Institutes of Health) the Generation of Neo-islets functionality in producing insulin. Research and anecdotal evidence provide increasing evidence that crimes against Hispanics are less likely to be reported to law enforcement; if reported, they are less likely to be cleared by arrest; and if cleared by arrest, they are less likely to be prosecuted. The high rate of attrition of Hispanic victims in the criminal justice system results permits suspects to continue to offend, often targeting similar vulnerable victims. Victim attrition undermines the confidence of Hispanics in the criminal justice system, leaving them highly vulnerable to further victimization. In this project, N.C. State University will work with three of North Carolina's District Attorneys representing prosecutorial districts that have had rapid increases in their Hispanic population and increases in violent crime. NCSU will assist the DA's in hiring Victim/Crime Prevention Coordinators to collaborate with local law enforcement agencies and assist Hispanic victims. Hispanic robbery victims will be provided with wrap-around assistance from the initial report of the crime to responding law enforcement officers and will supervise Enhancing Arrest and Prosecution progress of the case through judicial disposition, bridging gaps between crime investigation ET, HE, OE US Dept. of Justice of Suspects Victimizing Hispanics and adjudication and reducing the attrition of victims. We anticipate that the services 9/30/2009 9/29/2011 93.701 2009-2287 5/5/2009 8/1/2009 7/31/2011 16.808 2009-2289 5/5/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU McCarty, Gregory S. $56,534 $0 X HE, OE National Institutes of Health Implementing Nanogap Sensors in Neuroscience Research NCSU Rose, Robert B. $1,232,168 $0 X National Institutes ET, HE, OE of Health A High Flux X-Ray Generator For Protein Crystallography and Small Angle Scattering Disorders of the nervous system have significant negative affects on society. In order to address this problem, there is an urgent need to develop new techniques to monitor neuronal activity that will enable improved understanding of the nervous system, and more specifically brain function. These include ultrasensitive neurotransmitter detection techniques based on previously developed nanofabrication technologies. The expected result of the innovative nanofabrication work will be the creation of next-generation sensing devices and methodologies. In the proposed work, these devices and methodologies will be applied to monitor exocytotic release from individual neurons and model neurons to improve understanding of the mechanisms of exocytosis. The expected result of this effort will be new analytical tools that will enable ultra-sensitive detection of neurologically related molecules of interest in extremely small volumes of ionic solution. The measurement of these molecules will enable the acquisition of neuro-physiological data that was not practically available previously. The analysis of this now available data will lead to new treatment methods for neurological and neurodegenerative disorders. While these techniques are applicable to a variety of problems in the sciences, initial applications will be focused on neuronal function We propose to purchase a new, state of the art X-ray generator, CCD detector and cryo system to support on-going crystallographic studies at North Carolina State University (NCSU). In addition we propose to expand our capabilities by adding a small angle X-ray scattering (SAXS) detector on the second port of the generator. The generator will replace two obsolete and difficult to maintain generators that are 18 and 19 years old. The generator would be housed in the newly renovated crystallography facility. Protein crystallography and structural biology are currently well established and growing at NCSU, requiring access to a more reliable high intensity source. Crystallographic studies are contributing to a wide variety of biomedically important topics at NCSU including the study of ras mutations activated in many cancers, characterizing mutations in transcription factors associated with diabetes, defining the mechanism of activation of caspases and evasion of apoptosis in cancers, defining the mechanism of RNA modifications required for ribosome assembly, and characterizing the structure of a plant virus to be used for drug delivery. The X-ray generator will also support new efforts in neutron crystallography through ties with Oak Ridge National Labs. This 5/1/2007 6/30/2010 93.701 2007-0509 5/5/2009 12/1/2009 11/30/2010 93.701 2009-2293 5/5/2009 NCSU Sykes, Wanda D. Blankenship, Sylvia M. $290,000 $0 X Six week summer educational training delivered by staff in Nash, Edgecombe, Wilson, Halifax, and Northampton Counties to 120 youth. All youth will work 32 hours per week on job sites through CES and required to attend educational training for 8 hours per week for a total of 40 Turning Point WDB, hours per week. Grant is from stimulus dollars for targeted youth, ages 14-24 years of age. GR, AC, Inc. (US Dept. of RISE Respect and Integrity through Three temp employees (3 month employment only) will be hired to work with youth to secure ET, HE, OE Labor) Skills and Education eligibility, secure job placement and assist in educational training component. GR, AC, National Institutes ET, HE, OE of Health Avian National Resource for Ovarian Cancer Research Renovation of House 231 Lake Wheeler Road and Dearstyne Unit to support Avian Biomedical Ovarian Cancer Research This application addresses broad Challenge Area (13): Smart Biomaterials-Theranostics, and specific Challenge Topic, 13-DK-104: Islet Encapsulation, namely, the Development of novel islet encapsulation technologies/biomaterials for the optimization of a bioartificial pancreas. Microencapsulated islets offer the potential to fundamentally cure diabetes and prevent its complications thereby improving the quality of life of millions of Americans and reduce the health care cost in the United States. The science and technology of bioartificial pancreas for the cure of diabetes is sufficiently well developed from a biomedical point of view. Islet transplants with the Edmonton immunosuppressive regimen and microencapsulated islets from human and animal donors transplanted without immunosuppressive drugs have been shown to reverse diabetes in small animals, non-human primates, and humans. The appeal of the encapsulation technology is its potential to expand the islet donor source such as the use of pig islets. While, encapsulated pig islets have been successfully used to reverse diabetes in non-human primates, a major obstacle to realizing the full promise of the technology is the lack of large scale devices to encapsulate sufficient quantities of viable islets for clinical 6/1/2009 8/14/2009 17.259 2009-2299 5/5/2009 NCSU $4,943,518 $0 X 12/1/2009 11/30/2012 93.702 2009-2312 5/6/2009 NCSU Ramasubraman ian, Melur K. $949,070 $0 X GR, AC, National Institutes ET, HE, OE of Health Massively Parallel Approaches for the Large Volume Production of Microencapsulated Islets 10/1/2009 9/30/2011 93.701 2009-2332 5/8/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Hawari, Ayman I. $514,741 $0 X ET US Dept. of Energy North Carolina State University (NCSU) and Oak Ridge National Laboratory (ORNL) will collaborate to develop a holistic (fundamental and accurate) approach for generating thermal neutron scattering cross section libraries for a collection of important neutron moderators and reflectors. The primary components of this approach are the physical accuracy and completeness of the generated data libraries. Consequently, for the first time, thermal neutron scattering cross section data libraries will be generated that are based on accurate theoretical models, that are carefully benchmarked against experimental and computational data, and that contain complete covariance information that can be used in propagating the data uncertainties through the various components of the nuclear design and execution process. To achieve the above objectives, NCSU and ORNL will perform computational and Accurate Development of Thermal experimental investigations of a carefully selected subset of materials that play a key role in all Neutron Scattering Cross Section stages of the nuclear fuel cycle. The chosen materials are beryllium (Be), reactor-grade Libraries for Advanced Fuel Cycle graphite, light water (H2O), and silicon dioxide (SiO2). All these materials are important Applications neutron moderators and reflectors. Graphite and H2O are also the main moderators in key 10/1/2009 9/30/2012 81.049 2009-2336 5/8/2009 NCSU Chapman, Benjamin $595,334 $0 X GR, AC, HE, OE NCSU Orndorff, Paul E. $605,161 $0 X HE Pregnant women have been identified as a high risk group for foodborne illness as well as poor nutrition. Food choices during pregnancy can impact the health of both mother and child, with risky choices resulting in long-term health consequences. Much information on food risks such Listeria monocytogenes, methyl mercury and poor diet exist in the public health literature but connecting with moms-to-be and engaging the audience in a meaningful discussion around food risks has been problematic. To aid in better food choices and impact risk-reduction behavior, subject matter experts in food safety and nutrition will create, participate and populate social media networks. Through focus groups information tone, style and messages will be developed and tested. Using the results of the focus groups, popular information sources such as mommy blogs, Facebook, Twitter, Wikipedia and YouTube will be Investigation, Development and used to connect experts and extension personnel directly with the target audience. An Evaluation of Social Media evaluation of the effectiveness of the social media networks as an information channel will be National Institutes Networks Supporting Food Choices conducted using self-reported diary techniques, in-depth interviews and behavior of Health of Moms-To-Be assessments. The purpose of this application is to examine how bacteriophage resistance confers attenuation, while preserving immunogenicity of a Listeria monocytogenes strain that is oralvirulent for mice. Mutants of listerial strain F6214-1 that are resistant to phage P35h4 are attenuated when inoculated orally into female A/J mice and show impaired replication in cultured mouse enterocytes. One of these mutants, containing a Tn917 insertion in the glcV gene, has been extensively characterized. Phage binding studies indicate that the mutant has a cell surface alteration that precludes phage attachment. All phenotypes associated with the mutation are complemented in trans by a parental copy of the glcV gene. The glcV gene is Southeast Regional predicted to encode a group 2 glycosyl transferase. Interestingly, the glcV lesion, while Center of Excellence preventing phage attachment, does not affect the mutant?s ability to bind to cultured mouse for Emerging enterocyte monolayers. Rather, the mutation appears to alter a subsequent step in Infections and intracellular replication measured as a reduction in plaque forming efficiency and plaque size Biodefense Immunogenicity of an Attenuated in enterocytes. In vivo, the mutant is, in contrast to the highly invasive parent strain, (SERCEB) (National Listeria Monocytogenes undetectable in the liver and spleen 48 h post oral inoculation. The mutant is important, in Institutes of Health) Bacteriophage Resistant Mutant part, because of its outstanding potential as a live oral vaccine platform. Impediments to The proposed research aims at laying the fundaments for developing a sequencing device that can be deployed at point-of-care locations. In this capacity it will help guide therapies in which the genetic makeup of a patient is important to the suitability of treatments, or where the genetic identity of pathogens must be known. 10/1/2009 9/30/2011 93.701 2009-2350 5/11/2009 6/15/2009 6/14/2011 93.856 2009-2351 5/11/2009 NCSU Riehn, Robert $48,623 $0 X HE National Institutes of Health Sequencing DNA by Transverse Electrical Measurements in Nanochannels 9/1/2007 7/31/2010 93.701 2007-0869 5/12/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Hallen, Hans D. $485,355 $0 X ET National Institutes of Health Nanoscale Measurement of Metal Ions and Valence with Wide-Band Optical Sensors This application addresses broad Challenge Area (06):Enabling Technologies and specific Challenge Topic,06-GM-106: Subcellular imaging of metal ions. This project addresses the need to identify the types of metal ions present in a nanometer-sized (subcellular) region, and identification of the valence state of those ions. Both aspects of the measurement are crucial for evaluating the local physiological state of the cell. The ion concentration is crucial for signaling and metal assisted transport in the cell. The valence state is crucial for understanding the activity of the particular ions. Ions at different valence states will have very disparate reaction properties, so will participate differently in cell processes. Imbalance in metal ion concentrations can result in cell death, while knowledge of how cells regulate ion concentration and valence can elucidate function and suggest approaches for treatment of disease cause by or causing ion imbalance. The project will focus on the development of a novel probe rather than use of an existing probe. The design builds upon several past projects, and consists of a capillary tube drawn to a point, plugged with an ion nonselective membrane, filled with fluid and one or more types of indicator molecules, and sensed via an optical fiber 9/30/2009 9/29/2011 93.701 2009-2359 5/13/2009 NCSU MacKay, Trudy F. $114,524 $0 X National Institutes ET, HE, OE of Health Initiative for Maximizing Student Diversity NCSU Orndorff, Paul E. $616,954 $0 X HE Southeast Regional Center of Excellence for Emerging Infections and Biodefense (SERCEB) (National Institutes of Health) Live Oral Listeria Vaccine Vector The purpose of this administrative supplement to the NC State Initiative for Maximizing Student Diversity (IMSD) Program is to increase and extend the science and training opportunities to IMSD students. Funds from the supplement will allow the program to engage biomedical and behavioral science researchers, both internal and external to NC State University, to participate in various professional development and research components of the program. This will contribute to broadening of students? exposure to the research being conducted and the professional development and training opportunities available to them in the areas of biomedical and behavioral sciences. Additionally, this supplement will allow for recruitment and support of individuals with skills that will help to enhance the overall experience for the IMSD students. Although the aforementioned activities are being implemented successfully with funds from the parent grant, funds from the administrative supplement will accelerate the tempo and reach of the program, and improve the ways in which the current activities are being implemented. The purpose of this application is to explore the feasibility of using a bacteriophage resistant mutant of Listeria monocytogenes as an attenuated, oral vaccine delivery platform. Mutants of listerial strain F6214-1 that are resistant to phage P35h4 are attenuated when inoculated orally into female A/J mice and show impaired replication in cultured mouse enterocytes. One of these mutants, containing a Tn917 insertion in the glcV gene, has been extensively characterized. Phage binding studies indicate that the mutant has a cell surface alteration that precludes phage attachment. All phenotypes associated with the mutation are complemented in trans by a parental copy of the glcV gene. The glcV gene is predicted to encode a group 2 glycosyl transferase. The loss of this product results in a defective phage receptor and alters the normal host-pathogen interaction required for virulence. Interestingly, the glcV lesion, while preventing phage attachment, does not affect the mutant?s ability to bind to cultured mouse enterocyte monolayers. Rather, the mutation appears to alter a subsequent step in intracellular replication measured as a reduction in plaque forming efficiency and plaque size. In vivo, the mutant is, in contrast to the highly invasive parent strain, undetectable in the liver 2/1/2008 1/31/2012 93.701 2007-1385 5/13/2009 6/15/2009 6/14/2011 93.856 2009-2361 5/13/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Davidian, Marie $725,307 $0 X HE NCSU Smirnov, Alexej I. $200,000 $0 X HE NCSU Davidian, Marie $990,425 $0 X HE This application addresses broad Challenge Area (05) Comparative Effectiveness Research and specific Challenge Topic 05-HL-105: Optimizing of anti-platelet treatment after revascularization procedures. Dual thienopyridine-aspirin anti-platelet therapy, in particular clopidogrel+aspirin, has been shown to lower the risk of thrombotic complications in patients with bare-metal and drug-eluting stents but raise the risk of serious bleeding events. Accordingly, despite numerous studies yielding valuable insights toward optimizing antiplatelet regimen in these patients, considerable uncertainty remains on the best strategies to recommend for either type of device. In this project, a new approach will be taken to identifying optimal anti-platelet therapy regimens that takes into account the fact that management of patients following stent implantation is really a dynamic process that involves a series of therapeutic decisions made over time; these include the initial decision on antiplatelet maintenance regimen and duration, subsequent decisions on whether or not and how National Institutes Optimal Anti-Platelet Regimes and to modify the regimen if the patient experiences an intercurrent event, and whether or not of Health Clinical Trials Via Learning Methods and how to extend therapy when the intended duration is reached. At each of these ?decision Screening of saliva and other oral fluids offers potentially faster, cheaper and safer diagnostic method than conventional blood sampling. Human saliva contains a large number of proteins involved in various biological functions including digestion and modulation of microbial levels and metabolism. Blood pool proteins are also present in saliva in the same relative concentration. It is now established that the presence of specific bacteria and/or metabolites could be used for diagnostics of early childhood caries, periodontal diseases, and oral cancer. While the research in saliva proteomics continues to advance by combing state-of-the art mass spectrometry and 2-D gel electrophoresis, there is an urgent need for developing new technologies for rapid label-free screening of oral fluids. We propose to fill the gap in existing technologies by developing a biosensing platform that is based on newly introduced metallic New Jersey Institute screens with periodic openings. The screens are covered with graphene - a monolayer of of Technology carbon crystal. Graphene has many benefits of graphite (biocompatibility, chemical inertness, (National Institutes Monitoring Proteins by Graphene absence of IR signature in the 2-20 micron region). The unique electric properties of the of Health) Coated Infrared Platforms graphenated IR screens lead to concentrating the electric field in the centers of the screen This application addresses broad Challenge Area (07) Enhancing Clinical Trials and specific Challenge Topic 07-DK-101: Enhancing clinical trials in diabetes, obesity, and metabolic, endocrine, digestive, liver, renal and urological diseases. A key issue in solid organ transplantation is how best to use immunosuppressive medications to prevent rejection of the transplanted organ. Immunosuppressive strategies must strike a delicate balance between suppressing the immune system well enough to prevent rejection of the organ and organ dysfunction and maintaining sufficient immune system response to avoid serious infections, adverse side effects, and malignancies. Guidelines for using immunosuppressive therapies vary substantially across different transplant centers, which is a consequence of the unresolved questions and lack of consensus on how best to use the classes of available immunosuppressive agents and other therapies. There is thus a critical need for research on the development of evidence-based immunosuppressive strategies that optimize the longModeling of Immunosuppression term management of transplant recipients. Focusing on renal transplantation, this project will National Institutes and Clinical Trials in Renal take a new approach to the study of immunosuppression based on quantitative modeling of of Health Transplantation the processes of immunosuppression, which will be facilitated through the efforts of an 9/30/2009 9/29/2011 93.701 2009-2362 5/13/2009 9/30/2009 9/29/2011 93.701 2009-2364 5/13/2009 9/30/2009 9/29/2011 93.701 2009-2365 5/13/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM American Recovery and Reinvestment Act 2009 Preliminary Notice, Proposals and Awards NCSU Anholt, Robert R. $323,457 $0 X GR, AC, HE, OE National Institutes of Health Molecular Genetics of Olfaction in Drosophila This is a request for an administrative supplement to enable incorporating a proteomics component in specific aim 2 of grant R01-GM059469 (Molecular genetics of olfaction in Drosophila). This specific aim focuses on assessment of naturally occurring variation and environment-dependent plasticity in expression of chemoreceptors in Drosophila through transcriptional profiling using expression microarrays. The requested supplement will remain within the scope of this specific aim, but enhance its impact by enabling a correlation between the transcriptome and the proteome thus providing a more complete picture of environmental plasticity of chemoreceptor expression, specifically expression of odorant binding proteins. In preliminary experiments we have established the ability to identify soluble proteins from the Drosophila antenna using high resolution mass spectrometry. During the first year of support we will measure expression of odorant binding proteins between virgin and mated males and females, young versus old flies, and males and females reared in groups or in isolation or exposed to same sex or opposite sex odor in a standard laboratory Canton S (B) strain, and compare protein expression to previously measured transcriptional modulation. Based on the results with our Canton S (B) flies, we will target a select number of odorant 7/1/2005 3/31/2012 93.701 2006-0475 5/13/2009 NCSU Mitchell, Gary E. $405,000 $0 X GR, HE, OE US Dept. of Energy NCSU Breen, Matthew $177,721 $0 X ET Texas A & M Research Foundation (National Institutes of Health) NCSU Sherry, Barbara $588,748 $0 X Southeast Regional Center of Excellence for Emerging Infections and Biodefense (SERCEB) (National ET, HE, OE Institutes of Health) National Institutes of Health NCSU Sannes, Philip L. $0 $74,459 X HE One of the primary goals of the iniatives in in Applications of Nuclear Science and Technology is the measurement of relevant nuclear data required for advanced reactor fuel cycles. The neutron capture reaction is very important for the design of the proposed new advanced fuel Measurement and Analysis of cycle reactors. We propose to measure the neutron capture reaction using the Detector for Neutron Capture Data for Advanced Neutron Capture Experiments at Los Alamos National Laboratory. In addition to Advanced Reactor Fuel Cycles and measuring specific key elements, there will be focus on improving the understanding of the Other Applications parameters used in the modeling of the capture reaction. The gray, short-tailed opossum, Monodelphis domestica is the predominant laboratory-bred research marsupial in the world and is used in investigations that span a broad range of topics relevant to human development, physiology, and disease susceptibility. The recently completed opossum genome sequence furnishes a critical resource for examining the evolutionary histories of vertebrate genomes in general and is fostering the development of new research tools for M. domestica that are expanding its versatility as an experimental system for a broad range of research applications in basic biology and biomedically oriented research. The fine-scale accuracy of the opossum sequence is very high and has enabled indepth analyses of gene structure, gene content, non-coding element content, and other characteristics that exist in the range of kilobases (Kb) to a few megabases (Mb). However, as is generally true for newly assembled genome sequences, the large-scale structure contains many uncertainties that render studies of regional structure and long-distance functional Gene Expression Arrays for the interactions difficult or impossible. In attempting to integrate the opossum genetic linkage Laboratory Opossum map and genome assembly, we detected several examples wherein the linkage map and Our overall goal is to identify novel mechanisms by which viruses subvert the host innate antiviral response to cause disease. Here, we will investigate viral modulation of immunoreceptor tyrosine-based activation motif (ITAM) pathways during the innate antiviral response, an interaction not previously investigated for any virus. Viral infections stimulate an array of innate protective responses. For example, viruses can induce expression and secretion of interferon-beta (IFN-beta), to induce expression of antiviral genes in neighboring cells. Not surprisingly, viruses have evolved diverse mechanisms to subvert this IFN response. ITAM-associated cell receptors can modulate IFN and other cytokine signaling, and yet viral subversion of ITAMs has not previously been studied. While several enveloped viruses encode viral ITAMs which function as oncogenes, no other viral ITAM functions have been identified. We hypothesize that viral ITAMs can subvert the innate antiviral response. The non-enveloped Reoviruses provide an excellent model to study host innate responses. We previously Viral Subversion of identified three viral genes associated with reovirus strain-specific differences in induction of Immunoreceptor Tyr-Based and sensitivity to IFN: the M1, S2 and L2 genes. More recently, we demonstrated that M1 Activation Motif (ITAM) Signaling encodes a repressor of IFN signaling, but additional M1 roles and roles for S2 and L2 remain We will apply new concepts developed from recent in vitro modeling of normal human Differentiation of Alveolar alveolar eipthelial cell differentiation and in vivo modeling of pulmonary fibrosis in rats to Epithelium and Pulmonary Fibrosis study novel ideas 7/1/2009 6/30/2011 81.049 2009-2367 5/13/2009 7/1/2009 6/30/2011 93.701 2009-2371 5/13/2009 6/1/2009 5/31/2011 93.856 2009-2375 5/13/2009 5/11/2009 4/30/2010 93.701 2008-2185 5/13/2009 ab25087a-b4cd-4a92-bc82-1fd227824da0.xls 8/22/2009, 2:35 AM