Case Western Reserve University

CASE COMPREHENSIVE CANCER CENTER SUPPORT GRANT

EPIDEMIOLOGY OF DIABETES INTERVENTIONS AND COMPLICATIONS (EDIC)

CLINICAL AND TRANSLATIONAL SCIENCE COLLABORATIVE OF CLEVELAND

CASE WESTERN RESERVE UNIVERSITY/CLEVELAND CLINIC CTSA (UL1)

CASE AIDS CLINICAL TRIALS UNIT

CLINICAL AND TRANSLATIONAL SCIENCE COLLABORATIVE OF CLEVELAND

NSF CENTER FOR LAYERED POLYMERIC SYSTEMS

CENTER FOR AIDS RESEARCH(CFAR)

ASTHMA INFLAMMATION RESEARCH (AIR)

CASE GI SPORE

CLINICAL AND TRANSLATIONAL SCIENCE COLLABORATIVE OF NORTHERN OHIO, CATALYZING LINKAGES TO EQUITY IN HEALTH (CLE HEALTH) - PROJECT SUMMARY/ABSTRACT FOR THE PAST 15 YEARS, THE CLINICAL AND TRANSLATIONAL SCIENCE COLLABORATIVE (CTSC) AT CASE WESTERN RESERVE UNIVERSITY (CWRU) HAS LINKED CLINICAL AND TRANSLATIONAL RESEARCH EFFORTS AT FIVE INDEPENDENT INSTITUTIONS— CWRU, CLEVELAND CLINIC, METROHEALTH SYSTEM, UNIVERSITY HOSPITALS OF CLEVELAND, AND LOUIS STOKES CLEVELAND VETERANS AFFAIRS MEDICAL CENTER. TWO NEW PARTNERS (UNIVERSITY OF TOLEDO SCHOOL OF MEDICINE AND NORTHEAST OHIO MEDICAL UNIVERSITY) ARE NOW BEING ADDED TO EXTEND THE CTSC’S REACH ACROSS NORTHERN OHIO. THE CWRU CTSC HAS A STRONG TRACK RECORD OF ENHANCING THE QUANTITY AND QUALITY OF CLINICAL AND TRANSLATIONAL SCIENCE (CTS) AMONG OUR PARTNERS BY FACILITATING NOVEL RESEARCH PARADIGMS, TECHNOLOGIES, AND TRAINING. OUR CTSC HAS DEVELOPED A NEW GENERATION OF RESEARCHERS, ENHANCED COLLABORATIONS AMONG INVESTIGATORS, STREAMLINED DISCOVERY BY BUILDING PARTNERSHIPS AMONG INDUSTRY AND COMMUNITY AND ORGANIZATIONAL PARTNERS, AND FACILITATED MANY SUCCESSFUL ENTREPRENEURIAL STARTUPS. BUILDING ON THIS SOLID FOUNDATION, THE CWRU CTSC PROPOSES AN EXPANDED FOCUS ON HEALTH EQUITY, REFLECTED IN THE PROJECT THEME CATALYZING LINKAGES TO EQUITY IN HEALTH (CLE HEALTH). SOCIAL, ECONOMIC, AND ENVIRONMENTAL DISADVANTAGES ARE LINKED TO POOR HEALTH OUTCOMES AND LEAD TO DISPARITIES IN LIFE EXPECTANCY, INFANT MORTALITY, AND RATES OF CHRONIC CONDITIONS. MINORITY GROUPS ARE OFTEN UNDERREPRESENTED IN CLINICAL TRIALS AS WELL, MEANING THERE CAN BE INSUFFICIENT DATA FOR UNDERSTANDING THE EFFECTIVENESS OR SAFETY OF NEW DRUGS, PROCEDURES, OR HEALTH INTERVENTIONS FOR DIFFERENT POPULATIONS. THE OVERALL GOALS OF THIS PROJECT ARE TO 1) UNDERSTAND THE FUNDAMENTAL BARRIERS TO OPTIMAL RECRUITMENT OF UNDERREPRESENTED GROUPS IN CLINICAL TRIALS AND TEST AND SCALE INTERVENTIONS AIMED AT BREAKING DOWN THESE BARRIERS TO DIVERSIFY STUDY ENGAGEMENT, 2) FACILITATE AND EXPEDITE INNOVATION IN MULTICENTER CLINICAL AND TRANSLATIONAL RESEARCH BY FULLY INTEGRATING COMMUNITY AND STAKEHOLDER PARTNERS AND ENSURING THAT THIS RESEARCH REPRESENTS THE EXPERIENCES OF ALL AND RESULTS IN HEALTH IMPROVEMENTS FOR ALL, 3) DISSEMINATE AND IMPLEMENT NOVEL AND RESPONSIVE RESEARCH PROGRAMS ACROSS CLINICAL AND COMMUNITY SETTINGS TO ADVANCE ACCESS TO HEALTH INTERVENTIONS THAT AIM TO PROMOTE HEALTH EQUITY, AND 4) CREATE AND DISSEMINATE INCLUSIVE AND HIGH IMPACT EDUCATIONAL AND TRAINING PROGRAMS FOR TRANSLATIONAL RESEARCH PROFESSIONALS OF ALL DISCIPLINES AND LEVELS, BOTH IN CLINICAL AND COMMUNITY SETTINGS. THE CTSC HAS DESIGNED A STRATEGIC MANAGEMENT CORE AND SIX CTS RESEARCH AND TRAINING ELEMENTS TO ACCOMPLISH THESE GOALS: WORKFORCE DEVELOPMENT, COMMUNITY & STAKEHOLDER ENGAGEMENT, RESOURCES & SERVICES, CTS PILOT, HEALTH INFORMATICS, AND CTS RESEARCH PROGRAM. WE ARE COMMITTED TO INNOVATIVE AND COLLABORATIVE PRACTICE AND DISSEMINATION OF RESULTS SO THAT EVERYONE IN NORTHERN OHIO—AND BEYOND—CAN BENEFIT FROM ADVANCES IN CTS IN OUR PROGRAMS AND DISCOVERIES.

MEDICAL SCIENTIST TRAINING PROGRAM

BREAKTHROUGH ELECTROLYTES FOR ENERGY STORAGE (BEES)

IFNS AND CYTOKINES: SIGNALING AND ACTION

OXIDATION IN INFLAMMATION AND CARDIOVASCULAR DISEASE

PULMONARY VASCULAR DISEASE PHENOMICS PROGRAM (PVDOMICS) DATA COORDINATING CENTER

VASCULAR CELL FUNCTION AND ATHEROSCLEROSIS

STRUCTURE AND FUNCTION OF BETA3 INTEGRINS ON BLOOD CELLS

ACUTE HUMORAL REJECTION OF RENAL ALLOGRAFTS

INNATE IMMUNITY END EXPERIMENTAL CROHN'S DISEASE

ALCOHOL AND TISSUE INJURY FROM MECHANISMS TO TREATMENTS

CWRU CENTER FOR EXCELLENCE ON THE IMPACT OF SUBSTANCE USE ON HIV - PROJECT SUMMARY - OVERVIEW THE NEWLY DEVELOPED CWRU (CASE WESTERN RESERVE UNIVERSITY) CENTER FOR EXCELLENCE ON THE IMPACT OF SUBSTANCE USE ON HIV WAS CONCEIVED IN AUGUST 2017 AND WAS INITIATED TO EFFECTIVELY PROMOTE EXCELLENCE IN BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH CONCERNING THE INTERSECTION BETWEEN SUBSTANCE USE AND HIV. THE CENTER FOR EXCELLENCE INCLUDES 12 NIDA-FUNDED INVESTIGATORS WHO COLLECTIVELY HOLD 9 R01, 2 DP1, 3 R34, 2 R44, 1 U01, AND 2 K01 DRAWN FROM THE CWRU SCHOOL OF MEDICINE, UNIVERSITY HOSPITALS CLEVELAND MEDICAL CENTER, METROHEALTH MEDICAL CENTER, THE CLEVELAND CLINIC FOUNDATION, THE LOUIS STOKES CLEVELAND VETERANS ADMINISTRATION MEDICAL CENTER, THE CWRU MANDEL SCHOOL OF APPLIED SOCIAL SCIENCES, THE BEGUN CENTER FOR VIOLENCE PREVENTION RESEARCH AND EDUCATION, AND THE CUYAHOGA COUNTY, LORAIN COUNTY, AND CITY OF CLEVELAND DEPARTMENTS OF HEALTH. MAJOR RESEARCH STRENGTHS IN THE CENTER FOR EXCELLENCE INCLUDE IMPACT OF DRUG USE ON HIV IMMUNOPATHOGENESIS, HIV LATENCY AND CURE, NEUROAIDS, GASTROINTESTINAL DYSFUNCTION, SEXUAL RISK BEHAVIOR, AND HIV AND HCV CO-INFECTIONS. OUR STUDIES ARE ANCHORED BY ADVANCED COMPUTATIONAL, SYSTEMS BIOLOGY, BIOMIMETIC MODELS, AND INDUCED PLURIPOTENT STEM CELL (IPSC) TECHNOLOGIES THAT PROVIDE THE OPPORTUNITY TO PERFORM META-OMICS ANALYSES OF THE IMPACT OF OPIOID, METHAMPHETAMINE, CANNABIS, AND COCAINE MISUSE ON SEVERAL CLINICAL, VIROLOGICAL, IMMUNOLOGICAL, BEHAVIORAL, AND NEUROLOGICAL OUTCOMES OF HIV DISEASE. THE CENTER FOR EXCELLENCE HAS THE FOLLOWING SPECIFIC AIMS: - PROVIDE SCIENTIFIC LEADERSHIP TO POSITION THE CENTER AT THE FOREFRONT OF SUBSTANCE USE DISORDER RESEARCH AND FUNCTION AS A NATIONAL RESEARCH RESOURCE FOR THE STUDY OF DRUG USE IN PERSONS WITH HIV. - ESTABLISH AN ADMINISTRATIVE INFRASTRUCTURE THAT MAINTAINS FISCAL AND MANAGEMENT OVERSIGHT OF THE CORES. - APPLY ADVANCED COMPUTATIONAL BIOLOGY, PRIMARY CELLS, BIOMIMETIC MODELS, AND IPSC- DERIVED CELLS TO STUDY OF THE IMPACT OF SUBSTANCE USE ON HIV DISEASE. - SUPPORT TRANSLATIONAL, CLINICAL, AND BEHAVIORAL RESEARCH THROUGH ACCESS TO UNIQUE CLINICAL COHORTS OF PERSONS WITH SUBSTANCE USE DISORDER WITH HIV AND AT RISK FOR HIV. - ACCELERATE JUNIOR FACULTY DEVELOPMENT AND ENCOURAGE EXPERIENCED FACULTY TO ENTER THE SUBSTANCE USE RESEARCH ARENA TO SUPPORT THE NEXT GENERATION OF INVESTIGATORS. - PARTICIPATE IN COMMUNITY OUTREACH.

CONTINUING ENHANCED NATIONAL SURVEILLANCE FOR PRION DISEASES IN THE UNITED STATES

HYALURONAN MATRICES IN VASCULAR PATHOLOGIES

CLEVELAND ALZHEIMERS DISEASE RESEARCH CENTER - PROJECT SUMMARY THE CLEVELAND ALZHEIMER'S DISEASE RESEARCH CENTER (CADRC) IS A COLLABORATIVE EFFORT OF PHYSICIANS AND INVESTIGATORS FROM CASE WESTERN RESERVE UNIVERSITY (CWRU), CLEVELAND CLINIC FOUNDATION (CCF), METROHEALTH SYSTEM (MHS), UNIVERSITY HOSPITALS (UH), AND THE LOUIS STOKES CLEVELAND VA MEDICAL CENTER (LSCVAMC), TO FOSTER EXCELLENCE IN RESEARCH AND FACILITATE DISCOVERY AS AN ESTABLISHED NATIONAL INSTITUTE ON AGING (NIA) FUNDED ALZHEIMER'S DISEASE RESEARCH CENTER. THE CADRC REPRESENTS A RICH CLINICAL AND RESEARCH COMMUNITY AND AN ESTIMATED 220,000 OHIOANS WHO SUFFER FROM ALZHEIMER'S DISEASE (AD) OR AD-RELATED DEMENTIAS (ADRD). THE CADRC HAS 8 CORES AND A RESEARCH EDUCATION COMPONENT DESIGNED TO CREATE THE FOUNDATION THAT WILL ENHANCE THE RESEARCH EFFORTS OF THE NORTHEAST OHIO AD/ADRD RESEARCH COMMUNITY, AS WELL AS ADD UNIQUE VALUE TO THE NATIONAL ALZHEIMER'S DISEASE RESEARCH CENTERS (ADRC) PROGRAM AND OTHER NATIONAL AND INTERNATIONAL RESEARCH PROGRAMS. THE CADRC IS FOCUSED ON PARTICIPANTS THAT WILL HELP US UNDERSTAND THE PATHOBIOLOGY OF CLINICAL AND PATHOLOGICAL HETEROGENEITY OBSERVED IN DEMENTIA INCLUDING ATYPICAL AND AMNESTIC AD, DEMENTIA WITH LEWY BODIES, COGNITIVELY NORMAL INDIVIDUALS WITH DIFFERENT LEVELS OF GENETIC RISK FOR AD, AND DIVERSITY OF PARTICIPANT POPULATIONS (CLINICAL AND OUTREACH, RECRUITMENT, AND ENGAGEMENT CORES). TO SUPPORT THE CADRC GOALS, THE FOCUS WILL BE ON DEEP PHENOTYPING OF PARTICIPANTS WITH LONGITUDINAL AND SYSTEMATIC COGNITIVE, BEHAVIORAL AND MOTOR CHARACTERIZATION (CLINICAL CORE), GENETIC AND BIOFLUID BIOMARKER COLLECTION AND ANALYSIS (BIOMARKER CORE), IMAGING (NEUROIMAGING CORE), AND AUTOPSY AFTER DEATH (NEUROPATHOLOGY CORE). RESULTS WILL BE SHARED WITH THE RESEARCH COMMUNITY IN A TIMELY AND REGULAR MANNER TO ALLOW OTHER INVESTIGATORS TO BENEFIT FROM THE CADRC EFFORTS (DATA MANAGEMENT AND STATISTICS CORE). IN ADDITION, THE CADRC WILL TRAIN THE NEXT GENERATION OF INVESTIGATORS UTILIZING A RIGOROUS AND WELL-DESIGNED RESEARCH EDUCATION COMPONENT, SUPPORT TRANSLATION OF NEW LABORATORY FINDINGS THROUGH THE TRANSLATIONAL THERAPEUTICS CORE, AND SUPPORT HIGH RISK/HIGH GAIN PROJECTS THROUGH THE DEVELOPMENTAL PROGRAM AS A PART OF THE ADMINISTRATIVE CORE. THE ULTIMATE GOALS ARE TO ADVANCE THE PRECISION MEDICINE APPROACH TO DEMENTIA DIAGNOSIS AND TREATMENT, SUPPORT THE DEVELOPMENT OF EARLY STAGE INVESTIGATORS, ASSIST ALL STAGES OF INVESTIGATORS WITH TOOLS FOR PERFORMING HUMAN-BASED RESEARCH, AND BETTER ENGAGE UNDERREPRESENTED POPULATIONS IN AD/ADRD RESEARCH.

CLEVELAND OPEN SOURCE MODULAR IMPLANT INNOVATORS COMMUNITY (COSMIIC) - THE OVERALL GOAL OF THE CLEVELAND OPEN SOURCE MODULAR IMPLANT INNOVATORS COMMUNITY (COSMIIC) IS TO ESTABLISH AN OPEN SOURCE, MODULAR NETWORK OF ACTIVE IMPLANTABLE DEVICES FOR USE IN EARLY FEASIBILITY HUMAN RESEARCH AND TO PROVIDE ONGOING SUPPORT FOR THIS TECHNOLOGY THROUGH A VIBRANT, SUSTAINABLE COMMUNITY OF ACTIVE USERS. OUR TEAM IS POISED TO SUCCESSFULLY ACHIEVE ALL OF THE GOALS OF THE HORNET PROGRAM BECAUSE OUR PROPOSED CONCEPT IS BASED ON OUR ESTABLISHED PLATFORM ECOSYSTEM, THE NETWORKED NEUROPROSTHESIS (NNP). THIS PROVIDES A SOLID TECHNOLOGICAL PLATFORM WITH KNOWN REGULATORY STATUS FOR OUR COSMIIC HORNET PROJECT. CRITICALLY, ALL TECHNOLOGY DESCRIBED IN THIS PROPOSAL WAS INVENTED BY THE INVESTIGATIVE TEAM AND THEREFORE WE ARE ABLE TO FULLY EMBRACE THE OPEN SOURCE IDEOLOGY FOR THE END-TO-END TECHNOLOGY. THE PROPOSED COSMIIC HORNET SYSTEM, WHICH WILL BE ESTABLISHED ON THE PLATFORM NNP SYSTEM, IS A SYSTEM OF INTEROPERABLE AND INTEGRATED MODULES THAT CAN SIMULTANEOUSLY ELECTRICALLY ACTIVATE, BLOCK, AND SENSE THROUGHOUT THE BODY. THE SYSTEM CAN RECORD AND PROCESS ELECTRONEUROGRAM (ENG), ELECTROMYOGRAM (EMG), INTRACORTICAL SIGNALS, ELECTROCARDIOGRAM (EKG), KINEMATIC VARIABLES, PHOTOPLETHYSMOGRAM (PPG), AND TEMPERATURE. EACH MODULE CAN DIRECTLY COMMUNICATE WITH ALL OTHER MODULES THROUGH AN ESTABLISHED NETWORK COMMUNICATION PROTOCOL. THE SYSTEM CAN PROCESS SIGNALS TO IMPLEMENT COMPLEX CLOSED-LOOP CONTROL WITHOUT REQUIRING NON-IMPLANTED HARDWARE. IMPORTANTLY, THE EXISTING NNP PLATFORM COMPONENTS (POWER MODULE, STIMULATOR MODULE, BIOPOTENTIAL RECORDING MODULE, NETWORK CABLE, ELECTRODES) ALREADY HAVE IDE APPROVAL FROM THE FDA AND HAVE BEEN SUCCESSFULLY IMPLANTED AND IMPLEMENTED IN HUMAN RESEARCH PARTICIPANTS. THUS, THE COSMIIC HORNET SYSTEM HAS THE NECESSARY FEATURES TO PROVIDE THE MODULAR PLATFORM ECOSYSTEM FOR USE BY THE BIOELECTRONIC COMMUNITY FOR THE FORESEEABLE FUTURE. AIM #1. DISSEMINATION. WE WILL ESTABLISH THE COSMIIC COMMUNITY WITH FULL OPEN-SOURCE ACCESS TO AN ESTABLISHED MODULAR IMPLANTABLE DEVICE FOR USE IN THE PERIPHERAL AND CENTRAL NERVOUS SYSTEM. ACCESS WILL BE GIVEN FOR ALL CIRCUIT DESIGNS AND LAYOUTS; MECHANICAL DRAWINGS FOR ALL ENCLOSURES AND CONNECTORS AND CABLING; THE ANNOTATED CODE FOR ALL OPERATING SOFTWARE, FIRMWARE, AND BOOTLOADER; WRITTEN INSTRUCTIONS AND VIDEOS OF FABRICATION TECHNIQUES; AND ALL REGULATORY DOCUMENTS AND TEST DATA, INCLUDING OUR APPROVED IDE DOCUMENT. AIM #2. SUSTAINABILITY. WE WILL DEVELOP A SUSTAINABLE OPEN SOURCE MODEL THROUGH THE DEVELOPMENT OF TECHNOLOGY THAT ATTRACTS A BROAD INVESTIGATIVE TEAM TO ESTABLISH A CRITICAL MASS OF COSMIIC USERS. WE WILL PROVIDE ONGOING SUPPORT OF THE TECHNOLOGY AND PARTNER WITH COMMERCIAL PARTNERS TO CREATE A SUSTAINABLE BUSINESS PLAN SO THAT THE COSMIIC COMMUNITY REMAINS INDEPENDENTLY VIBRANT AND ACTIVE AFTER THREE YEARS.

GUT MICROBIOTA AND CARDIOMETABOLIC DISEASES

THE ALZHEIMER DISEASE SEQUENCE ANALYSIS COLLABORATIVE

CONTINUING AN ENHANCED AND MULTIFACETED NATIONAL SURVEILLANCE PROGRAM FOR HUMAN PRION DISEASES

THE CLEVELAND CLINIC INNOVATION ACCELERATOR

PATHOBIOLOGY OF ASTHMA

GENETIC DETERMINANTS OF BARRETT'S ESOPHAGUS AND ESOPHAGEAL ADENOCARCINOMA

THE CLEVELAND DIGESTIVE DISEASES RESEARCH CORE CENTER (DDRCC)

PHARMACOLOGICAL TREATMENT OF RETINAL DISEASES

CWRU CENTER FOR MULTIMODAL EVALUATION OF ENGINEERED CARTILAGE

COHORT STUDY OF CHRONIC RENAL INSUFFICIENCY

IBUDILAST PHASE II TRIAL IN PROGRESSIVE MS

HIGHER EDUCATION EMERGENCY RELIEF FUND-INSTITUTIONAL PORTION CARES ACT

CASE AIDS CLINICAL TRIALS UNIT

TARGETING OBESITY AND BLOOD PRESSURE IN URBAN YOUTH

CELL ADHESION AND SIGNALING IN BLOOD AND VASCULAR CELLS - PROJECT SUMMARY THIS APPLICATION HAS AS ITS THEME THE INTEGRINS, THEIR REGULATION AND THEIR CONTRIBUTION TO THE FUNCTIONAL RESPONSES OF BLOOD AND VASCULAR CELLS. THE INTEGRINS OF FOCUS ARE AMSS2 (MAC-1), AIIBSS3, AVSS3, AND A5SS1 BUT FINDINGS SHOULD APPLY TO BROADLY INTEGRINS. THE CELLS OF EMPHASIS ARE VASCULAR CELLS- ENDOTHELIAL CELLS, SMOOTH MUSCLE CELLS AND PERICYTES- AND BLOOD CELLS- LEUKOCYTES AND PLATELETS. ON THE BLOOD CELLS, THE CONJUGATION OF MAC-1 ON LEUKOCYTES AND GPIB ON PLATELETS WILL BE CONSIDERED. MAJOR EMPHASIS WILL BE PLACED ON THE MOLECULES THAT REGULATE INTEGRIN FUNCTION- KINDLINS, TALIN AND PAXILLIN- TO DETERMINE HOW THEY COLLABORATE TO REGULATE INTEGRIN ACTIVATION. THE FUNCTION OF THESE CYTOSKELETAL PROTEINS INDEPENDENT OF INTEGRIN ACTIVATING ACTIVITY WILL ALSO BE DISSECTED. THE PROGRAM CONSISTS OF THREE PROJECTS, EACH DIRECTED BY AN ACCOMPLISHED FACULTY MEMBER AT THEIR HOME INSTITUTIONS, CLEVELAND CLINIC, UNIVERSITY HOSPITALS OF CLEVELAND AND CASE WESTERN RESERVE UNIVERSITY WHICH ARE ALL CLOSELY LOCATED AND GOVERNED BY INTERINSTITUTIONAL AGREEMENTS. DR. EDWARD F. PLOW, PH.D. WILL SERVE AS PROGRAM DIRECTOR AND LEAD PROJECT 1. THIS PROJECT DEALS WITH THE MECHANISMS BY WHICH KINDLIN-2 REGULATES BOTH INTEGRIN-DEPENDENT AND INDEPENDENT RESPONSES OF BLOOD VESSEL CELLS. MOLECULAR, CELLULAR AND UNIQUE MOUSE MODELS ARE ALL BROUGHT TO BEAR TO DETERMINE HOW KINDLIN-2 SERVES AS A MASTER REGULATOR OF VASCULAR CELL RESPONSES. IN PROJECT 2, DR. JUN QIN WILL USE HIGH RESOLUTION STRUCTURAL APPROACHES IN COMBINATION WITH MUTAGENESIS AND CELLULAR STUDIES TO DETERMINE HOW TALIN REGULATE INTEGRIN ACTIVATION AND COOPERATES WITH KINDLINS AND PAXILLIN TO GAIN SUCH NOVEL INSIGHTS. HE WILL DETERMINE HOW TALIN INTERACTS WITH ACTIN TO CONTROL ORGANIZATION OF THE CYTOSKELETON. DR. DANIEL SIMON, M.D. WILL LEAD PROJECT 3 AND WILL CONSIDER HOW ENGAGEMENT OF INTEGRIN MAC-1 ON LEUKOCYTES AND GPIB ON PLATELETS REGULATES THE PARTICIPATION OF THESE CELLS IN INFLAMMATION AND THROMBOSIS. HIS STUDIES RANGE FROM BASIC STRUCTURAL APPROACHES TO TRANSLATIONAL STUDIES IN MICE AND TO HUMANS TO PROVIDE INSIGHTS INTO THEIR THROMBOTIC AND INFLAMMATORY CONTRIBUTIONS TO SYSTEMIC LUPUS ERYTHEMATOSUS. THE PROGRAM IS SUPPORTED BY TWO SCIENTIFIC CORES, PROTEIN EXPRESSION AND PURIFICATION (CORE B), AND ANIMAL MODELS AND TISSUE ANALYSIS (CORE C) AS WELL AS BY AN ADMINISTRATIVE CORE (AC1). A COMMON OBJECTIVE OF THE PROGRAM IS TO CONTINUE AND CREATE NEW COLLABORATIONS AMONG THE PROJECTS AND THEIR LEADERS TO RESOLVE THE STRUCTURAL AND BIOLOGICAL MECHANISMS THAT REGULATE THE FUNCTIONS OF INTEGRINS IN BLOOD AND VASCULAR CELLS. THE INFORMATION DERIVED FROM THESE STUDIES WILL PROVIDE INSIGHTS INTO BIOLOGICALLY IMPORTANT RESPONSES REGULATED BY INTEGRINS AND THEIR ACTIVATION THAT ARE RELEVANT TO THROMBOSIS AND CARDIOVASCULAR DISEASES.

HDL STRUCTURE AND ITS FUNCTION IN ATHEROSCLEROSIS

P30 - CORE GRANT FOR VISION RESEARCH

DEVELOPMENT OF NEW DIAGNOSTIC METHODS/SURVEILLANCE PROGRAM

FRMI OF THE PERSON IDENTITY NETWORK: AGING AND APOE

GRANT AWARD TO CASE WESTERN RESERVE UNIVERSITY (CWRU) CONTRIBUTES TO NNSA’S STOCKPILE STEWARDSHIP MISSION BY ESTABLISHING A UNIQUE PUBLIC-PRIVATE PARTNERSHIP MERGING MATERIALS SCIENCE WITH NOVEL COMPUTER SCIENCE AND DATA SCIENCE TO ADVANCE THE UNDERSTANDING OF FUNDAMENTAL MECHANISMS OF MATERIALS DEGRADATION AND FAILURE IN OUR NUCLEAR STOCKPILE MATERIALS AND COMPONENTS, THROUGH COMBINED RESEARCH AND EDUCATIONAL MULTI-DISCIPLINARY VISION. PROJECT TITLE: CENTER TO MATERIALS DATA SCIENCE FOR STOCKPILE STEWARDSHIP (MDS3) COE

ATRIAL FIBRILLATION POST-GWAS: MECHANISMS TO TREATMENT - OVERALL COMPONENT PROJECT/SUMMARY ABSTRACT ATRIAL FIBRILLATION (AF), THE MOST COMMON CARDIAC ARRHYTHMIA, AFFLICTS THE U.S. AND WORLD WITH INCREASING PREVALENCE. AF INCIDENCE, PROGRESSION TO PERSISTENT AF, AND AF COMPLICATIONS, INCLUDING STROKE, ARE FED BY INCREASING OBESITY AND AGE. CURRENT THERAPIES ARE LIMITED BY RISKS AND LIMITED EFFICACY, WORSE AS AF PROGRESSES, BUT NO NEW PHARMACOLOGIC AGENTS HAVE BEEN APPROVED FOR AF IN >10 YEARS. WITH IDENTIFICATION OF >100 GENETIC LOCI THAT PREDISPOSE TO AF RISK IN GENOME-WIDE ASSOCIATION STUDIES (GWAS), THE HOPE HAS BEEN THAT GENETICS WOULD YIELD NOVEL THERAPEUTIC TARGETS. HOWEVER, EVEN FOR THE TOP LOCUS ON CHR. 4Q25 NEAR PITX2, A GENE INVOLVED IN FORMATION OF PULMONARY VEINS, THE TARGET OF AF ABLATION, MECHANISMS LINKING VARIANTS TO AF REMAIN ELUSIVE. GENETIC FINDINGS HAVE SO FAR FAILED TO YIELD CLINICALLY ACTIONABLE RESULTS. TO FILL THESE GAPS, WE SEEK TO GO BEYOND GWAS FINDINGS TO IDENTIFY DIRECT GENOMIC MECHANISMS UNDERLYING AF AND BETTER UNDERSTAND THEIR INTERACTIONS WITH ENVIRONMENT, COMORBIDITIES OR CELL STRESSORS. OUR LONG-TERM GOAL IS TO USE GENOMIC FINDINGS TO PERSONALIZE PREVENTIVE AND THERAPEUTIC STRATEGIES FOR AF. OUR OVERALL P01 THEME IS TO TRANSLATE AF GENETIC DISCOVERIES TOWARDS THE BEDSIDE, FOCUSING ON GENES TO MECHANISMS, GENES TO DRUGS, AND INTERACTIONS OF GENES WITH METABOLISM AND ENVIRONMENT. WE BUILD ON STRONG PRELIMINARY DATA AND COALESCE UNIQUE HUMAN ATRIAL TISSUE BIOREPOSITORY AND GENOMIC DATA RESOURCES, NOVEL CELL AND ANIMAL MODELS, AND COMPLEMENTARY EXPERTISE FROM OUR MULTIDISCIPLINARY TEAM WITH A STRONG COLLABORATION HISTORY. OUR CENTRAL HYPOTHESIS IS THAT GENOMIC MECHANISTIC DISCOVERIES IN AF CELLULAR AND ANIMAL MODELS WILL TRANSLATE TO HUMAN THERAPIES. OUR THEMATIC AIMS INCLUDE: 1) IDENTIFY CAUSAL GENES AND FUNCTIONAL MECHANISMS WITH A GOAL TOWARDS IDENTIFICATION OF NEW THERAPEUTIC APPROACHES FOR AF; 2) INVESTIGATE METABOLIC AND INFLAMMATORY MECHANISMS, IMPLICATED BY GENOMICS STUDIES TO BE IMPORTANT IN AF PATHOPHYSIOLOGY, TO IDENTIFY NEW THERAPEUTIC TARGETS FOR AF PREVENTION AND TREATMENT; AND 3) IDENTIFY CANDIDATE NOVEL DRUGS FOR AF AND DEVELOP A PIPELINE FOR IN VITRO AND IN VIVO FUNCTIONAL TESTING OF CANDIDATE THERAPIES. PROJECT 1 GENES TO FUNCTION WILL DETERMINE CAUSAL GENES, VARIANTS AND MECHANISMS UNDERLYING TWO AF GWAS LOCI. PROJECT 2 GENES AND METABOLISM WILL STUDY THE CONTRIBUTION OF MITOCHONDRIAL DYSFUNCTION TO AF ONSET AND PROGRESSION. EARLY STAGE INVESTIGATOR PROJECT GENES AND NUTRITION BUILDS ON NOVEL ASSOCIATIONS OF AF WITH TRIMETHYLAMINE N-OXIDE (TMAO), PRODUCED BY GUT MICROBIOTA FROM PRECURSORS SUCH AS CHOLINE FOUND IN EGGS, MEATS AND CHEESES. PROJECT 4 GENES TO OMICS-INFORMED DRUGS WILL IDENTIFY MECHANISMS AND REPURPOSABLE DRUGS TO PREVENT AF PROGRESSION. PROJECTS ARE SUPPORTED BY 4 CORES PROVIDING ADMINISTRATION, ENGINEERED HEART TISSUE AND ATRIAL PHENOTYPING, ELECTROPHYSIOLOGY, AND NETWORK AND SYSTEMS BIOLOGY ANALYTICS SUPPORT THAT SYNERGIZE DISCOVERY AND TRANSLATION IN AF AND INCREASE THE SCOPE AND IMPACT OF EACH PROJECT. ALL P01 COMPONENTS AIM TO BRIDGE BASIC RESEARCH IN AF TOWARDS CLINICAL UTILITY, THEREBY ADVANCING GENOMIC DATA AND RESEARCH TOWARDS THE BEDSIDE TO HELP OUR PATIENTS SUFFERING FROM ATRIAL FIBRILLATION.

RESISTANCE TO MTB INFECTION IN HIV INFECTED INDIVIDUALS IN UGANDA AND S. AFRICA

CONTINUING THE DEVELOPMENT OF NEW DIAGNOSTIC METHODS/SURVEILLANCE PROGRAM

CASE COMPREHENSIVE CANCER CENTER NCTN LEAD ACADEMIC PARTICIPATING SITE

CLINICAL AND TRANSLATIONAL SCIENCE COLLABORATIVE OF CLEVELAND

DEFINING THE PATHOGENESIS OF IMMUNE DEFICIENCY IN CHRONIC HIV INFECTION

SELF REGULATING CONTINUOUS FLOW TOTAL ARTIFICIAL HEART

GUT FLORA METABOLISM OF DIETARY PHOSPHATIDYLCHOLINE AND CARDIOVASCULAR DISEASE

CLINICAL ONCOLOGY RESEARCH CAREER DEVELOPMENT PROGRAM (CORP)

SEX-BASED DIFFERENCES IN GLIOMA

HIGHER EDUCATION EMERGENCY RELIEF FUND CARES ACT

RESEARCH TO CONTROL AND ELIMINATE MALARIA IN SE ASIA AND SW PACIFIC

PILOT RANDOMIZED CONTROLLED TRIAL OF THE ISENS SYSTEM FOR SENSORIMOTOR RESTORATION AFTER LIMB LOSS

EMBODIED ROBOTICS FOR REMOTE OPERATIONS

NASH PROJECT

INFLAMMASOME AND GASDERMIN SIGNALING NETWORKS FOR REGULATION OF PYROPTOSIS AND CYTOKINE RELEASE

OXIDIZED PHOSPHOLIPIDS IN VASCULAR PATHOBIOLOGY

PATHOGENETIC MECHANISMS OF PRION DISEASE

NEW CA CWRU

ORAL MUCOSAL IMMUNITY IN VULNERABLE HIV INFECTED POPULATIONS

ALLIANCE OF RANDOMIZED TRIALS OF MEDICINE VS METABOLIC SURGERY IN TYPE 2 DIABETES - (ARMMS-T2D)

CELLULAR S-NITROSOTHIOL SIGNALING IN RESPIRATORY BIOLOGY

ENGAGING COMMUNITIES AND INSTITUTIONS TO REDUCE HEALTH DISPARITIES IN CLEVELAND

CASE CENTER FOR SYNCHROTRON BIOSCIENCES

PROTECTIVE GENETIC VARIANTS FOR ALZHEIMER DISEASE IN THE AMISH

COCAINE EXPOSED CHILDREN AT SCHOOL AGE

RESTORATION OF GRASP AND REACH IN CERVICAL SPINAL CORD INJURY

NEURONEX: COMMUNICATION, COORDINATION, AND CONTROL IN NEUROMECHANICAL SYSTEMS (C3NS)

PROTECTIVE GENETIC VARIANTS FOR ALZHEIMER DISEASE IN THE AMISH - RENEWAL - ALZHEIMER DISEASE (AD) IS A DEVASTATING NEURODEGENERATIVE DISORDER THAT AFFECTS MILLIONS OF INDIVIDUALS IN THE U.S. IT HAS SO FAR RESISTED ATTEMPTS TO DEVELOP EFFECTIVE THERAPIES DESPITE NUMEROUS (FAILED) CLINICAL TRIALS BASED ON KNOWN TARGETS, MOST IDENTIFIED OVER 20 YEARS AGO. WHILE GENOMIC RESEARCH (E.G. THE ALZHEIMER’S DISEASE SEQUENCING PROJECT; ADSP) HAS IDENTIFIED NUMEROUS ADDITIONAL RISK LOCI, THESE RESULTS DERIVE PRIMARILY FROM CASE- CONTROL DATASETS. IN CONTRAST, COHORTS DESIGNED TO IDENTIFY VARIANTS THAT MAY PROTECT FROM AD, AND THOSE USING COMPLEMENTARY STUDY DESIGNS, ARE FEW. WE USED OUR EXTENSIVE EXPERIENCE WITH THE AMISH COMMUNITIES IN INDIANA AND OHIO TO ESTABLISH A COHORT OF OLDER INDIVIDUALS AT HIGH RISK OF DEVELOPING AD BUT WHO ARE COGNITIVELY UNIMPAIRED (CU). THE AMISH PROVIDE A UNIQUE OPPORTUNITY TO IDENTIFY PROTECTIVE VARIANTS FOR AD BECAUSE OF THEIR REDUCED BACKGROUND GENETIC VARIATION AND ENVIRONMENTAL RISK FACTORS. THEIR SMALL FOUNDING POPULATION AND ENDOGAMY PROVIDES ENRICHMENT FOR RARE VARIANTS. FOUNDER POPULATIONS ALSO ENABLE TESTING FOR NON-ADDITIVE ALLELIC EFFECTS AND CAN MAGNIFY SUB-SIGNIFICANT ASSOCIATION SIGNALS IDENTIFIED IN CASE-CONTROL STUDIES. THE STABILITY AND ENGAGEMENT OF OUR AMISH PARTICIPANTS ENABLES LONGITUDINAL ASSESSMENTS OF COGNITION AND BIOMARKERS. OUR PRIMARY GOALS ARE TO IDENTIFY AD PROTECTIVE LOCI AND CHARACTERIZE PRE-CLINICAL BIOMARKERS OF PROGRESSION TO COGNITIVE IMPAIRMENT. BUILDING ON OUR EXISTING LARGE COHORT, OUR REPLICATED PROTECTIVE LOCUS AND SEVERAL SUGGESTIVE PROTECTIVE LOCI, AND OUR EXISTING BIOBANK OF DNA AND PLASMA AND DATABANK OF GWAS AND WGS, WE PROPOSE TO: 1) PERFORM LONGITUDINAL ASSESSMENT OF COGNITION IN OUR FAMILY-BASED AMISH COHORT; 2) IDENTIFY PROTECTIVE FACTORS FOR AD AND PREDICTORS OF PROGRESSION TO COGNITIVE IMPAIRMENT BY ANALYZING GENOMIC AND LONGITUDINAL COGNITIVE, BIOMARKER, AND SDOH DATA; AND 3) EXAMINE THE FUNCTIONAL IMPLICATIONS OF CURRENT AND NOVEL GENES AND VARIANTS BY PRIORITIZING LOCI USING IN SILICO ANNOTATION FOR FUNCTIONAL CONSEQUENCES FOLLOWED BY IN VITRO FUNCTIONAL CHARACTERIZATION. OUR RESULTS WILL IDENTIFY POTENTIAL DRUGGABLE TARGETS AND ACCELERATE THE DEVELOPMENT OF BETTER TREATMENTS FOR AD.

REGULATION OF CNS VIRAL PERSISTENCE

GENETIC AND CELLULAR DETERMINANTS OF ARTERIAL THROMBOSIS

MECHANISMS OF TRANSMISSIBILITY IN PRION DISEASES

HEMODIALYSIS FISTULA MATURATION CONSORTIUM DATA COORDINATING CENTER

TISSUE INJURY AND INFLAMMATION IN MULTIPLE SCLEROSIS

MOLECULAR DISSECTION OF CYTOKINE CROSSTALK IN THE TUMOR MICROENVIRONMENT - PROJECT SUMMARY DESPITE RECOGNITION OF THE BROAD CONSEQUENCES OF INFLAMMATION IN CANCER BIOLOGY, THE MECHANISTIC IMPACT ON THE TUMOR LANDSCAPE REMAINS INCOMPLETELY UNDERSTOOD. INDEED, INNATE AND ADAPTIVE IMMUNE FUNCTIONS IN CANCER CAN BE BENEFICIAL OR DETRIMENTAL AND THE OPPOSING ROLES HIGHLIGHT THE GAP OF KNOWLEDGE IN OUR UNDERSTANDING OF HOW INFLAMMATION SCULPTS THE TUMOR MICROENVIRONMENT (TME). THIS PROGRAM PROJECT WILL ADDRESS THIS GAP OF KNOWLEDGE BY DEFINING AND DELINEATING HOW CYTOKINES MODULATE THE FUNCTIONS OF THE MULTIPLE CELL TYPES COMPOSING THE TUMOR MICROENVIRONMENT. OUR PREVIOUS WORK HAS REVEALED THE POTENTIAL FOR THESE INFLAMMATORY CYTOKINES TO REGULATE A SPECTRUM OF CANCER CELL PHENOTYPES, INCLUDING THEIR SELF-RENEWAL AND CELLULAR HIERARCHY OR STEMNESS, THAT ARE ASSOCIATED WITH THE EPITHELIAL-MESENCHYMAL TRANSITION (EMT). MOREOVER, THESE PHENOTYPES ARE COMMONLY ASSOCIATED WITH CANCER PROGRESSION THROUGH MODULATION OF DIFFERENTIATION POTENTIAL, CELL-CELL INTERACTIONS AND MOBILITY, FIBROSIS, AND SENSITIVITY TO MULTIPLE THERAPEUTIC MODALITIES. THE PROGRAM IS NOW CENTERED ON TWO MAJOR THEMES. THE FIRST IS TO DEFINE THE SIGNALING MECHANISMS THAT GOVERN HOW CYTOKINES (TYPE I IFNS, IL- 17,TGFSS) MODULATE (BOTH POSITIVELY AND NEGATIVELY) THE EMT PROCESS. THE CELLULAR TARGETS INCLUDE STEM-LIKE TUMOR CELLS AS WELL AS THE NON-TUMOR DERIVED POPULATIONS, INCLUDING FIBROBLASTS AND IMMUNE CELLS. THE SECOND THEME RELATES THESE CELL-SPECIFIC EMT RESPONSES TO SPECIFIC EFFECTS ON METASTASIS, FIBROSIS, AND RESISTANCE TO MULTIPLE THERAPEUTIC STRATEGIES. OUR MAJOR GOAL IS TO PARLAY OUR IMPROVED UNDERSTANDING OF CYTOKINE EFFECTS IN THE TME INTO SPECIFIC IMPROVEMENTS IN CANCER THERAPY. COLLECTIVELY THE THREE PROJECTS IN THE APPLICATION WILL TEST THE FOLLOWING OVERARCHING HYPOTHESIS: CYTOKINE SIGNALS HAVE DISTINCT AND SOMETIMES CONFLICTING MECHANISTIC ROLES IN CANCER PROGRESSION THOUGH ALTERATIONS IN EMT AND CANCER STEM CELL DEVELOPMENT. SUCH MECHANISMS LEAD TO CRITICAL PHENOTYPIC PROPERTIES RESPONSIBLE FOR CONTINUOUS METASTATIC SPREAD AND RESISTANCE TO MULTIPLE THERAPEUTIC MODALITIES (CHEMOTHERAPY, IMMUNE THERAPY). THIS HYPOTHESIS WILL BE TESTED BY (1) DEFINING THE SIGNALING EVENTS INITIATED BY TGFSS, IL-17, AND/OR TYPE I IFNS AND THE ENDPOINT CHANGES IN SPECIFIC GENE EXPRESSION THAT ARE CAUSALLY LINKED WITH CONTROL OF TME AND CANCER CELL PHENOTYPES, (2) DETERMINATION OF HOW THESE SPECIFIC SIGNALING PATHWAYS AND GENE EXPRESSION EVENTS ARE MECHANISTICALLY RESPONSIBLE FOR ACQUISITION OF THERAPEUTIC RESISTANCE AND (3) EVALUATION OF THE DISTINCT CELL TYPE CONTRIBUTIONS TO TUMOR PHENOTYPES AND THERAPEUTIC RESISTANCE, WITH EMPHASIS ON TUMOR CELL INTRINSIC MECHANISMS, IMMUNE CELL INFILTRATES AND ACTIVITIES, AND STROMAL CELL CONTROL OF TUMOR ACCESS.

PROGNOSIS AND PREDICTORS OF ACL RECONSTRUCTION: A MULTICENTER COHORT STUDY

MOLECULAR MECHANISMS AND PATHWAYS FOR GAS TRANSPORT ACROSS BIOLOGICAL MEMBRANES AND IMPLICATIONS FOR PHYSIOLOGY AND PERFORMANCE MURI 2016

CYCLE-AD: RANDOMIZED CONTROLLED TRIAL TO ASSESS THE EFFICACY OF INDOOR CYCLING IN SLOWING DISEASE PROGRESSION IN HEALTHY OLDER PERSONS AT GENETIC RISK FOR ALZHEIMER?S DISEASE - PROJECT SUMMARY/ABSTRACT THE APOLIPOPROTEIN E EPSILON 4 (APOE 4) ALLELE IS THE MOST IMPORTANT GENETIC RISK FACTOR FOR LATE ONSET ALZHEIMER'S DISEASE (AD). A RECENT REVIEW BY THE WORLD HEALTH ORGANIZATION HIGHLIGHTED THE POTENTIAL PROTECTIVE ROLE OF PHYSICAL ACTIVITY AND EXERCISE AGAINST COGNITIVE DECLINE, ALL-CAUSE DEMENTIA, AD, AND VASCULAR DEMENTIA IN HEALTHY INDIVIDUALS. IN AN 18-MONTH LONGITUDINAL OBSERVATIONAL STUDY, WE SHOWED THAT SEDENTARY 4 CARRIERS EXPERIENCE SIGNIFICANT DECLINES IN EPISODIC MEMORY AND HIPPOCAMPAL VOLUME COMPARED TO 4 CARRIERS WHO ENGAGED IN MODERATE PA. IMPORTANTLY, AMONG 4 NON-CARRIERS, NO SIGNIFICANT LONGITUDINAL CHANGES IN COGNITION AND BRAIN IMAGING WERE OBSERVED WHETHER THE NON-CARRIERS WERE SEDENTARY OR ENGAGED IN MODERATE PA, SUGGESTING THAT PA HAS A SPECIFIC NEUROPROTECTIVE ROLE IN DELAYING THE PROGRESSION OF AD IN 4 CARRIERS. BASED ON OUR RESULTS, A PRAGMATIC, RANDOMIZED CONTROLLED TRIAL WITH BLINDED CLINICAL AND IMAGING OUTCOMES IS PROPOSED TO DETERMINE THE IMPACT OF A HOME BASED, HIGH INTENSITY EXERCISE INTERVENTION IN HEALTHY, COGNITIVELY INTACT 4 CARRIERS BETWEEN THE AGES OF 65 AND 80 YEARS. THE CYCLE-AD (CYCLING TO CEASE OR LIMIT THE EFFECTS OF ALZHEIMER'S DISEASE) TRIAL WILL RECRUIT OTHERWISE HEALTHY SEDENTARY CARRIERS RANDOMIZED TO ONE OF TWO GROUPS (N=75 EACH): 1) AN INDOOR CYCLING (IC) GROUP THAT PARTICIPATES IN HIGH-INTENSITY INTERVAL TRAINING (HIIT; 60-90% OF HEART RATE RESERVE) IN THEIR HOME VIA THE COMMERCIALLY AVAILABLE PELOTON® CYCLING SYSTEM OR 2) A USUAL AND CUSTOMARY CARE (UCC) GROUP, IN WHICH PARTICIPANTS ENGAGE IN THEIR HABITUAL LEVEL OF PA. WE HYPOTHESIZE THAT AN 18-MONTH HIGH-INTENSITY AEROBIC EXERCISE REGIMEN WILL SLOW AD-RELATED DISEASE PROGRESSION IN SEDENTARY ELDERS AT GENETIC RISK FOR AD. PARTICIPANTS IN THE INTERVENTION GROUP WILL ENGAGE IN EXERCISE 3X/WEEK (MINIMUM 90 MINUTES/WEEK) FOR 18 MONTHS. PRIMARY OUTCOME MEASURES, OBTAINED AT STUDY ENTRY AND AT 18 MONTHS, WILL INCLUDE COMPREHENSIVE COGNITIVE TESTING AND BRAIN MR IMAGING TO ASSESS DISEASE PROGRESSION AND A COMPREHENSIVE PA/FITNESS ASSESSMENT TO MEASURE THE DEGREE OF CHANGE IN PHYSICAL FITNESS DUE TO HIGH INTENSITY AEROBIC EXERCISE. THE OVERALL GOAL OF THE CYCLE-AD TRIAL IS TO DETERMINE THE ROLE OF LONG-TERM, HIGH INTENSITY EXERCISE IN SLOWING OR DELAYING THE ONSET OF COGNITIVE AND AD-RELATED BRAIN CHANGES IN 4 CARRIERS. SUCCESSFUL TRANSLATION AND DEMONSTRATION OF THE EFFECTIVENESS OF A SCALABLE HOME-BASED EXERCISE INTERVENTION CAPABLE OF SLOWING OR DELAYING DISEASE ONSET WILL TRANSFORM AD TREATMENT, IMPROVE PATIENT OUTCOMES AND QUALITY OF LIFE, AND REDUCE HEALTH CARE COSTS.

POST-TRANSPLANT INFLAMMATORY RESPONSE

CAPTURING SPATIAL PATTERNS OF NEW M. TUBERCULOSIS INFECTION IN KAMPALA, UGANDA

MULTI-FUNCTIONAL NEUROPROSTHETIC SYSTEMS FOR RESTORATION OF MOTOR FUNCTION

CENTRAL VEIN SIGN: A DIAGNOSTIC BIOMARKER IN MULTIPLE SCLEROSIS

INVOLVING COMMUNITIES IN DELIVERING AND DISSEMINATING HEALTH DISPARITY INTERVENTIONS

REGULATION OF GENE EXPRESSION DURING STRESS

CASE WESTERN RESERVE UNIVERSITY/CLEVELAND CLINIC CTSA (KL2)

MOLECULAR BASIS OF ILK SIGNALING IN CELL ADHESION

TOWARDS PRECISION IMMUNO-ONCOLOGY: UNRAVELING THE GENOMIC DETERMINANTS AND MECHANISMS UNDERLYING IMMUNOTHERAPY EFFICACY AND RESISTANCE

NEI CENTER CORE GRANT FOR VISION RESEARCH

PATHOGENESIS OF NEUROLOGICAL DISABILITY IN PRIMARY DISEASES OF MYELIN

INSTITUTIONAL CAREER DEVELOPMENT CORE

MOLECULAR DETERMINANTS OF CORONARY ARTERY DISEASE

PREVENTION RESEARCH CENTER FOR HEALTHY NEIGHBORHOODS

IDENTIFY AND VALIDATE NOVEL EPIGENETIC MOLECULAR MARKERS FOR COLORECTAL NEOPLASM

CLEVELAND CLINIC CARDIOTHORACIC COLLABORATIVE CLINICAL CENTER (C6)

PATHWAYS OF INJURY AND REPAIR IN BARRETT'S CARCINOGENESIS - PROGRAM SUMMARY THE CENTRAL HYPOTHESIS OF THIS PROGRAM PROJECT IS THAT “ALTERED SQUAMOUS EPITHELIAL INTEGRITY (PRJ 1) AND INFLAMMATORY INJURY (PRJ 2) ACTIVATE SIGNALING PATHWAYS INCLUDING EPHB2 (PRJ 3) THAT AFFECT PRECURSOR CELLS AT THE SQUAMOCOLUMNAR JUNCTION (SCJ) TRANSITION, ESOPHAGEAL SUBMUCOSAL GLAND (ESMG), AND BASAL SQUAMOUS NICHES, RESULTING IN THE ALTERATION OF REGULATORY FACTORS THAT INCLUDE NOTCH, MYC, P63, AND SOX9, LEADING TO ACINAR DUCTAL METAPLASIA (ADM), MULTI-LAYERED EPITHELIUM (MLE), BARRETT'S ESOPHAGUS (BE), AND ULTIMATELY ESOPHAGEAL ADENOCARCINOMA (EAC).” THE SPECIFIC AIMS OF OUR PROGRAM ARE: 1) TO ELUCIDATE SIGNALING PATHWAYS BY WHICH MUTATED VSIG10L ALTERS EPITHELIAL INTEGRITY LEADING TO MLE AND BE LIKE METAPLASIA ON NOVEL MOUSE MODELS. 2) TO DEFINE THE SPATIAL AND TEMPORAL PATTERN OF CXCL8 (IL-8) IN ESMG FOLLOWING ESOPHAGEAL INJURY AND PHENOTYPE THE INFLAMMATORY INFILTRATE THAT LEADS TO THE DEVELOPMENT OF ACINAR DUCTAL METAPLASIA (ADM) IN ESMG ASSOCIATED WITH BE/EAC. 3)TO IDENTIFY MEDIATORS OF EPHB2 SIGNALING THAT LEAD TO C-MYC ACTIVATION AND METAPLASTIC CELLULAR DIFFERENTIATION AFTER INJURY IN THE DEVELOPMENT OF BE AND ITS PROGRESSION TO EAC. 4) TO DEFINE HOW ALTERED EPITHELIAL INTEGRITY, INFLAMMATORY CELLS, AND ALTERATION OF SIGNALING MOLECULES THAT CONTROL DIFFERENTIATION (EPHB2) LEAD TO METAPLASIA BY ALTERING TRANSCRIPTION FACTORS. 5) INTEGRATE PROJECTS BY PROVIDING INVESTIGATORS EFFECTIVE SUPPORT THROUGH CORE RESOURCES WITH STATE-OF-THE-ART BIOREPOSITORY, BIOINFORMATICS, AND ADMINISTRATIVE SERVICES. THESE OBJECTIVES BUILD AND SYNERGIZE ON THE CONSIDERABLE CLINICAL, BASIC SCIENCE, AND TRANSLATIONAL EXPERTISE AVAILABLE AT OUR INSTITUTIONS, 1) TO FOCUS LABORATORY RESEARCH ON UNDERSTANDING THE GENETIC SUSCEPTIBILITY AND MOLECULAR CHANGES THAT INFLUENCE THE DEVELOPMENT OF BE AND EAC; AND 2) TO THEN TRANSLATE LABORATORY DISCOVERIES INTO CLINICAL APPLICATIONS FOR EFFECTIVE DETECTION, MOLECULAR RISK STRATIFICATION, AND PREVENTION OF PROGRESSION FROM BE TO EAC.

TARGETING 15-PROSTAGLANDIN DEHYDROGENASE (15-PGDH) IN CANCER RISK, PREVENTION, AND TREATMENT

SIGNIFICANCE OF CYP46A1 AND OTHER P450S IN RETINAL FUNCTION

PSORIASIS CENTER OF RESEARCH TRANSLATION

PHOTOTRANSDUCTION IN HEALTH AND DISEASE

OPTICAL TOOLS TO ASSESS THE ROLE OF HEMODYNAMICS IN THE DEVELOPMENT OF CONGENITAL HEART DEFECTS

TRANSLATIONAL RESEARCH IN CYSTIC FIBROSIS

CIRCUIT ARCHITECTURE AND DYNAMICS REPRESENTATION IN ODOR PERCEPTION

GENOMIC AND MICROENVIRONMENTAL DETERMINANTS, TEMPORAL DYNAMICS, AND TREATMENT EFFICACY OF RADIATION-BASED COMBINATION THERAPIES - PROJECT SUMMARY OVERALL SECTION OUR ROBIN CENTER FOCUSES ON ELUCIDATING THE GENOMIC AND MICROENVIRONMENTAL DETERMINANTS, AND TEMPORAL DYNAMICS UNDERLYING EFFICACY OF RADIATION-BASED COMBINATION THERAPIES. RADIOTHERAPY (RT), ALONE OR IN COMBINATION WITH OTHER TREATMENTS, IS USED TO TREAT ABOUT TWO-THIRDS OF ALL CANCER PATIENTS. DESPITE THE WIDESPREAD USE OF RADIATION THERAPY IN ONCOLOGY, OUR UNDERSTANDING OF THE MECHANISMS DRIVING RESPONSE AND RESISTANCE REMAINS POOR. OUR LONG-TERM GOAL IS TO UNDERSTAND THE MECHANISMS THAT UNDERLIE EFFICACY AND RESISTANCE OF RADIATION-BASED THERAPIES. NEW EFFORTS TO IMPROVE TREATMENT FOR MANY CANCER TYPES NOW FOCUS ON USING COMBINATION THERAPIES IN WHICH RADIATION IS USED WITH SYSTEMIC AGENTS, HIGHLIGHTING THE URGENT NEED TO UNDERSTAND THE DRIVERS OF EFFICACY. AMONG THE MOST PROMISING NEW BIOLOGICS BEING STUDIED FOR USE WITH RADIATION ARE ANTIBODY-DRUG CONJUGATES (ADC) AND IMMUNE CHECKPOINT INHIBITORS (ICI). WE WILL USE AN INNOVATIVE MOLECULAR CHARACTERIZATION TRIAL TESTING RADIATION PLUS ADC IN BLADDER CANCER AND RADIATION PLUS ICI IN HEAD AND NECK CANCER TO CHARACTERIZE THE MECHANISTIC DRIVERS UNDERLYING THESE NEXT GENERATION RT-BASED COMBINATIONS. THE CENTRAL HYPOTHESIS OF THIS U54 APPLICATION IS THAT SPECIFIC GENETIC AND IMMUNOLOGIC MECHANISMS UNDERLIE SENSITIVITY AND RESISTANCE TO RADIATION-BASED COMBINATION THERAPIES. WE WILL ADDRESS THESE QUESTIONS THROUGH 3 SPECIFIC AIMS. IN AIM 1, WE WILL WORK TO UNDERSTAND THE MOLECULAR MECHANISMS THAT UNDERLIE EFFICACY OF TREATMENT WITH RADIATION PLUS ADC. HERE, OUR WORKING HYPOTHESIS IS THAT SPECIFIC GENETIC AND IMMUNOLOGIC EVENTS UNDERLIE RESPONSE TO RT PLUS SACITUZUMAB GOVITECAN (SG) TREATMENT. WE WILL LEVERAGE OUR MOLECULAR CHARACTERIZATION TRIAL (PART A) INVESTIGATING THE USE OF RT AND SACITUZUMAB FOR BLADDER PRESERVATION THERAPY. WE WILL DETERMINE THE DIFFERENTIAL MOLECULAR EFFECTS WITH STANDARD-OF-CARE RT + CISPLATIN VERSUS RT + SG. IN AIM 2, WE WILL IMPROVE IDENTIFICATION OF PATIENTS WHO ARE SENSITIVE OR RESISTANT TO RT-BASED THERAPIES BASED ON NEW INSIGHTS INTO TRANSCRIPTIONAL DYNAMICS AND TEMPORAL REPROGRAMMING DURING TREATMENT WITH RADIATION-BASED THERAPIES. HERE, WE WILL LEVERAGE OUR MOLECULAR CHARACTERIZATION TRIAL TREATING HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC) OR BLADDER CANCER PATIENTS WITH RT + CHEMOTHERAPY VERSUS RT + SG OR ICI. WE WILL BUILD ON RECENT EXPERIMENTAL AND CLINICAL BREAKTHROUGHS LED BY OUR RESEARCH GROUPS, WHICH HAVE IDENTIFIED HIGHLY REFINED GENE EXPRESSION PROGRAMS ASSOCIATED WITH RT SENSITIVITY AND DELTA RADIOMICS. IN AIM 3, WE WILL IDENTIFY THE DIFFERENTIAL MECHANISMS UNDERLYING THE ANTI-TUMOR ACTIVITIES OF RT + CISPLATIN VERSUS RT + IMMUNE CHECKPOINT BLOCKADE. HERE, USING OUR HEAD AND NECK TRIAL (PART B), WE WILL UNCOVER THE UNIQUE GENETIC AND IMMUNOLOGIC FACTORS THAT GOVERN RESPONSE TO RT WHEN COMBINED WITH THESE TWO CLASSES OF AGENTS. WE WILL ELUCIDATE THE DIFFERENTIAL MOLECULAR EFFECTS OF THE TWO APPROACHES, IMMUNE REPROGRAMMING, AND MECHANISMS OF ACQUIRED RESISTANCE. OUR STUDIES WILL HELP BUILD A FOUNDATION TO OPTIMIZE MULTIMODAL, RADIATION- BASED DEFINITIVE TREATMENT STRATEGIES.

MULTIDRUG RESISTANT ACINETOBACTER BAUMANNII,

A FAMILIAL STUDY OF SEVERE PHONOLOGY DISORDERS

MOLECULAR BASIS OF KSHV ONCOGENESIS

MECHANISMS OF TUBULAR ATROPHY IN RENAL DISEASE

AN INTEGRATED COMPUTATIONAL AND EXPERIMENTAL APPROACH TOWARD THE DESIGN OF MATERIALS FOR FUEL CELLS SYSTEMS

FUNCTIONAL GENOMICS OF ATRIAL FIBRILLATION IN HUMAN ATRIA

CWRU CASE COMPREHENSIVE CANCER CENTER NCTN LEAD ACADEMIC PARTICIPATING SITE

BEAR-MOON: A TWO ARM NONINFERIORITY BLINDED RANDOMIZED CLINICAL TRIAL COMPARING ACL REPAIR WITH BEAR DEVICE VS. STANDARD OF CARE AUTOGRAFT PATELLAR TENDON ACL RECONSTRUCTION

RANDOMIZED TRIAL OF ASSISTED AMBULATION TO IMPROVE HEALTH OUTCOMES FOR OLDER MEDICAL INPATIENTS - PROJECT SUMMARY/ABSTRACT FOR OLDER ADULTS, PROLONGED HOSPITALIZATION CAN LEAD TO A DEVASTATING LOSS OF MOBILITY AND INDEPENDENCE. EACH YEAR, 12 MILLION ADULTS OVER THE AGE OF 65 ARE HOSPITALIZED, AND 30% ARE DISCHARGED TO A POST-ACUTE CARE FACILITY. ONE OF THE RISKS OF HOSPITALIZATION IS BED REST, WHICH IS ASSOCIATED WITH A NUMBER OF HOSPITAL-ACQUIRED COMPLICATIONS, INCLUDING FALLS, DELIRIUM, VENOUS THROMBOSIS AND SKIN BREAKDOWN. HOSPITAL MOBILITY PROGRAMS ATTEMPT TO AMBULATE PATIENTS UP TO THREE TIMES DAILY, BUT THIS WORK IS GENERALLY ASSIGNED TO NURSES, WHO HAVE MANY COMPETING AND OFTEN MORE PRESSING TASKS. CONSEQUENTLY, AMBULATING PATIENTS IS THE MOST FREQUENTLY OVERLOOKED NURSING DUTY. THIS PROBLEM HAS BEEN EXACERBATED BY THE COVID-19 PANDEMIC AND THE RESULTING NURSING SHORTAGE. SMALL STUDIES HAVE EXAMINED THE BENEFITS OF MOBILITY TECHNICIANS (MTS), WHOSE SOLE JOB IS TO SAFELY AMBULATE PATIENTS. THESE STUDIES HAVE DEMONSTRATED THAT MTS CAN INCREASE STEPS TAKEN, BUT THEY ARE TOO SMALL TO PROVE THE IMPACT OF MTS ON OTHER OUTCOMES, SUCH AS WHETHER PATIENTS HAVE IN-HOSPITAL COMPLICATIONS OR WHETHER THEY CAN GO HOME INSTEAD OF TO A POST-ACUTE CARE FACILITY. HOSPITALS ARE HESITANT TO ADOPT MT PROGRAMS BECAUSE THEY PERCEIVE THEM TO BE EXPENSIVE AND UNPROVEN. WE PROPOSE TO CONDUCT A LARGE RANDOMIZED TRIAL TO TEST THE IMPACT OF MTS ON SHORT AND INTERMEDIATE TERM OUTCOMES FOR 3000 PATIENTS AGED 65 YEARS AND OLDER AT 5 HOSPITALS IN 2 HEALTH SYSTEMS. PATIENTS WILL BE RANDOMIZED TO RECEIVE SUPERVISED AMBULATION UP TO 3 TIMES DAILY WITH A MT OR TO RECEIVE USUAL CARE. ALL PARTICIPANTS WILL WEAR AN ACCELEROMETER ON THEIR WRIST TO TRACK THEIR MOVEMENT THROUGHOUT THE HOSPITAL STAY. THE STUDY HAS 3 AIMS. FIRST, WE WILL COMPARE THE MOBILITY OF PATIENTS AT DISCHARGE (OR 10 DAYS) TO ASSESS THE IMPACT OF THE MTS ON THIS OUTCOME. WE ARE PARTICULARLY INTERESTED IN WHETHER THE USE OF MTS WILL INCREASE THE PROPORTION OF PATIENTS WHO CAN GO HOME VS. POST-ACUTE CARE, AND WHETHER THE IMPROVEMENTS IN MOBILITY ARE SUSTAINED AT 30 DAYS. SECOND, WE WILL USE PREDICTIVE MODELING TO IDENTIFY WHICH PATIENTS ARE MOST LIKELY TO BENEFIT FROM THIS INTERVENTION. THIRD, WE WILL ASSESS THE IMPACT OF THE INTERVENTION ON OVERALL COSTS ASSOCIATED WITH THE EPISODE OF CARE, INCLUDING INPATIENT COSTS AND THE 30 DAYS AFTER DISCHARGE. THIS INFORMATION WILL BE IMPORTANT TO CONVINCE HEALTH SYSTEMS TO ADOPT THIS APPROACH.

TISSUE ENGINEERED CARTILAGE REPAIR

ENSURING PATIENTS' INFORMED ACCESS TO NONINVASIVE PRENATAL TESTING

FUNCTION OF THE PET-1 ETS FACTOR IN THE MAMMALIAN 5-HT SYSTEM

ACTIVATION OF BLOOD AND ENDOTHELIAL CELL A5B3 INTEGRIN

LOCAL CIRCUITS IN THE OLFACTORY BULB

BASIC AND COMPARATIVE STUDIES OF CCR5 INHIBITION TO PREVENT HIV TRANSMISSION

EFFECTS OF IL-6 BLOCKADE IN TREATED HIV INFECTION

DEFINING THE VIRAL PTMOME: TOWARDS THE DEVELOPMENT OF NOVEL ANTIVIRAL APPROACHES - PROJECT SUMMARY OVER THE PAST SEVERAL DECADES, THE TRADITIONAL APPROACH TO COMBATING VIRAL INFECTIOUS DISEASES HAS BEEN TO TARGET THE VIRUS ITSELF, IN MOST CASES BY EITHER BLOCKING VIRUS-ENCODED ENZYMES THAT ARE REQUIRED FOR VIRAL REPLICATION, OR BY PREVENTING THE VIRUS FROM ENTERING HOST CELLS. ONE OF THE MAJOR CAVEATS OF THESE APPROACHES HAS BEEN THE ABILITY OF THE VIRUS TO READILY MUTATE AND THEREBY BECOME RESISTANT TO THESE CLASSICAL TYPES OF ANTIVIRAL THERAPIES. IN FACT, THIS IS A SERIOUS PROBLEM FOR THE THERAPY OF RNA VIRUS INFECTIONS, SUCH AS HIV OR INFLUENZA VIRUS, WHICH ARE KNOWN TO RAPIDLY MUTATE AND THEREBY ESCAPE ANTIVIRAL DRUGS. ADDITIONALLY, TRADITIONAL ANTIVIRAL APPROACHES ARE DESIGNED TO TARGET A SPECIFIC VIRUS, AND THEREFORE ARE INEFFECTIVE AGAINST ANY NEW VIRUS THAT MAY EMERGE IN THE FUTURE, AND IT IS IMPOSSIBLE TO PREDICT WHAT VIRUS WILL CAUSE THE NEXT OUTBREAK OR PANDEMIC. THEREFORE, THERE IS THE URGENT NEED TO DEVELOP NEW WAYS FOR TARGETING VIRAL PATHOGENS, WHICH WILL REQUIRE CREATIVE AND INNOVATIVE RESEARCH. LIKE HUMAN PROTEINS, VIRAL PROTEINS ROBUSTLY UNDERGO POSTTRANSLATIONAL MODIFICATIONS (PTMS) FOR THEIR REGULATION AND PROPER FUNCTIONING IN THE VIRUS LIFE CYCLE. IN MOST CASES, VIRAL PTMS ARE DYNAMICALLY REGULATED BY HUMAN ENZYMES, SUCH AS KINASES/PHOSPHATASES, UBIQUITIN E3 LIGASES/DEUBIQUITINATING ENZYMES, OR ACETYL TRANSFERASES/DEACETYLASES. THUS, CELLULAR ENZYMES PLAY AN IMPORTANT ROLE IN CONTROLLING THE ABILITY OF THE VIRUS TO REPLICATE AND TO CAUSE DISEASE. THIS PROPOSAL’S OVERARCHING GOAL IS TO COMPREHENSIVELY MAP THE ‘VIRAL PTMOME’ TO IDENTIFY THE PTMS THAT ARE ESSENTIAL FOR VIRUS REPLICATION AND PATHOGENESIS. WE WILL COMBINE PROTEOMICS SCREENS AND MOLECULAR VIROLOGY APPROACHES INCLUDING REVERSE GENETICS TECHNIQUES WITH CUTTING- EDGE MOLECULAR, BIOCHEMICAL AND BIOPHYSICAL STUDIES. THIS WILL ALLOW US TO IDENTIFY AND CHARACTERIZE VIRAL PTMS AND THE RESPONSIBLE HOST MODIFYING ENZYMES, AS WELL AS TO DETERMINE THEIR ROLES FOR EFFECTIVE VIRAL REPLICATION AND PATHOGENESIS. THIS POWERFUL APPROACH, COMBINED WITH COLLABORATIVE STUDIES TO DESIGN AND TEST CHEMICAL INHIBITORS TO BLOCK THE ENZYMES THAT REGULATE CRITICAL VIRAL PTMS, WILL NOT ONLY PROVIDE UNIQUE MECHANISTIC INSIGHT INTO HOST CONTROL OF VIRUS REPLICATION BUT WILL ALSO LAY THE GROUNDWORK FOR DEVELOPING NEW ANTIVIRALS FOR A RANGE OF EMERGING VIRAL INFECTIOUS DISEASES.

NERVE RESHAPING FOR IMPROVED ELECTRODE SELECTIVITY

EFFECT OF CORNEAL PRESERVATION TIME ON LONG-TERM GRAFT SUCCESS (CPTS)

UNDERSTANDING NEURAL CONTROL OF THE OCULAR SURFACE - PROJECT SUMMARY CURRENTLY OUR UNDERSTANDING OF HOW THE NERVOUS SYSTEM MAINTAINS OCULAR SURFACE HOMEOSTASIS IS EXTREMELY LIMITED. NEW TECHNOLOGIES, METHODS AND MODELS ARE NEEDED TO ADVANCE OUR SCIENTIFIC UNDERSTANDING AND ADDRESS KNOWLEDGE GAPS. THE OCULAR SURFACE AND TEAR FILM-SECRETING GLANDS (INCLUDING THE LACRIMAL AND MEIBOMIAN GLANDS, AS WELL AS THE GOBLET CELLS) ARE CAREFULLY CONTROLLED TO PROVIDE AN OPTICALLY SMOOTH, LOW-SCATTERING SURFACE WITH APPROPRIATE IMMUNE AND INJURY RESPONSES. SENSORY FEEDBACK TO MAINTAIN THE STRUCTURAL AND FUNCTIONAL INTEGRITY OF THE OCULAR SURFACE IS PROVIDED BY THE CORNEAL NERVES, WHICH SEND FEEDBACK FROM STIMULI (CHEMICAL, THERMAL, MECHANICAL) TO GANGLIA (E.G., TRIGEMINAL) AND BRAIN REGIONS (E.G., VENTRAL POSTEROMEDIAL THALAMUS) TO DRIVE PRODUCTION OF TEAR FILM COMPONENTS AS WELL AS THE BLINK REFLEX. THIS DELICATE BALANCE OF NEURAL CONTROL IS DISRUPTED BY DAMAGE, PERIPHERAL NEUROPATHIES, INFLAMMATION AND FURTHER COMPLICATED BY A WIDE ARRAY OF IMMUNE RESPONSES TO VARIOUS DISEASES. DYSFUNCTION OF THIS FEEDBACK LOOP CAN LEAD TO A DOWNWARD SPIRAL OF FURTHER DYSREGULATION. ABERRANT NEURAL CONTROL OF THE OCULAR SURFACE CAN LEAD TO ABNORMAL SENSATION AND PAIN, WHICH IN THE WORST CASES CAN BE DISABLING. TO FIND REMEDIES, IT IS FIRST ESSENTIAL TO UNDERSTAND THE UNDERLYING NEURAL CONTROL SYSTEM AND HOW IT ADAPTS TO ITS ENVIRONMENT. IN THIS PROPOSAL, WE AIM TO BRING NEW TOOLS AND MODELS TO STUDY MOLECULAR, CELLULAR, AND FUNCTIONAL INTERACTIONS ACROSS SYSTEMS RESPONSIBLE FOR NEURAL CONTROL OF THE OCULAR SURFACE AND EXAMINE HOW THEY CHANGE UNDER DIFFERENT INFLAMMATORY AND PAIN CONDITIONS. WE HAVE ASSEMBLED AN EXCELLENT TEAM WITH EXPERTISE ACROSS MULTIPLE FIELDS INCLUDING ADVANCED 3D MICROSCOPY, NEUROSCIENCE, ELECTROPHYSIOLOGY, PAIN, OCULAR IMMUNOLOGY, OCULAR LIPID METABOLISM, OCULAR SURFACE DISORDERS, SPATIAL STATISTICS, AND MACHINE/DEEP LEARNING. HERE, WE WILL UTILIZE CUTTING EDGE TECHNIQUES AND TECHNOLOGIES INCLUDING OPTICAL CLEARING, TRACT TRACING, ETHOLOGICALLY-VALID BEHAVIOR ANALYSIS, MACHINE/DEEP LEARNING, SPATIAL STATISTICS, GENETICALLY ENCODED CALCIUM IMAGING, LIGHT-SHEET MICROSCOPY, MULTIPLEXED 3D FLUORESCENCE IN SITU HYBRIDIZATION (FISH) IMAGING, AND MULTI-ARRAY ELECTRODES IMPLANTED IN THE BRAIN. THESE TOOLS WILL HELP US ASSESS MOLECULAR, CELLULAR, AND FUNCTIONAL INTERACTIONS ACROSS ORGANS AND BEGIN TO UNDERSTAND OCULAR SURFACE CONTROL AT THE ORGANISM LEVEL. WE WILL ALSO EMPLOY SEVERAL RELEVANT ANIMAL MODELS TO ASSESS OCULAR SURFACE CONTROL UNDER DIFFERENT INFLAMMATORY AND PAIN CONDITIONS. MODELS INCLUDE AWAT2 DEFICIENT MICE THAT MIMIC EVAPORATIVE DRY EYE DISEASE (DED), DIABETIC MICE, AN EPITHELIAL DEBRIDEMENT MODEL WITH PSEUDOMONAS AERUGINOSA THAT MIMICS BACTERIAL KERATITIS, AND HUMAN DONOR EYES. THE MOUSE MODELS ALL HAVE GCAMP6F EXPRESSED IN CORNEAL NERVES ALLOWING FUNCTIONAL IMAGING OF CALCIUM TRANSIENTS. WITH THESE MODELS WE WILL STUDY BOTH INNATE AND ADAPTIVE IMMUNITY AS WELL AS NOCICEPTIVE AND NEUROPATHIC PAIN RESPONSES. IN ADDITION, WE WILL APPLY NERVE GROWTH FACTOR (NGF) TO OUR MODELS TO STUDY HOW A POTENTIAL TREATMENT OPTION ALTERS THE OCULAR SURFACE CONTROL SYSTEM.

ACTIVATION OF THE BETA-3 INTEGRINS: ROLE OF THE KINDLINS

MULTI-LEVEL INTERVENTIONS TO REDUCE CARIES DISPARITIES IN PRIMARY CARE SETTINGS

NOVEL THERAPIES FOR ALCOHOLIC HEPATITIS

DATA COORDINATING CENTER FOR PILOT STUDIES OF CANDIDATE THERAPIES FOR CKD

DEVELOPMENT OF NETWORKED IMPLANTABLE NEUROPROSTHESES

AUTOMATIC CONTROL OF STANDING BALANCE WITH FNS

MODULATING GLIAL FATE AND FUNCTION IN DEVELOPMENT AND DISEASE

THERAPEUTIC IMPLICATIONS OF MOLECULAR DEFECTS IN BONE MARROW FAILURE

NIAMS: CORT (PSORIASIS CENTER OF RESEARCH TRANSLATION)

DEVELOPING A ONE-TUBE CIRCULARIZED LIGATION PRODUCT SEQUENCING (CLP-SEQ) METHOD FOR THE MAPPING OF 3D GENOME ARCHITECTURE IN SMALL CELL POPULATIONS OR SINGLE CELLS.

ER-TO-GOLGI TRANSPORT OF COAGULATION FACTORS V AND VIII

INTERDISCIPLINARY BIOMEDICAL IMAGING TRAINING PROGRAM

LRP4 SIGNALING IN NEUROMUSCULAR JUNCTION FORMATION

MEDICAL SCIENTIST TRAINING PROGRAM AT CASE WESTERN RESERVE UNIVERSITY - OUR SCHOOL OF MEDICINE LAUNCHED THE FIRST MD-PHD TRAINING PROGRAM IN 1956, AND THE PROGRAM HAS A LONG HISTORY OF INNOVATION AND SUCCESS WITH MANY PROMINENT ALUMNI, INCLUDING TWO NOBEL LAUREATES. OUR MISSION IS TO DEVELOP MD-PHD TRAINING TO TRAIN A DIVERSE POOL OF PHYSICIAN-SCIENTIST LEADERS TO MEET FUTURE BIOMEDICAL RESEARCH WORKFORCE NEEDS FOR RESEARCH LEADERS TO ACCELERATE RESEARCH TO ADVANCE THE UNDERSTANDING, DETECTION, TREATMENT AND PREVENTION OF HUMAN DISEASE. OBJECTIVES INCLUDE DEVELOPMENT OF PHYSICIAN-SCIENTISTS WITH DEEP EXPERTISE IN ONE OR MORE BIOMEDICAL SCIENTIFIC DISCIPLINES COUPLED WITH A BROAD UNDERSTANDING ACROSS BIOMEDICAL DISCIPLINES; SKILLS TO INDEPENDENTLY DESIGN AND DEVELOP RESEARCH PROGRAMS; ABILITY TO USE CLINICAL INSIGHTS TO INFORM RESEARCH; AND COMMITMENT TO SCIENTIFIC INTEGRITY AND DEI GOALS. PROGRAM GOALS INCLUDE MD- PHD COMPLETION WITH AN EFFICIENT TIME TO DEGREE (TTD), PUBLICATION AND GRANTS ATTAINMENT PRODUCTIVITY, POST- GRADUATION PLACEMENT IN TRAINING PROGRAMS RELATED TO PHYSICIAN-SCIENTIST CAREER DEVELOPMENT, AND LONG-TERM ATTAINMENT OF PRODUCTIVE RESEARCH CAREERS. OUR AIMS INCLUDE DEVELOPMENT OF AN MD-PHD CURRICULUM THAT INTEGRATES RESEARCH AND CLINICAL TRAINING WITH DEEP RESEARCH EXPERIENCES FROM THE BEGINNING OF THE PROGRAM TO PROMOTE RETENTION OF TRAINEES IN THE RESEARCH MISSION AND FOSTER CURRICULAR EFFICIENCY. WE WILL DEVELOP REQUIRED AND ELECTIVE MSTP ACTIVITIES THAT PROMOTE THE PROGRAM OBJECTIVES, INCLUDING DIDACTIC, RESEARCH, MENTORING AND CAREER DEVELOPMENT ELEMENTS (RCR, RRR, GRANTSMANSHIP, RESEARCH COMMUNICATION AND OTHERS) AND PROGRAM ACTIVITIES (MSTP RETREAT, MSTP DINNER SEMINARS, MSTP VISITING PHYSICIAN-SCIENTIST CAREER SESSIONS). WE WILL WORK WITH OUR RESEARCH TRAINING COMMUNITY TO IMPROVE PHD PROGRAMS AND TRAINING OF RESEARCH MENTORS IN BEST PRACTICES. OUR APPROACH INCLUDES INTEGRATION OF RESEARCH AND CLINICAL TRAINING WITHIN EACH OF THE THREE BASIC PHASES: FIRST TWO YEARS (M1-M2), PHD PHASE (E.G. G1-4), AND LAST TWO YEARS (M3-M4). THE CURRICULUM HAS FLEXIBILITY TO MEET THE DIFFERING INTERESTS AND NEEDS OF INDIVIDUAL STUDENTS. A KEY STRATEGY IS EARLY AND DEEP ENGAGEMENT WITH RESEARCH TO PROMOTE RESEARCH CAREER DEVELOPMENT AND RETENTION - IN M1-M2, STUDENTS COMPLETE A RESEARCH ROTATION OR GRADUATE COURSE IN EVERY SEMESTER IN COMBINATION WITH THE MD CURRICULUM. ALMOST ALL STUDENTS MATCH INTO THEIR PHD LAB BY FALL OF M2, ALLOWING EARLY LAUNCH OF PHD RESEARCH IN M2. THIS IS A KEY DISTINCTION FOR THE CWRU MSTP AND PROVIDES UNIQUE CURRICULAR OPPORTUNITIES. WE WILL ESTABLISH A CULTURE OF SUPPORT FOR STUDENTS AND ENGAGEMENT OF STUDENT LEADERSHIP IN MSTP COUNCIL TO SHAPE THE PROGRAM TO SUPPORT STUDENT PROFESSIONAL DEVELOPMENT AND WELLNESS. WE WILL CONTINUE TO ADMIT 14-15 STUDENTS PER YEAR. THE INTEGRATED RESEARCH AND CLINICAL CURRICULUM, PROGRAM ACTIVITIES, DEI FOCUS AND ACTIVITIES, AND SUPPORT FOR STUDENTS WILL PRODUCE A HIGHLY SKILLED AND DIVERSE PHYSICIAN-SCIENTIST WORKFORCE, WHICH WILL CONTRIBUTE TO NATIONAL GOALS FOR BASIC, TRANSLATIONAL AND CLINICAL RESEARCH IN ACADEMIA, GOVERNMENT AND INDUSTRY.

REGULATORY MECHANISMS OF GLYCOPROTEIN SIALYLATION

REGENERATIVE AND DEGENERATIVE RESPONSES TO AXONAL INJURY

RESTORATION AND FUNCTION OF S-NITROSOTHIOL IN STORED BLOOD

PHOTOTRANSDUCTION ENZYMES

(CIRCADIAN) CIRCADIAN DISRUPTION AS MEDIATOR OF CARDIOMETABOLIC RISK IN AIR POLLUTION - ABSTRACT PARTICULATE MATTER AIR POLLUTION <2.5ΜM (PM2.5) IS THE LEADING ENVIRONMENTAL RISK FACTOR GLOBALLY, CONTRIBUTING MORE TO GLOBAL MORTALITY THAN AIDS, MALARIA, TUBERCULOSIS AND WARS/FAMINES COMBINED. THE HEALTH RISKS ASSOCIATED WITH PM2.5 ARE PREDOMINANTLY FROM CARDIOVASCULAR (CV) CAUSES, WITH DATA SUPPORTING A MAJOR PUBLIC HEALTH IMPACT DUE TO DISORDERS SUCH AS TYPE 2 DIABETES. BUILDING ON THE SUBSTANTIAL SUCCESSES OF OUR RESEARCH PROGRAM, THAT IN LARGE PART HAVE PROVIDED THE FOUNDATIONAL BASIS FOR OUR UNDERSTANDING OF MECHANISMS OF PM2.5-INDUCED CARDIOMETABOLIC DISORDERS, WE PROPOSE AN INNOVATIVE FRAMEWORK OF TRANSLATIONAL INVESTIGATIONS. OUR NEW DATA PROVIDE COMPELLING LINKS BETWEEN PM2.5 EXPOSURE AND CIRCADIAN RHYTHM (CR) DISRUPTION THROUGH EPIGENETIC REPROGRAMMING, RESULTING IN METABOLIC DYSFUNCTION AND INSULIN RESISTANCE. IN ACCORDANCE WITH THE NIEHS TRANSLATIONAL RESEARCH FRAMEWORK, WE PROPOSE AN AMBITIOUS PLAN ENCOMPASSING 3 GOALS OVER 8 YEARS THAT WILL ENCOMPASS HARMONIZED STUDIES INVOLVING CONCENTRATED AMBIENT PM2.5 EXPOSURES (ANIMAL) AND HUMAN INTERVENTION TRIALS ACROSS THE AMBIENT EXPOSURE SPECTRUM, PREDICATED AND SUPPORTED BY RESULTS FROM GENOME WIDE ASSOCIATION AND MENDELIAN RANDOMIZATION APPROACHES, THAT WILL IDENTIFY PATHWAYS OF AIR POLLUTION MEDIATED CV RISK. LEVERAGING ON-GOING TRANSLATIONAL CLINICAL TRIALS OF AIR POLLUTION REDUCTION USING PERSONALIZED STRATEGIES IN VULNERABLE POPULATIONS IN BEIJING, AND THROUGH ONE NEW STUDY INVOLVING MITIGATION OF AIR POLLUTION (ITS-MY-AIR), WE WILL EVALUATE THE IMPACT OF EXPOSURE REDUCTION ON CR DISRUPTION/SLEEP AND METABOLIC ENDPOINTS. COLLECTIVELY, RESULTS FROM THIS PROJECT WILL HELP SHED IMPORTANT NEW LIGHT ON AIR POLLUTION, ITS IMPACT ON CR AND CARDIOMETABOLIC DISORDERS AND PROVIDE INFLUENTIAL DATA ON PROTECTIVE EFFECTS OF PERSONAL INTERVENTION STRATEGIES, THAT TOGETHER COULD CHANGE PUBLIC HEALTH POLICY.

LUNG CANCER IN EAST AFRICA AND THE RELATIONSHIP TO HIV-1 INFECTION: EPIDEMIOLOGY, MOLECULAR CHARACTERIZATION AND IMAGING

CASE POSTBACCALAUREATE RESEARCH EDUCATION PROGRAM (PREP)

AUTOPHAGY AND OCULAR TOXOPLASMOSIS

DEEP CEREBELLAR ELECTRICAL STIMULATION FOR POST-STROKE MOTOR RECOVERY

CILIA ASSEMBLY AND TRANSPORT IN THE VERTEBRATE RETINA

ASSESSING NOVEL BIOMARKERS FOR COGNITIVE FLUCTUATIONS IN DLB - AGE-RELATED DISEASES, SUCH AS ALZHEIMER DISEASE (AD) AND DEMENTIA WITH LEWY BODIES (DLB), ARE DEFINING PUBLIC HEALTH CONCERNS OF THE 21ST CENTURY AND ARE THE LEADING CAUSE OF DISABILITY WORLDWIDE. NOVEL DISEASE MODIFYING THERAPIES HAVE OPENED A NEW HORIZON FOR MANAGING THESE PROGRESSIVE DISEASES. HOWEVER CLINICAL TRIALS ASSESSING THESE THERAPEUTIC MEDICATIONS ARE BEDEVILED BY SMALL EFFECT SIZES AND SUBSTANTIAL INTERSUBJECT VARIABILITY THAT CHALLENGES EVALUATION OF THEIR EFFECTIVENESS. TO MEET THIS CHALLENGE, ADDITIONAL FACTORS MEDIATING VARIABILITY IN COGNITIVE PERFORMANCE ARE A KEY KNOWLEDGE GAP TO OVERCOME. COGNITIVE FLUCTUATIONS (CFS) ARE INTERMITTENT EPISODES OF DECREASED ALERTNESS, ATTENTION, AND RESPONSIVENESS THAT OCCUR IN SOME PATIENTS WITH DEMENTIA. THE UNPREDICTABLE NATURE OF THESE EVENTS POSES A MAJOR BURDEN FOR PATIENTS AND CAREGIVERS, AS WELL AS COMPLICATING THE MEASUREMENT OF TREATMENT EFFICACY IN CLINICAL TRIALS, PARTICULARLY WHEN THE TREATMENT IS INTENDED TO IMPROVE COGNITION. UNFORTUNATELY, METHODS TO TRACK CFS EFFECTIVELY AND THE PATHOPHYSIOLOGY OF THIS CONDITION ARE POORLY UNDERSTOOD. IN THIS PROPOSAL, WE AIM TO VALIDATE NOVEL BIOMARKERS THAT CAPTURES THE MOST RELEVANT FEATURES OF COGNITIVE FLUCTUATIONS IN AD AND DLB. TOWARDS THIS GOAL, WE WILL PROVIDE A MULTIMODAL CHARACTERIZATION OF THE FREQUENCY AND SEVERITY OF CFS AND THEIR LONGITUDINAL VARIABILITY AT ANNUAL VISITS. THE DEMENTIA WITH LEWY BODY CONSORTIUM (DLBC) COHORT PRESENTS A GOLD STANDARD COHORT FOR DLB BIOMARKER DIAGNOSIS (CSF Α-SYNUCLEIN, AGGREGATION ASSAY), WHILE THE ALZHEIMER’S DISEASE RESEARCH CENTERS (ADRC) PRESENTS COHORTS FOR AD DIAGNOSIS (CSF A-BETA42,40, T-TAU, AND P-TAU181) ALONG WITH AUTOPSY CONFIRMATION. IN THESE COHORTS, WE WILL OBTAIN BOTH CLINICAL (FLUCTUATION SCALES, COGNITIVE VARIABILITY) AND MULTIPLE OBJECTIVE DIGITAL BIOMARKERS (ACTIGRAPHY, EEG, SLEEP, RESTING STATE FUNCTIONAL MRI) TO EVALUATE THE FREQUENCY AND SEVERITY OF CFS AT BASELINE AND LONGITUDINAL VARIABILITY ANNUALLY OVER FOUR YEARS. THIS PROJECT WILL ENABLE US TO HELP DEVELOP APPROPRIATE BIOMARKERS THAT CAPTURE THE MOST RELEVANT FEATURES THAT CAN BE SCALED TO TRACK CFS EFFECTIVELY IN LARGE CLINICAL TRIALS. FURTHER, THIS PROJECT WILL HELP US DEVELOP A MODEL OF THE UNDERLYING NEURAL FEATURES OF CFS TO ENABLE FUTURE TARGETED THERAPIES.

TRANSLATIONAL CONTROL BY NUTRIENTS

(EPI)GENETIC RISK ARCHITECTURES IN OPIOID DEPENDENT BRAIN

SALT-SENSITIVE HYPERTENSION: ROLE OF RENAL SUPEROXIDE

ADVANCING GENETICS THROUGH THE AMDGENE CONSORTIUM

SKIN DISEASES RESEARCH CENTER

EARLY INTERVENTION TO REDUCE ALCOHOL MISUSE AND ABUSE IN THE OHIO ARMY NATIONAL GUARD

THE CYCLICAL LOWER-EXTREMITY EXERCISE FOR PARKINSON'S TRIAL

CAROTINOIDS IN VISION

FUNCTIONAL CARDIO-METABOLOMICS

INTEGRATED ENGINEERING AND REHABILITATION TRAINING

NOVEL APPROACHES TO IMPROVE PREDICTION OF CANCER-ASSOCIATED THROMBOSIS

TRANSLATIONAL CONTROL BY OSMOTICALLY ACTIVE SOLUTES

NON-INFERIORITY STUDY OF ADJUVANTED VS. HIGH DOSE FLU VACCINE IN RESIDENTS OF LONG TERM CARE

STRUCTURE AND FUNCTION OF PENTAMERIC LIGAND-GATED ION CHANNELS

CORNEAL EPITHELIAL GROWTH FACTORS AND RECEPTORS

CYTOKINES AND INFLAMMATORY BOWEL DISEASE

IDENTIFYING INBORN GENETIC SUSCEPTIBILITY TO DEVELOPMENT OF CANCER METASTASIS

CLEVELAND ALZHEIMER'S DISEASE RESEARCH CENTER

CASE CENTER FOR TRANSDISCIPLINARY RESEARCH ON ENERGETIC*

IMAGING POST-TRAUMATIC OSTEOARTHRITIS 10-YEARS AFTER ACL RECONSTRUCTION: A MULTICENTER COHORT STUDY WITH QUANTITATIVE MRI

ANTIVIRAL ACTIONS OF INTERFERONS

DESIGNING INDUCTION THERAPIES TO TARGET MEMORY T CELLS IN HIGH RISK RECIPIENTS

THE ROLE OF PROTEASE ACTIVATED RECEPTORS ON PLATELETS.

CENTER FOR GENETIC RESEARCH, ETHICS, AND LAW

IMPROVED CARDIAC AND VASCULAR MAGNETIC RESONANCE IMAGING USING A COMBINATION OF P

NITRIC OXIDE PRODUCTION AND REACTIONS IN THE LUNG

TRAINING IN COMPUTATIONAL GENOMIC EPIDEMIOLOGY OF CANCER

REPRODUCIBILITY IN SIMULATION-BASED PREDICTION OF NATURAL KNEE MECHANICS

NURSE FACULTY LOAN PROGRAM

TAS::57 3600::TAS "(MURI 11) NANOFABRICATION OF TUNABLE 3D NANOTUBE ARCHITECTURES"

TRAINING PROGRAM IN MUSCULOSKELETAL RESEARCH

MOLECULAR BASIS OF DROSOPHILA HOMEOTIC GENE REGULATION

MULTI-OMIC BIOMARKERS FOR NEUROPATHIC PAIN SECONDARY TO CHEMOTHERAPY

STRUCTURAL DETERMINANTS OF AMYLOID STRAIN HETEROGENEITY IN DISTINCT PHENOTYPES OF ALZHEIMER'S DISEASE

ENHANCING WALKING AND INDEPENDENCE AFTER INCOMPLETE SCI WITH A FULLY IMPLANTED NEUROPROSTHESIS

GRADUATE TRAINING IN CELL AND MOLECULAR BIOLOGY

ELUCIDATING THE MOLECULAR MECHANISMS THAT SHAPE THE HAIR BUNDLE

COMPUTER MODELING OF MYOSIN BINDING PROTEIN C AND ITS EFFECTS ON CARDIAC CONTRACTION

NEUREGULIN-1 REGULATION OF NEUROTRANSMISSION

A MECHANISM-BASED APPROACH TO METALLO-BETA-LACTAMASE INHIBITION

THE ROLE OF THE PROXIMAL NEPHRON IN SALT-SENSITIVE HYPERTENSION

FUNCTIONAL CONSEQUENCES OF FHC MUTATIONS IN CARDIAC MYBPC

CHOLESTEROL METABOLIZING P450S: STRUCTURE AND FUNCTION

1/2 POMALIDOMIDE FOR BLEEDING IN PATIENTS WITH HEREDITARY HEMORRHAGIC TELANGIECTASIA (HHT)

EARLY CLINICAL TRIALS OF NEW ANTI-CANCER AGENTS WITH PHASE I EMPHASIS

THE IMPACT OF INTRAVENOUS HEROIN USE ON IMMUNE ACTIVATION IN TREATED HIV