Vanderbilt University Medical Center

DATA AND RESEARCH SUPPORT CENTER

AVANTE

CANCER CENTER SUPPORT GRANT

SUPPORTING SUSTAINABLE IMPLEMENTATION OF HIV AND TB SERVICES FOR EPIDEMIC CONTROL IN THE REPUBLIC OF

VANDERBILT INSTITUTE FOR CLINICAL AND TRANSLATIONAL RESEARCH (VICTR)

VANDERBILT VACCINE AND TREATMENT EVALUATION UNIT

SOUTHERN COMMUNITY COHORT STUDY

THE VANDERBILT INSTITUTE FOR CLINICAL AND TRANSLATIONAL RESEARCH (VICTR)

CCASANET: CARIBBEAN, CENTRAL AND SOUTH AMERICA NETWORK

BUNYAVIRUS AND PICORNAVIRUS PANDEMIC PATHOGEN PREPAREDNESS (BP4) CENTER - PROJECT SUMMARY PATHOGENIC PICORNAVIRUSES AND BUNYAVIRUSES HAVE AN ENORMOUS IMPACT ON PUBLIC HEALTH WORLDWIDE, AND OUR UNDERSTANDING OF MECHANISTIC CORRELATES OF IMMUNITY FOR MEMBERS OF THESE VIRUS FAMILIES IS LIMITED. BECAUSE OF THE DIVERSITY OF VIRUSES IN THESE FAMILIES, IT IS UNLIKELY MEDICAL COUNTERMEASURES (SUCH AS VACCINES AND ANTIBODIES) CAN BE DEVELOPED AHEAD OF TIME FOR EACH ONE OF THESE VIRUSES, THEREFORE A PROTOTYPE PATHOGENS APPROACH IS WARRANTED. WE HAVE ASSEMBLED A HIGHLY INTERDISCIPLINARY CONSORTIUM OF LEADING INVESTIGATORS IN THE FIELD OF PICORNAVIRUS AND BUNYAVIRUS VIROLOGY, IMMUNOLOGY, VACCINE BIOLOGY AND ANTIBODY SCIENCES TO STUDY THE MECHANISTIC CORRELATES OF IMMUNITY TO PROTOTYPE PATHOGENS FOR THESE FAMILIES, AND THEN APPLY THE PRINCIPLES WE LEARN WITH THE PROTOTYPE PATHOGENS TO DIFFERENT PATHOGENIC VIRUSES IN THOSE FAMILIES THAT ARE ANTIGENICALLY DISTINCT. ALL FIVE RESEARCH PROJECTS (RP) IN THE CENTER FOCUS ON DEVELOPING STRATEGIES EFFECTIVE AGAINST ALL PATHOGENIC MEMBERS OF A GROUP OF VIRUSES, PICORNAVIRUSES, HANTAVIRUSES, AND DIVERSE ARENAVIRUSES. RP1 FOCUSES ON INNOVATIVE VACCINE STRATEGIES FOR PICORNAVIRUSES (ENTEROVIRUS D68, ENTEROVIRUS A71, ECHOVIRUS 11 AND RHINOVIRUS C TYPES), RP2 FOCUSES ON HUMAN ANTI-PICORNAVIRUS MONOCLONAL ANTIBODIES, RP3 FOCUSES ON NOVEL VACCINE CANDIDATES FOR HANTAVIRUSES, RP4 FOCUSES ON HUMAN MABS FOR SIN NOMBRE, ANDES AND HANTAAN HANTAVIRUSES, AND RP5 PROPOSES STUDIES ON ARENAVIRUS VACCINES AND ANTIBODIES, WITH LCMV AS AN INITIAL PROTOTYPE FOR STUDY. A UNIQUE ASPECT OF THIS CENTER IS THAT IT INCLUDES FULL COMPLEMENTARY RESEARCH PROJECTS FOR BOTH VACCINE AND MABS, WHICH ARE THE TWO MOST WELL-STUDIED COUNTERMEASURES THAT PROVIDE COMPLETE PRE- OR POST-EXPOSURE PROTECTION AGAINST VIRUS INFECTIONS. THE ADVANCED LEVEL OF CERTAIN PRELIMINARY FINDINGS IN THE WORK DESCRIBED IN THE RPS IS A MAJOR STRENGTH AND ADVANTAGE OF OUR CENTER. THERE HAS RELATIVELY LITTLE SIGNIFICANT PROGRESS OVER THE LAST DECADE IN THE DEVELOPMENT OF VACCINES OR POSTEXPOSURE THERAPIES FOR PICORNAVIRUSES OR BUNYAVIRUSES. PREVENTIVE VACCINES WOULD HAVE UTILITY FOR THE PUBLIC DURING LOCAL OR LARGE-SCALE OUTBREAKS, FOR LABORATORY WORKERS, FOR FIRST RESPONDERS OR INDIVIDUALS AT HIGH-RISK EXPOSURE, AND FOR CERTAIN TRAVELERS OR MILITARY PERSONNEL. IN THE CASE OF A BIOLOGICAL ATTACK OR NATURAL OUTBREAK, HOWEVER, A PREVENTATIVE OR POSTEXPOSURE ANTIBODY TREATMENT WOULD BE THE MOST PRACTICAL APPROACH FOR RAPID DEPLOYMENT AND HAS THE ADVANTAGE THAT ANTIBODIES CAN BE USED IN ANY AGE OR HEALTH CONDITION, INCLUDING THE IMMUNOCOMPROMISED. PERFORM PIVOTAL STUDIES THAT WILL FACILITATE THE DEVELOPMENT OF PRODUCTS USED FOR THE PREVENTION AND TREATMENT OF NIPAH AND HENDRA INFECTIONS. THE COOPERATION AMONG THE PAIRED VACCINE + MAB RPS, THE ADMINISTRATIVE CORE, THE SAMPLE ACQUISITION, STRUCTURAL BIOLOGY, AND VACCINE TECHNOLOGY CORES IS BUILT INTO THE CENTER BY DESIGN, AS ALL COMPONENTS WORK TOGETHER TO PROVIDE BROADLY EFFECTIVE CANDIDATE COUNTERMEASURES. QUALITY SYSTEM DATA MANAGEMENT WILL BE EMPLOYED IN BOTH THE PREPARATION OF ADVANCED STAGE TEST ARTICLES AND IN THE CONDUCT OF ANIMAL STUDIES.

ALZHEIMER'S DISEASE SEQUENCING PROJECT PHENOTYPE HARMONIZATION CONSORTIUM - ABSTRACT IN RESPONSE TO PAR-20-099 “HARMONIZATION OF ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (AD/RD) GENETIC, EPIDEMIOLOGIC, AND CLINICAL DATA TO ENHANCE THERAPEUTIC TARGET DISCOVERY”, WE HAVE ASSEMBLED A MULTIDISCIPLINARY TEAM THAT INCLUDES EXPERTS IN NEUROIMAGING, NEUROPSYCHOLOGY, FLUID BIOMARKERS, NEUROPATHOLOGY, AND VASCULAR CONTRIBUTIONS TO ADRD TO WORK IN CLOSE PARTNERSHIP WITH THE NIH AND THE ALZHEIMER’S DISEASE SEQUENCING PROJECT (ADSP). OUR ADSP PHENOTYPE HARMONIZATION CONSORTIUM, OR “ADSP-PHC”, SEEKS TO WORK IN COORDINATION WITH EXISTING ADSP WORKGROUPS AND INITIATIVES TO (1) STREAMLINE ACCESS TO ENDOPHENOTYPE DATA, (2) PROVIDE HIGH QUALITY ENDOPHENOTYPE HARMONIZATION ACROSS MULTIPLE RESEARCH DOMAINS, AND (3) PROVIDE COMPREHENSIVE DOCUMENTATION OF BOTH DATA AVAILABILITY AND HARMONIZATION PROCEDURES. THIS PROJECT INCLUDES TWO COORDINATING CENTERS, THREE CORES, AND EIGHT DOMAIN- SPECIFIC HARMONIZATION TEAMS LED BY WORLD-RENOWNED EXPERTS IN THEIR FIELDS. WHILE OUR EFFORTS WILL FOCUS ON DATA ACCESS, DOCUMENTATION, AND HARMONIZATION, WE WILL WORK CLOSELY WITH OTHER ADSP WORKGROUPS AND OTHER LARGE-SCALE HARMONIZATION EFFORTS TO MAXIMIZE THE IMPACT AND ALIGN WITH NIH PRIORITIES. IN PARTICULAR, WE WILL FOCUS HARMONIZATION ON ADRD-RELATED ENDOPHENOTYPES, INCLUDING COGNITIVE SCORES DERIVED FROM DETAILED NEUROPSYCHOLOGICAL ASSESSMENTS, MEASURES OF NEUROPATHOLOGY MEASURED BOTH EX VIVO (NEUROPATHOLOGICAL ASSESSMENT AT AUTOPSY) AND IN VIVO (FLUID BIOMARKERS AND POSITRON EMISSION TOMOGRAPHY BIOMARKERS), CONCOMITANT PATHWAYS OF INJURY (VASCULAR RISK FACTORS AND VASCULAR BRAIN INJURY), AND MEASURES OF NEURODEGENERATION FOCUSING ON BOTH WHITE (DIFFUSION-WEIGHTED MRI) AND GREY MATTER (T1-WEIGHTED MRI). THE PROPOSED HARMONIZATION EFFORT WILL PROVIDE AN UNPRECEDENTED OPPORTUNITY TO DISENTANGLE THE GENETIC ARCHITECTURE OF INDIVIDUAL BIOLOGICAL CONTRIBUTORS TO ADRD RISK AND PROGRESSION. THE HARMONIZED DATA, PROTOCOLS, AND EDUCATIONAL TOOLS DEVELOPED BY THE ADSP-PHC WILL TRANSFORM THE ADRD LANDSCAPE, ACCELERATE DISCOVERY, AND FACILITATE THE APPLICATION OF EMERGING BIG DATA ANALYTIC APPROACHES LEVERAGING MACHINE LEARNING AND ARTIFICIAL INTELLIGENCE.

SPORE IN BREAST CANCER

THE PURPOSE OF THIS AGREEMENT IS TO FUND RESEARCH IN SUPPORT OF BTO IN THE AMOUNT OF 2,524,411 ON CONTRACT HR0011-18-2-0001.

HOST AND VIRAL DETERMINANTS OF INFANT AND CHILDHOOD ALLERGY AND ASTHMA

VANDERBILT HIV CLINICAL TRIALS UNIT

GH12-1224: TECHNICAL ASSISTANCE TO THE MINISTRY OF HEALTH (MOH) FOR HIV SERVICES AND PROGRAM TRANSITION IN ZAMB

IMPROVING CLINICAL TRIAL EDUCATION, RECRUITMENT, AND ENROLLMENT AT CTSA HUBS (I-CERCH)

VANDERBILT DIABETES RESEARCH CENTER

H. PYLORI-INDUCED INFLAMMATION AND GASTRIC CANCER

ECHO LABORATORY CORE AT VANDERBILT FOR INTEGRATED SAMPLE BIOBANKING AND PROCESSING - SUMMARY EARLY-LIFE ENVIRONMENTAL EXPOSURES (E.G., SOCIAL-ENVIRONMENTAL, PARENTAL RISK FACTORS, NICOTINE, DIET, INFECTION) ARE INCREASINGLY IMPLICATED IN THE EARLY PATHOGENESIS OF CHILDHOOD DISEASES THAT HAVE LIFE-LONG CONSEQUENCES. MECHANISMS LINKING THESE EXPOSURES TO LONGER-TERM OUTCOMES REMAIN LIMITED. IN 2016, THE NIH ESTABLISHED THE ENVIRONMENTAL INFLUENCES ON CHILD HEALTH OUTCOMES (ECHO) PROGRAM, A COLLABORATIVE MULTI-DIMENSIONAL RESEARCH INITIATIVE TO CHARACTERIZE THE IMPACT OF EARLY-LIFE ENVIRONMENTAL FACTORS ON CHILDHOOD HEALTH (>70 COHORTS, >50K PARTICIPANTS). WHILE TARGETED ASSAYS WITHIN ECHO ARE LIKELY TO LEAD TO DISEASE-SPECIFIC INSIGHT, BROAD, COMPREHENSIVE, UNBIASED ASSESSMENT OF THE MOLECULAR SPACE FOR NOVEL DISCOVERY—A KEY MISSION OF ECHO— WILL NECESSITATE CENTRALIZATION OF BIOBANKING EFFORTS/LABORATORY MANAGEMENT WITH CAPABILITY FOR HIGH-THROUGHPUT “OMICS”/NON-“OMICS” ASSAY AS WELL AS NOVEL ASSAY DEVELOPMENT, BIOINFORMATICS, AND CLOUD ARCHITECTURE/DATA SHARING FOR COLLABORATIVE SCIENCE. IN RESPONSE TO RFA-OD-22-016, VANDERBILT WILL ADDRESS THIS NEED BY ESTABLISHING THE ECHO LABORATORY CORE AT VANDERBILT FOR INTEGRATED SAMPLE BIOBANKING AND PROCESSING (ELVIS). ELVIS FACILITATES THE COLLECTION AND PROCESSING OF BIOSPECIMENS; MANAGES THE BIOREPOSITORY; PERFORMS A WIDE RANGE OF BIOSPECIMEN ASSAYS (INCLUDING NOVEL DEVELOPMENT), AND COORDINATES METADATA AND ASSAY DATA TRANSFER TO THE COORDINATING CENTER. ELVIS IS ORGANIZED IN CORE “RESOURCES” TO PROVIDE LEADERSHIP/INTEGRATION TO MANAGE ECHO BIOBANKING, ASSAY PERFORMANCE, AND DATA DELIVERY: (1) ADMINISTRATIVE/LIMS/BIOBANKING; (2) METABOLOMICS; (3) PROTEOMICS; (4) NUCLEIC ACID ASSESSMENT; (5) METAGENOMICS; (6) BIOINFORMATICS/STUDY DESIGN. WE ARE UNIQUELY POSITIONED FOR THIS INITIATIVE, LEVERAGING VANDERBILT’S UNIQUE LONG-TERM STRATEGIC INVESTMENT IN FUNCTIONAL BIOBANKING AND ASSAY: (1) LARGE-SCALE, RELIABLE BIOREPOSITORY RECEIPT AND LABORATORY MANAGEMENT (“LIMS”) CAPABILITY (>350K PATIENTS CURRENTLY WITH BIOSPECIMENS; MANY OTHER NIH FUNDED BIOBANKS); (2) NATIONALLY RECOGNIZED SYSTEMS FOR CLINICAL METADATA CAPTURE (REDCAP, REDBRICS; USED IN NIH INITIATIVES, LIKE ALL OF US); (3) CUTTING-EDGE LABORATORY CORES WITH CAPABILITY FOR NOVEL ASSAY DEVELOPMENT/VALIDATION. WE WILL ESTABLISH HARMONIZED PROTOCOLS AND WORKFLOW FOR ECHO COHORT BIOSPECIMEN COLLECTION AND TRACKING INFRASTRUCTURE FROM THE POINT OF SAMPLE COLLECTION TO LONG-TERM STORAGE (AIM 1); PERFORM HIGH-QUALITY, WELL-POWERED MULTI-OMICS AND TARGETED ASSAYS TO IDENTIFY MOLECULAR CORRELATES OF DISEASE TRAJECTORIES IN EARLY LIFE (AIM 2), AND PROVIDE COMPREHENSIVE DATA MANAGEMENT PLATFORM TO FACILITATE INTEGRATED DATA ANALYSIS (AIM 3). ELVIS IS AN IDEAL MECHANISM FOR ECHO GIVEN (1) DEEP, FUNDED EXPERIENCE IN HANDLING THE REQUISITE SAMPLE SIZES IN BANKING AND HIGH-THROUGHPUT ASSAY, INCLUDING QUALITY ASSURANCE MEASURES; (2) PRIOR TRACK RECORD IN ECHO TO ENSURE ECHO- SPECIFIC METADATA COLLECTION, CURATION, AND HARMONIZATION; (3) SECURE METHODS FOR CLOUD INFRASTRUCTURE FOR DATA ANALYSIS PIPELINES AND DATA FLOW TO CLINICAL SITES AND DATA ANALYSIS CENTER. SUCCESSFUL COMPLETION WILL ENABLE THE SUCCESS OF ECHO’S MISSION TO DISCOVER MOLECULAR UNDERPINNINGS OF EARLY CHILDHOOD DETERMINANTS OF DISEASE.

AIDS EDUCATION AND TRAINING CENTERS PROGRAM

HDL FUNCTION IN HUMAN DISEASE

CARDIAC FUNCTION AS A MECHANISM FOR MALADAPTIVE BRAIN AGING

TENNESSEE CENTER FOR AIDS RESEARCH (TN-CFAR)

MOLECULAR AND CELLULAR BASIS FOR DIGESTIVE DISEASES

COORDINATION FOR ARDS, PNEUMONIA, AND SEPSIS SUPPORTING TRAINING, ORGANIZATION AND NETWORK EFFICIENCY (CAPSTONE) - THE ARDS, PNEUMONIA, AND SEPSIS (APS) COORDINATING CENTER WILL SUPPORT A HIGHLY FUNCTIONAL AND INTEGRATED CLINICAL AND TRANSLATIONAL RESEARCH INFRASTRUCTURE THAT WILL ENHANCE THE QUALITY AND SCIENTIFIC RIGOR OF THE RESEARCH CONDUCTED BY THE APS PHENOTYPING CONSORTIUM. WE ARE A TEAM COMPOSED OF LEADING CONTENT AND METHODS EXPERTS AT VANDERBILT, JOHNS HOPKINS, AND UNIVERSITY OF CALIFORNIA SAN FRANCISCO. WE WILL PROVIDE COORDINATION FOR ARDS, PNEUMONIA, AND SEPSIS SUPPORTING TRAINING, ORGANIZATION AND NETWORK EFFICIENCY: ‘CAPSTONE’. WE WILL SUPPORT THE CLINICAL CENTERS (CCS) IN ENROLLING AND SUSTAINING A DIVERSE COHORT; ENABLE THE EFFICIENT AND STANDARDIZED CAPTURE OF MULTI-MODAL COHORT DATA WITH REPEATED MEASUREMENTS; MODEL THE DATA TO UNDERSTAND MECHANISTIC UNDERPINNINGS OF APS, INCLUDING THE INTERPLAY OF UNDERLYING AND STATIC RISK FACTORS; AND SEGMENT THE POPULATION INTO SIMILAR PROGNOSTIC AND PREDICTIVE PHENOTYPES. THIS WILL ENABLE SCIENTIFIC PROGRESS TOWARDS A DEEPER MECHANISTIC UNDERSTANDING OF CRITICAL ILLNESS SYNDROMES AND RECOVERY. FUNCTIONALLY, WE WILL 1) IMPLEMENT THE STUDY DESIGN, DATA CAPTURE, AND STATISTICAL ANALYSIS UNIT. COORDINATE PROTOCOL DEVELOPMENT; ESTABLISH A REDCAP-BASED DATA COLLECTION, MANAGEMENT, AND SECURITY FRAMEWORK; CONDUCT AND SUPPORT ANALYSES; GENERATE REPORTS; MAKE CURATED DATA WIDELY AVAILABLE FOR RESEARCH THROUGH A FACILITATED STOREFRONT; 2) IMPLEMENT THE CLINICAL RESEARCH MANAGEMENT UNIT. MAINTAIN COHORT INTEGRITY AND ADHERENCE TO THE PROTOCOL AND MANUAL OF OPERATIONS, PERFORM ROUTINE MONITORING OF DATA QUALITY AND SITE PERFORMANCE; TRAINING OF STUDY STAFF; IMAGE AND BIOSPECIMEN MANAGEMENT. SUPPORT SITE COMMUNICATIONS; FACILITATE RECRUITMENT AND RETENTION; AND 3) IMPLEMENT THE STAKEHOLDER ENGAGEMENT AND DEVELOPMENT UNIT. ESTABLISH BIDIRECTIONAL, LONGITUDINAL ENGAGEMENT FROM DIVERSE COMMUNITIES; HELP CCS BUILD AND SUSTAIN TRUST; ENSURE STRENGTHS OF EACH CC ARE NURTURED AND SHARED; FACILITATE DISSEMINATION OF FINDINGS; SUPPORT SKILLS AND CAREER DEVELOPMENT AMONG RESEARCH TEAMS. OUR EFFORTS WILL EXPAND FOUNDATIONAL WORK ON APS PHENOTYPING, IDENTIFY GAPS, AND HELP CREATE METHODS FOR REDEFINING CRITICAL ILLNESS SYNDROMES WITH THE ULTIMATE GOAL OF IMPROVING AND PERSONALIZING MANAGEMENT STRATEGIES THAT WILL CURTAIL THE DEVASTATING MORBIDITY AND MORTALITY CAUSED BY APS.

SOUTHERN COMMUNITY COHORT STUDY

HORMONAL, METABOLIC AND SIGNALING INTERACTIONS IN PAH

MECHANISMS OF FAMILIAL PULMONARY FIBROSIS

CATALYZING AND HARMONIZING OPERATIONAL INNOVATION FOR RECRUITMENT (CHOIR) - WHILE RECRUITMENT INTO CLINICAL RESEARCH HAS BEEN A LONGSTANDING CHALLENGE FOR NIH FUNDED MULTI-SITE STUDIES, IT HAS BECOME CLEAR THAT THERE IS SUBSTANTIAL VARIABILITY IN RECRUITMENT SUCCESS ACROSS THE NATIONAL PORTFOLIO CAUSED BY MANY FACTORS: ELIGIBILITY PARAMETERS, REQUIRED PROCEDURES, COMPENSATION LEVELS, ENGAGEMENT PRACTICES, RECRUITMENT RESOURCES, SKILL AND AWARENESS OF RECRUITMENT TEAMS, GEOGRAPHIC CONSTRAINTS, TRUST, AND PERCEIVED BENEFIT/RISK. STUDIES THAT DO NOT INTEGRATE THESE FACTORS INTO RECRUITMENT AND RETENTION OFTEN CLOSE FOR POOR ACCRUAL. IN ADDITION, THERE ARE NOW MORE EQUITABLE DEFINITIONS OF WHAT CONSTITUTES “RECRUITMENT SUCCESS” BEYOND AN ABSOLUTE TARGET, INCLUDING: DIVERSITY, REPRESENTATIVENESS OF THE ACTUAL POPULATION, COSTS OF ENROLLMENT, RETENTION, AND TIME REQUIRED. THESE COMPLEX DYNAMICS SUGGEST THERE IS NO ‘ONE SIZE FITS ALL’ SOLUTION, AND CAREFUL ATTENTION AND CONSIDERATION MUST BE A PART OF THE RECRUITMENT PLAN. OUR TEAM HAS BEEN FORMING EFFECTIVE RECRUITMENT COLLABORATIONS FOR THE PAST 6 YEARS -- CONSIDERING THE STUDY SPECIFICS, CAPABILITIES OF THE STUDY TEAM, AND NEEDS AND VALUES OF THE PARTICIPANT POPULATION -- TO TOGETHER CRAFT FEASIBLE, EFFECTIVE PLANS. IN THE NEXT CYCLE, WE WILL CATALYZE AND HARMONIZE OPERATIONAL INNOVATION FOR RECRUITMENT (CHOIR) AND WILL CONTINUE TO BE LED BY A LONG-STANDING SYNERGISTIC PARTNERSHIP BETWEEN PAUL HARRIS, PHD, AS PI RESPONSIBLE FOR INFORMATICS DEVELOPMENT, AND CONSUELO WILKINS, MD, MSCI, AS PI OF COMMUNITY AND STAKEHOLDER ENGAGEMENT. FORMAL PARTNERSHIPS WITH 10 OTHER CTSAS PROVIDE BROAD UNDERSTANDING OF HUB NEEDS, ALONG WITH KEY AREAS OF EXPERTISE. WE WILL EXTEND AND BUILD UPON EXISTING RECRUITMENT-RELATED ASSETS AND DATA TOOLS AND RESOURCES ALREADY IN USE BY OUR TEAM AND OTHERS (FASTERTOGETHER, RESEARCHMATCH, REDCAP TRIALSTODAY, FHIR CLINICAL DATA-BASED RECRUITMENT INFRASTRUCTURE). THESE INNOVATIONS ACKNOWLEDGE RECRUITMENT IS NOT A ONE-TIME ACTIVITY BUT IS A CONTINUUM. WE WILL PROVIDE A NATIONAL, DISEASE AGNOSTIC HOME FOR SHARING RECRUITMENT TOOLS, TRAINING, MATERIALS, AND BEST PRACTICES FOR DIVERSE POPULATIONS. SPECIFIC AIMS ARE: 1) PARTNER WITH STUDY TEAMS TO CREATE STUDY-SPECIFIC RECRUITMENT PLANS, AND SUPPORT ONGOING SKILLS DEVELOPMENT. 2) EVALUATE CLINICAL TRIAL RECRUITMENT AND RETENTION METHODS AND MAKE CONTINUAL IMPROVEMENTS. 3) ENHANCE NATIONAL CLINICAL TRIAL AWARENESS THROUGH ENGAGEMENT AND EDUCATION; FACILITATE PARTICIPANT IDENTIFICATION OF STUDIES WITH ONLINE TOOLS. AND, 4) DEVELOP AND DISSEMINATE TECHNICAL AND PROCEDURAL APPROACHES TO CATALYZE ENROLLMENT IN CLINICAL TRIALS ACROSS ALL CTSAS.

ENGAGING COOPERATIVE SITES FOR TRIAL ACCELERATION, TRUST, INNOVATION, AND CAPABILITY (ECSTATIC) - CLINICAL RESEARCH COMES IN MANY DIFFERENT SHAPES AND SIZES, AND A ROBUST NETWORK MUST ACCOMMODATE ALL TRIAL TYPES. NO SINGLE ORGANIZATION CAN DO THIS WORK ALONE. WE HAVE A DEEP COMMITMENT TO BOTH TRIAL INNOVATION AND COLLECTIVE NETWORK CAPACITY WITHIN AND BEYOND THE CTSA CONSORTIUM AND HAVE A LENGTHY HISTORY OF SUPPORTING THIS APPROACH. WE HAVE DEMONSTRATED AN EXCEPTIONAL ABILITY TO COLLABORATIVELY INNOVATE AND SHARE TOOLS SUPPORTING CLINICAL RESEARCH COORDINATION, INCLUDING: GLOBAL DATA MANAGEMENT, MOBILE DATA COLLECTION, RECRUITMENT, ELECTRONIC HEALTH RECORD (EHR) RESEARCH, SINGLE IRB COORDINATION, CONTRACTING, COMMUNITY ENGAGEMENT, RETURNING VALUE TO PARTICIPANTS, ECONSENT, VIRTUAL/REMOTE PARTICIPATION IN STUDIES, AND EHR INTEGRATION WITH REDCAP. WE WILL LEVERAGE AND EXPAND UPON THESE PROGRAMS AS WE ARE ENGAGING COOPERATIVE SITES FOR TRIAL ACCELERATION, TRUST, INNOVATION, AND CAPABILITY (ECSTATIC). WE WILL ESTABLISH A DISTRIBUTED ALLIANCE OF 6 CTSA-ALIGNED COORDINATING CENTERS TO ADD ELASTIC CAPACITY AND BROADEN EXPERTISE TO THE TIN’S CCC/DCC INFRASTRUCTURE. OUR ALLIANCE HAS 14 EXPERT TRIALISTS THAT CAN INFORM THE USE OF INTEGRATED APPROACHES FOR MORE EFFICIENT CLINICAL RESEARCH. ADDITIONALLY, WE WILL PARTNER WITH THE WELL-ESTABLISHED BIOSTATISTICS, EPIDEMIOLOGY, AND RESEARCH DESIGN (BERD) GROUP AND HEALTH EQUITY EXPERTS TO ENSURE EVERY STUDY HAS ACCESS TO NEEDED EXPERTISE STARTING FROM STUDY DESIGN THROUGH ANALYSIS. WE WILL BROADEN THE TYPES OF ORGANIZATIONS THAT CAN READILY PARTICIPATE IN CLINICAL RESEARCH ACROSS THE U.S., INCLUDING HISTORICALLY BLACK COLLEGES AND UNIVERSITIES (HBCUS), TO REACH THE POPULATIONS MOST IN NEED OF SUPPORT. BASED ON OUR NOVEL STRUCTURE, MERGING TEAMS FROM SIX DIFFERENT COORDINATING CENTER GROUPS, OUR TIC’S CAPACITY IS BOTH SCALABLE AND MATCHED BY EXPERTISE TO INTENTIONALLY ACCOMMODATE ALL STUDY DESIGN TYPES. LED BY GORDON BERNARD, MD, WESLEY SELF, MD, AND CHRISTOPHER LINDSELL, PHD, EACH SEASONED IN LEADING AND COLLABORATING WITH MULTISITE CLINICAL TRIAL NETWORKS, ECSTATIC WILL EMBRACE AND DRAW ON DIVERSE EXPERTISE TO BUILD, TEST, AND SHARE NEW RESOURCES THAT WILL ENHANCE AND ACCELERATE RIGOROUS, REPRODUCIBLE RESEARCH FOR ALL CTSAS, TO MORE RAPIDLY IMPROVE HUMAN HEALTH. OUR SPECIFIC AIMS ARE TO: 1) DEMONSTRATE AND DISSEMINATE NOVEL INTEGRATED APPROACHES FOR MORE EFFICIENT CLINICAL RESEARCH INCLUDING EHR-EMBEDDED, REMOTE NO-TOUCH, AND PLATFORM TRIALS, ALIGNING WITH STUDY NEEDS; 2) EXPAND AND ENRICH CLINICAL TRIAL CAPABILITY BY INCREASING POTENTIAL PARTICIPATING SITE EXPRESSION OF INTEREST (EOI) REACH AND READINESS SUPPORT (HBCUS AND RURAL PRACTICE-BASED RESEARCH NETWORKS), BETTER PROCESS INTEGRATION WITH CTSAS, PREPARING STUDY TEAMS, AND BROADER EXPERT ENGAGEMENT; 3) INNOVATE CLINICAL TRIAL METHODOLOGY BY CREATING, EVALUATING, AND DISSEMINATING NEW METHODS FOR RISK MONITORING, AE REPORTING, DIRECT EHR TO REDCAP DATA CAPTURE, AND DATA STANDARDS TO ALL CTSAS; AND 4) PROVIDE A DISTRIBUTED ALLIANCE OF CLINICAL AND DATA COORDINATING CENTERS WITH EXTENSIVE AND DIVERSE EXPERTISE TO OFFER SUPPORT TAILORED FOR TRIAL DESIGN, POPULATION, AND CONDITION.

SPORE IN GL CANCER

MMC, VICC & TSU: PARTNERS IN ELIMINATING CANCER DISPARITIES ( 2 OF 3)

TRANSFORMING CLINICAL PRACTICE INITIATIVE (TCPI), PRACTICE TRANSFORMATION NETWORKS (PTN)

REVERSE-LONG COVID: A MULTICENTER RANDOMIZED, PLACEBO-CONTROLLED CLINICAL TRIAL OF IMMUNOMODULATION (WITH BARICITINIB) FOR LONG COVID RELATED ADRD - PROJECT SUMMARY/ABSTRACT COGNITIVE IMPAIRMENT, INCLUDING ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD), AND CARDIOPULMONARY DYSFUNCTION FOLLOWING COVID-19, ARE COMPONENTS OF THE CHRONIC SYNDROME KNOWN AS LONG COVID (LC). LC IS AN UNPRECEDENTED PUBLIC HEALTH CRISIS LEADING TO COGNITIVE, MENTAL HEALTH, AND FUNCTIONAL DISABILITIES FOR MILLIONS OF PEOPLE LIVING IN THE UNITED STATES AND AROUND THE WORLD. LARGE EPIDEMIOLOGIC STUDIES HAVE DEMONSTRATED THAT THE RISK OF ADRD INCREASES MULTIFOLD IN MANY OLD AND YOUNG PATIENTS FOLLOWING EVEN MILD SARS-COV-2 INFECTION. PATIENTS WITH LC ALSO FREQUENTLY EXPERIENCE PROFOUND LIMITATIONS IN PHYSICAL FUNCTION AND EXERCISE INTOLERANCE THAT, WHEN PAIRED WITH ADRD, ARE LIFE ALTERING AND RESULT IN INABILITY TO WORK AND LEAD A FAMILY. RAPIDLY GROWING EVIDENCE LINKS THE CLINICAL MANIFESTATIONS OF LC TO PATHOPHYSIOLOGIC MECHANISMS OF ABNORMAL INFLAMMATION AND IMMUNE DYSREGULATION. THERE IS A DRIVING, UNMET NEED FOR ROBUST CLINICAL TRIALS DIRECTLY TARGETING IMMUNE DYSREGULATION TO REDUCE ADRD AND CARDIOPULMONARY INJURY RELATED TO LC. OUR CENTRAL HYPOTHESIS IS THAT IMMUNOMODULATORS MAY BE THE MOST EFFECTIVE TREATMENT FOR THESE SEQUELAE OF LC. BARICITINIB IS AN IMMUNOMODULATOR (JAK1/2 INHIBITOR) THAT IS FDA-APPROVED TO TREAT ACUTE COVID-19 INFECTION AS WELL AS CERTAIN AUTOIMMUNE CHRONIC DISEASES LIKE RHEUMATOID ARTHRITIS. JAK1/2 SIGNALING IS A CARDINAL DRIVER OF BOTH SYSTEMIC AND NEUROINFLAMMATION. OUR STUDY, THE RANDOMIZED TRIAL EVALUATING BARICITINIB ON PERSISTENT NEUROLOGIC AND CARDIOPULMONARY SYMPTOMS OF LONG COVID (REVERSE-LC), WILL ENROLL 500 PATIENTS WITH LC AND COGNITIVE IMPAIRMENT AT HIGH RISK FOR LONG-TERM ADRD ACROSS 4 SITES TO TEST THE HYPOTHESIS THAT 6 MONTHS OF BARICITINIB VERSUS MATCHED PLACEBO WILL IMPROVE NEUROCOGNITIVE AND PHYSICAL FUNCTION IN LC. AIM 1 WILL MEASURE THE TRAJECTORY OF NEUROCOGNITIVE FUNCTION AT ENROLLMENT, 6- AND 12-MONTHS IN BARICITINIB VERSUS PLACEBO PATIENTS USING AN OBJECTIVE NEUROPSYCHOLOGICAL BATTERY AS WELL AS PATIENT-REPORTED COGNITIVE FUNCTION. AIM 2 WILL MEASURE PHYSICAL FUNCTION USING CARDIOPULMONARY EXERCISE TESTING AND OTHER FUNCTIONAL MEASURES IN ADDITION TO PATIENT-REPORTED PHYSICAL SYMPTOMS IN PATIENTS TREATED WITH BARICITINIB VERSUS PLACEBO. AIM 3 WILL EVALUATE THE EFFECT OF BARICITINIB VERSUS PLACEBO ON PLASMA, CEREBROSPINAL FLUID, AND NEUROIMAGING INFLAMMATORY MARKERS AT ENROLLMENT, AS WELL AS 6- AND 12-MONTH FOLLOW-UP STUDY VISITS IN PATIENTS WITH LC TO IDENTIFY INFLAMMATORY MEDIATORS OF NEUROPSYCHOLOGICAL (ADRD) OUTCOMES. THE REVERSE-LC TRIAL IS NOVEL IN TARGETING IMMUNE DYSREGULATION AND INFLAMMATION FOR PATIENTS WITH LC AND IS BASED ON OUR GROWING UNDERSTANDING OF THE MECHANISM OF THIS EMERGING, POST-INFECTIOUS CAUSE OF RAPIDLY-ACQUIRED ADRD RISK. REGARDLESS OF THE OUTCOME OF REVERSE-LC, THIS STUDY WILL PROVIDE CRUCIAL INSIGHTS INTO TREATMENT OF ADRD, SEQUELAE OF COVID, AND DISEASE PATHOGENESIS. THIS INVESTIGATION WILL ALSO ESTABLISH AN INNOVATIVE TRIAL PLATFORM BY WHICH TO TEST FUTURE INTERVENTIONS FOR RAPIDLY-ACQUIRED NEUROCOGNITIVE DYSFUNCTION, CARDIOPULMONARY DISEASE, LC, AND OTHER AGE- RELATED COMORBIDITIES LEADING TO ADRD. IT WILL ADVANCE THE SCIENCE OF AGING BRAIN DISEASE AND DISABILITY.

BRAIN-2 COVID-19 ADMINISTRATIVE SUPPLEMENT

PHARMACOGENOMICS OF ARRHYTHMIA THERAPY

AUTONOMIC CARDIOVASCULAR REGULATION

REGIONAL AIDS EDUCATION AND TRAINING CENTERS PROGRAM - VANDERBILT UNIVERSITY MEDICAL CENTER (VUMC) PROPOSES TO LEAD THE SOUTHEAST AIDS EDUCATION AND TRAINING CENTER (SE AETC). THE SOUTHEAST (SE) HAS A POPULATION OF OVER 67 MILLION PEOPLE LIVING IN EIGHT STATES INCLUDING ALABAMA, FLORIDA, GEORGIA, KENTUCKY, MISSISSIPPI, NORTH CAROLINA, SOUTH CAROLINA, AND TENNESSEE. ACCORDING TO THE CDC, AN ESTIMATED 323,100 PEOPLE IN THE SE LIVE WITH HIV (BOTH DIAGNOSED AND UNDIAGNOSED), AND THE AVERAGE RATE OF NEW DIAGNOSES IN 2021 WAS 16.8 PER 100,000 POPULATION. VUMC WILL BUILD UPON SUCCESSFUL INTERVENTIONS AND INTRODUCE INNOVATIVE PROGRAMS, ORGANIZED AS FOUNDATIONS OF HIV (FH), CAPABILITY AND EXPERTISE EXPANSION (CEE), PRACTICE TRANSFORMATION (PT), HIV INTERPROFESSIONAL EDUCATION (IPE), MINORITY AIDS INITIATIVE (MAI), AND ENDING THE HIV EPIDEMIC (EHE) IN THE US INITIATIVES. VUMC WILL BUILD UPON RELATIONSHIPS ESTABLISHED OVER THE PAST NINE YEARS AS THE SE AETC CENTRAL OFFICE (CO). VUMC HAS A GROWING REACH INCLUDING 81,970 TRAINEES REPRESENTING PRIORITY POPULATIONS IN DIVERSE ORGANIZATIONS. THIS NETWORK PROVIDES OPPORTUNITIES FOR STRATEGIC PARTNERSHIP WITH ORGANIZATIONS SUCH AS HEALTH DEPARTMENTS, PRIMARY CARE ASSOCIATIONS (PCAS), RYAN WHITE HIV/AIDS PROGRAM (RWHAP)-FUNDED ENTITIES, EHE-FUNDED JURISDICTIONS, FEDERALLY QUALIFIED HEALTH CENTERS (FQHCS), MINORITY SERVING INSTITUTIONS (MSIS), HEALTH PROFESSIONAL PROGRAMS (HPPS), AND OTHER HEALTH RESOURCES AND SERVICES ADMINISTRATION (HRSA)-FUNDED GROUPS. FOR EXAMPLE, AN EXISTING PARTNERSHIP WITH THE UNITED SOUTHERN AND EASTERN TRIBES (USET) WILL CONTINUE TO BE VITAL TO REACH AND SUPPORT TRIBAL HEALTH CLINICS. ACTIVITIES WILL BE DIRECTED AT PRIORITY PROVIDERS THROUGHOUT THE SE THROUGH INTERACTIVE CASE-BASED SESSIONS, SMALL GROUP WORKSHOPS, ONLINE SELF-PACED LEARNING, AND OTHER INNOVATIVE ADULT LEARNING APPROACHES FOR BUSY PROVIDERS (E.G., THE TEXT/EMAIL-BASED MICROLEARNING TOOL QUIZTIME). VUMC WILL INCREASE HIV WORKFORCE TRAINING THROUGH CLINICAL SKILLS DEVELOPMENT VI A IN-PERSON CONFERENCES AND WORKSHOPS, CLINICAL CONSULTATIONS, PRECEPTORSHIPS, AND INTENSIVE HIV FELLOWSHIPS AND ACADEMIES. AN INNOVATIVE STRUCTURE WILL BE USED TO ORGANIZE CONTENT EXPERTISE AND TRAINING PARTNERS INTO DISTINCT COMMUNITIES OF PRACTICE (COP) FOCUSED ON ACHIEVING MAJOR PROGRAM GOALS AND ACTIVITIES. EVALUATION STRATEGIES TO MEASURE TRAINING ACCEPTABILITY AND OUTCOMES WILL BE APPLIED THROUGH VARIOUS METHODS, BASED ON QUANTITATIVE AND QUALITATIVE DATA, AND ADAPTIVE TO HRSA REQUIREMENTS AND REQUESTS. USE OF THE EVENT REGISTRATION AND EVALUATION DATABASE DEVELOPED BY VUMC (MEASURING OUTCOMES ACROSS THE SOUTHEAST [MOXSE]) ALLOWS REAL-TIME DATA TRACKING AND MARKETING OF TRAINING EVENTS TO HEALTH PROFESSIONALS FROM A VARIETY OF BACKGROUNDS. LOCAL PARTNERS (LPS) WILL COLLABORATE WITH THE CO IN ASSESSING NEED, PROVIDING TRAINING, COLLECTING EVALUATION DATA, AND FACILITATING COLLABORATION WITH STATE AND REGIONAL PUBLIC HEALTH INITIATIVES. LPS WILL EXECUTE LOCAL WORKPLANS AND COLLABORATE WITH PERTINENT ORGANIZATIONS (E.G., THEIR STATES RWHAP FUNDED ENTITIES). THE UNIVERSITY OF ALABAMA AT BIRMINGHAM, UNIVERSITY OF MIAMI, UNIVERSITY OF FLORIDA, MOREHOUSE SCHOOL OF MEDICINE, UNIVERSITY OF KENTUCKY, UNIVERSITY OF MISSISSIPPI MEDICAL CENTER, UNIVERSITY OF NORTH CAROLINA, DUKE UNIVERSITY (MAI), AND UNIVERSITY OF SOUTH CAROLINA WILL SERVE AS LPS TO EXPAND REACH AND PARTNERSHIP TO INCLUDE BOTH URBAN AND RURAL AREAS OF EACH STATE. VUMC WILL SERVE AS BOTH THE CO AND THE LP FOR TN. SPECIFIC INITIATIVES WILL BE SUPPORTED BY LPS BASED ON EXPERTISE AND OPPORTUNITIES; FOR EXAMPLE, MOREHOUSE SCHOOL OF MEDICINE AND DUKE UNIVERSITY WILL LEAD MAI EFFORTS AND WORK WITH MSIS TO INTEGRATE HIV EDUCATION INTO HPP CURRICULA. IN SUMMARY, VUMC SEEKS TO LEAD THE SE AETC TO CONTINUE TO INNOVATE HIV TRAINING AND TECHNICAL ASSISTANCE ACROSS AN ESSENTIAL US REGION WITH STRONG PARTNERSHIPS AND COLLABORATIONS.

THE ELECTRONIC MEDICAL RECORDS AND GENOMICS (EMERGE) NETWORK PHASE III - COORDINATING CENTER (U01)

AIDS EDUCATION AND TRAINING CENTERS PROGRAM

SOUTHEAST COLLABORATIVE FOR INNOVATIVE AND EQUITABLE SOLUTIONS TO CHRONIC DISEASE DISPARITIES - THE BURDEN OF RACIAL AND ETHNIC HEALTH DISPARITIES IS MOST EVIDENT IN THE SOUTHEASTERN UNITED STATES, WHERE BLACK AND LATINO POPULATIONS SUFFER THE HIGHEST RATES OF CARDIOVASCULAR DISEASE, DIABETES, OBESITY, HYPERTENSION, CANCER, AND ASTHMA. THESE CHRONIC CONDITIONS ARE A PRIMARY CAUSE OF POOR HEALTH, REDUCED QUALITY OF LIFE, AND PREMATURE DEATH, AND ACCOUNT FOR MORE THAN 50% OF HEALTH CARE EXPENDITURES. DESPITE SUBSTANTIAL REDUCTION OF SOME CHRONIC DISEASES AND RISK FACTORS OVER THE LAST FEW DECADES, THE SOUTHEAST CONTINUES TO HAVE THE HIGHEST NUMBER OF POTENTIALLY PREVENTABLE DEATHS FOR EACH OF THE FIVE LEADING CAUSES OF DEATH. RACIAL AND ETHNIC MINORITIES COMPRISE 39% OF THE POPULATION OF THE SOUTHEAST (HHS REGION IV), WHICH INCLUDES NEARLY 15 MILLION AFRICAN AMERICANS AND 9 MILLION LATINOS. MINORITIES IN THE SOUTHEAST FARE WORSE ON MANY HEALTH INDICATORS COMPARED TO OTHER REGIONS, IN LARGE PART DUE TO POOR SOCIOECONOMIC STATUS, WITH MORE THAN 22% OF SOUTHEASTERN RESIDENTS LIVING IN POVERTY. EFFECTIVELY ADDRESSING PERVASIVE CHRONIC DISEASE DISPARITIES WILL REQUIRE INTERVENTIONS THAT CONSIDER THE NEEDS, PRIORITIES, AND LIVED EXPERIENCES OF THOSE DISPROPORTIONATELY IMPACTED. RESEARCH TEAMS WITH EXPERTISE IN SOCIAL, ENVIRONMENTAL, BEHAVIORAL, AND BIOLOGICAL DISCIPLINES MUST COLLABORATE TO DEVELOP AND TEST MULTICOMPONENT STRATEGIES AIMED AT THE MULTILEVEL DETERMINANTS THAT DRIVE DISPARITIES. VIA A NEW CENTER - THE SOUTHEAST COLLABORATIVE FOR INNOVATIVE AND EQUITABLE SOLUTIONS TO CHRONIC DISEASE DISPARITIES, WE WILL BRING TOGETHER VANDERBILT UNIVERSITY MEDICAL CENTER, UNIVERSITY OF MIAMI, AND MEHARRY MEDICAL COLLEGE TO ADDRESS TO REDUCE RISK FACTORS FOR AND DISPARITIES IN DIABETES, CARDIOVASCULAR DISEASE, OBESITY, AND RELATED CONDITIONS AMONG AFRICAN AMERICAN AND LATINO POPULATIONS IN THE SOUTHEAST. WE AIM TO: SPECIFIC AIM 1: ESTABLISH THE HUMAN AND TECHNICAL INFRASTRUCTURE TO FOSTER HIGHLY COLLABORATIVE, TRANSDISCIPLINARY RESEARCH COLLABORATIONS FOCUSED ON USING TECHNOLOGY AND DATA SCIENCE TO REDUCE CHRONIC DISEASE DISPARITIES AMONG AFRICAN AMERICAN AND LATINO POPULATIONS IN THE SOUTHEASTERN UNITED STATES. SPECIFIC AIM 2: FACILITATE A REGIONAL, CROSS-INSTITUTIONAL PILOT AWARDS PROGRAM FOCUSED ON CHRONIC DISEASE DISPARITIES THAT NURTURES AND SUPPORTS CAREER DEVELOPMENT, ADVANCES USE OF DATA SCIENCE, TECHNOLOGY, AND BIOINFORMATICS TO ADDRESS THE COMPLEX DRIVERS OF HEALTH DISPARITIES, AND PROMOTES INCLUSIVE EXCELLENCE. SPECIFIC AIM 3: PROPEL NOVEL HEALTH DISPARITIES RESEARCH LEVERAGING TECHNOLOGY, INDIVIDUAL-LEVEL AND COMMUNITY- LEVEL SOCIAL DETERMINANTS OF HEALTH DATA, AND GENOMIC AND PHENOTYPIC DATA TO PREVENT, TREAT, AND MANAGE DIABETES, CARDIOVASCULAR DISEASE, OBESITY AND RELATED CONDITIONS IN AFRICAN AMERICAN AND LATINO POPULATIONS. SPECIFIC AIM 4: PARTNER WITH AFRICAN AMERICAN AND LATINO COMMUNITIES IN THE SOUTHEAST INTEGRATE THEIR PRIORITIES INTO THE CENTER’S INFRASTRUCTURE, AND COLLABORATIVELY DEVELOP, ADAPT, AND TEST SOCIALLY AND CULTURALLY APPROPRIATE INTERVENTIONS TO SECURE THE EARLIEST IMPACT ON ELIMINATING CHRONIC DISEASE DISPARITIES.

VANDERBILT-INGRAM CANCER CENTER SPORE IN GASTROINTESTINAL CANCER

CODA:?COVID AND?DIABETES?ASSESSMENT - PROJECT SUMMARY SEVERAL STUDIES HAVE FOUND THAT INFECTION WITH SARS-COV-2 AND COVID-19 DIAGNOSIS ARE ASSOCIATED WITH THE DEVELOPMENT AND PROGRESSION OF BOTH TYPE 1 (T1D) AND TYPE 2 DIABETES (T2D), POSSIBLY THROUGH INFECTION OF BETA CELLS, INCREASED INSULIN RESISTANCE, INCREASED INFLAMMATION AND FIBROSIS, AND OTHER BIOLOGICAL PROCESSES. THE PROPOSED STUDY WILL TAKE ADVANTAGE OF ROBUST EXISTING INFRASTRUCTURE TO RAPIDLY IDENTIFY, RECRUIT, AND RETAIN DIVERSE COHORTS OF ENGLISH AND SPANISH SPEAKING PEDIATRIC AND ADULT PATIENTS WITH RECENTLY DIAGNOSED T1D OR T2D. THE STUDY WILL INCLUDE 1600 STUDY PARTICIPANTS DIAGNOSED WITH DIABETES IN THE LAST 3 MONTHS, WHO HAVE HAD A KNOWN COVID-19 INFECTION IN THE PAST 90 DAYS AND THOSE WITH RECENT DIAGNOSIS OF DIABETES AND NO KNOWN COVID-19 INFECTION IN THE PAST YEAR. THE STUDY WILL LEVERAGE PCORNET, A UNIQUE NATIONAL NETWORK OF OVER 60 HEALTH SYSTEMS WITH ELECTRONIC HEALTH RECORD (EHR) DATA ON OVER 80 MILLION PATIENTS AND A TRACK RECORD FOR SUCCESSFUL STUDY RECRUITMENT. WE WILL QUERY EHR RECORDS TO SWIFTLY IDENTIFY POTENTIAL STUDY SUBJECTS WITH RECENT DIAGNOSIS OF DIABETES AND CONTACT THEM VIA PATIENT PORTALS, TELEPHONE, FACE-TO-FACE ENCOUNTERS, AND OTHER APPROACHES. WE WILL ALSO LEVERAGE THE T1D EXCHANGE (T1DX), A NATIONAL NETWORK OF 54 DIABETES CENTERS AND AN ONLINE PATIENT REGISTRY OF 17,000 INDIVIDUALS WITH T1D. CONSENTED PARTICIPANTS WILL PARTAKE IN REGULAR WEB/MOBILE OR TELEPHONE SURVEYS LEVERAGING A PREVIOUSLY DEVELOPED REDCAP/TWILIO PLATFORM. PARTICIPANTS WILL ALSO COME TO SITES FOR REGULAR SEROLOGICAL TESTING, AND A SUBSAMPLE WILL PARTICIPATE IN MORE ROBUST TESTING OF GLUCOSE TOLERANCE, BIOMARKERS, AND VASCULAR FUNCTION. THIS DATA WILL BE SUPPLEMENTED BY LONGITUDINAL EHR DATA FROM PARTICIPATING SITES AND ACROSS PCORNET. PARTICIPANTS WILL BE FOLLOWED FOR 2 YEARS. AIM 1 WILL EXAMINE IF PATIENTS WITH RECENT T2D WHO HAVE RECENT COVID-19 ARE MORE LIKELY TO HAVE WORSE GLYCEMIC CONTROL, INCREASED INFLAMMATION AND INCREASED INSULIN RESISTANCE THAN PATIENTS WITHOUT RECENT COVID-19. AIM 2 WILL EXAMINE IF PATIENTS WITH RECENT T1D WHO HAVE RECENT COVID-19 ARE MORE LIKELY TO HAVE WORSE GLYCEMIC CONTROL, INCREASED INFLAMMATION AND MORE RAPID REDUCTION IN BETA CELL FUNCTION THAN PATIENTS WITHOUT RECENT COVID-19. AIM 3 WILL EVALUATE A SUBSET OF PATIENTS WITH DIABETES TO EXAMINE IF COVID-19 IS ASSOCIATED WITH WORSE VASCULAR FUNCTION, INCREASED INFLAMMATION AND HYPERCOAGULABILITY. AIM 4 WILL EXPLORE THE ROLE OF GENOMIC/SOCIAL/ENVIRONMENTAL FACTORS ON INFLAMMATION AND METABOLIC FUNCTION. AIM 5 WILL LEVERAGE EHR DATA TO EXPLORE THE ROLE OF COVID-19 AND COVID-19 TREATMENTS ON DIABETES DEVELOPMENT AND DIABETES-RELATED OUTCOMES ACROSS THE PANDEMIC. THE STUDY WILL BE LED BY A TEAM WITH SIGNIFICANT EXPERIENCE RELATED TO COVID-19, POST-ACUTE SEQUELAE OF COVID-19 (PASC), OBESITY AND DIABETES IN CHILDREN AND ADULTS, EPIDEMIOLOGICAL RESEARCH, INFORMATICS, HEALTH SERVICES RESEARCH, GENOMICS, METABOLOMICS, PHYSIOLOGY, PATIENT AND FAMILY ENGAGEMENT AND OTHER AREAS. THE PROPOSED WORK WILL PROVIDE A DEEPER UNDERSTANDING OF THE RELATIONSHIP BETWEEN COVID-19 AND DIABETES, THAT CAN SUPPORT FUTURE INTERVENTIONS AND PUBLIC HEALTH APPROACHES TO IMPROVE HEALTH.

CORE GRANT IN VISION RESEARCH

CLINICAL AND TRANSLATIONAL SCIENCE COORDINATING CENTER

NATIENS: A PHASE III RANDOMIZED DOUBLE BLINDED STUDY TO DETERMINE THE MECHANISMS AND OPTIMAL MANAGEMENT OF STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS

BREAST CANCER GENETIC STUDY IN AFRICAN-ANCESTRY POPULATIONS

VANDERBILT CLINICAL ONCOLOGY RESEARCH CAREER DEVELOPMENT PROGRAM

IMPROVING PREDICTION OF DRUG ACTION

VALIDATION OF BIOMARKERS OF RISK FOR THE EARLY DETECTION OF LUNG CANCER

VANDERBILT CENTER FOR UNDIAGNOSED DISEASES (VCUD)

TENNESSEE VALLEY COOPERATIVE HUMAN TISSUE NETWORK

HARMONIST: A SCALABLE TOOLKIT FOR STANDARDIZING AND COORDINATING DATA SHARING ACROSS INTERNATIONAL RESEARCH NETWORKS

LONG-TERM NICOTINE TREATMENT OF MCI PA-14-077

STUDIES ON THE STRUCTURE OF BASEMENT MEMBRANES

THE ROLE OF INFLAMMATION IN CARDIOVASCULAR DISEASE

PHARMACOGENOMICS OF HIV THERAPY

INTEGRATIVE SINGLE-CELL ATLAS OF HOST AND MICROENVIRONMENT IN COLORECTAL NEOPLASTIC TRANSFORMATION

STRUCTURE BASED DESIGN OF ANTIBODIES AND VACCINES

CENTER OF EXCELLENCE IN PRECISION MEDICINE AND POPULATION HEALTH

GROWING RIGHT ONTO WELLNESS (GROW): CHANGING EARLY CHILDHOOD BMI TRAJECTORIES

AUTONOMIC RARE DISEASES CLINICAL RESEARCH CONSORTIUM

ETIOLOGICAL STUDIES OF GASTRIC CARCINOMA

ENHANCED SURVEILLANCE FOR NEW VACCINE PREVENTABLE DISEASES

ROLE OF ICOSANIODS IN RENAL FUNCTION

VANDERBILT ALZHEIMER'S DISEASE RESEARCH CENTER - VANDERBILT ALZHEIMER’S DISEASE RESEARCH CENTER – OVERALL PROJECT SUMMARY WE AIM TO ESTABLISH THE VANDERBILT ALZHEIMER’S DISEASE RESEARCH CENTER (VADRC) AS A WORLD-CLASS INTERDISCIPLINARY CENTER IN NASHVILLE, TENNESSEE. WITH HIGH REGIONAL BURDEN OF ALZHEIMER’S DISEASE (AD) AND RELATED DEMENTIAS (ADRD) AS WELL AS VASCULAR RISK FACTORS, THERE IS A PRESSING NEED TO UNDERSTAND THE COMPLEXITIES UNDERLYING THE INTERSECTION BETWEEN VASCULAR RISK AND ADRD. VASCULAR RISK FACTORS, THE MAJORITY OF WHICH ARE MODIFIABLE, ARE LINKED TO ADRD RISK AND HIGHLY PREVALENT IN OUR REGION, ESPECIALLY WITHIN THE BLACK AND AFRICAN AMERICAN COMMUNITY. THE VADRC’S MISSION IS TO CHARACTERIZE HOW VASCULAR BURDEN INTERSECTS WITH ADRD PATHOGENESIS, MANIFESTATION, PREVENTION, AND TREATMENT AT THE CELLULAR, SYSTEMS BIOLOGICAL, AND POPULATION LEVELS. THIS EFFORT WILL CAPITALIZE ON THE SCIENTIFIC STRENGTHS OF OUR CAMPUS-WIDE INVESTIGATORS, EXPANSIVE AND COLLABORATIVE INSTITUTIONAL RESOURCES, AND FOUNDATIONAL WORK COMPLETED OVER THE LAST SEVERAL YEARS. THE ADMINISTRATIVE CORE WILL SERVE AS THE HUB FOR ALL LOCAL ADRD RESEARCH ACTIVITIES AND COORDINATE AND INTEGRATE ALL CENTER INTERACTIONS AND COLLABORATIONS. THE OUTREACH, RECRUITMENT, AND ENGAGEMENT CORE WILL BUILD UPON EXISTING COMMUNITY PARTNERSHIPS TO BRING AWARENESS OF ADRD AND RELEVANT VASCULAR RISK FACTORS TO THE COMMUNITY. THE OUTREACH, RECRUITMENT, AND ENGAGEMENT CORE TEAM WILL RECRUIT PARTICIPANTS WITH A VASCULAR RISK PROFILE REFLECTIVE OF OUR LOCAL COMMUNITY INTO OUR CLINICAL CORE ALONGSIDE A SPECIFIC FOCUS ON OUTREACH IN THE BLACK AND AFRICAN AMERICAN COMMUNITY. THE CLINICAL CORE WILL ENROLL, DEEPLY PHENOTYPE, AND ANNUALLY FOLLOW 400 PARTICIPANTS, CAPTURING CLINICAL, NEUROPSYCHOLOGICAL, CARDIAC IMAGING, NEUROIMAGING, AND BIOFLUID DATA IN COLLABORATION WITH THE BIOMARKER CORE. THE NEUROPATHOLOGY CORE WILL OBTAIN POST-MORTEM BRAINS AND BIOFLUIDS FROM PARTICIPANTS, ALLOWING FOR COMPLETE POST-MORTEM CHARACTERIZATION OF ADRD AND VASCULAR PATHOLOGIES. OUR DATA MANAGEMENT AND STATISTICAL CORE WILL ENSURE ALL DATA COLLECTED IS PROPERLY STORED IN AN INTEGRATED INFORMATICS INFRASTRUCTURE, IS SHARED WITH NATIONAL REPOSITORIES, AND IS READILY ACCESSIBLE TO OTHER INVESTIGATORS VIA OUR WEB-BASED DATA SHARING PLATFORM. FINALLY, THE VADRC WILL FOSTER PROFESSIONAL DEVELOPMENT FOR THE NEXT GENERATION OF ADRD CLINICIANS, SCIENTISTS, AND LEADERS, WITH A PARTICULAR FOCUS ON SUPPORTING EARLY CAREER FACULTY SCHOLARS THROUGH THE RESEARCH EDUCATION COMPONENT. THE VADRC IS EXCEPTIONALLY WELL POSITIONED TO BECOME THE FIRST CENTER OF ITS KIND IN TENNESSEE AND SERVE A GROWING POPULATION SUFFERING FROM ADRD.

CLINICAL PHARMACOLOGY TRAINING PROGRAM

EFFECT OF EARLY WEIGHT BEARING ON REHABILITATION OUTCOMES IN PATIENTS WITH UNICONDYLAR PROXIMAL TIBIA FRACTURES AND BIMALLEOLAR ANKLE FRACTURES

INSTITUTIONAL CAREER DEVELOPMENT CORE

KINASE MODULATION OF NA+-DEPENDENT CI-COUPLED TRANSPORTERS IN MOUSE KIDNEY

GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONIST TREATMENT IN ADULT, OBESITY-RELATED, SYMPTOMATIC ASTHMA - PROJECT SUMMARY OBESITY IS CLEARLY DETRIMENTAL IN ASTHMA, YET WE LACK TOOLS TO TREAT THE UNIQUE OBESE ASTHMA PHENOTYPE. COMORBID OBESITY IMPACTS >40% OF ADULT ASTHMATICS1 AND INCREASES ASTHMA SEVERITY, SYMPTOMS AND EXACERBATIONS WHILE SIMULTANEOUSLY REDUCING THE EFFICACY OF CONVENTIONAL THERAPIES.2-5 OUR LONG-TERM GOAL IS TO DEVELOP NOVEL TREATMENTS FOR AIRWAY INFLAMMATION IN THE OBESE ASTHMA PHENOTYPE. OUR OVERALL OBJECTIVE, WHICH IS THE NEXT STEP IN TRANSLATING OUR PRECLINICAL AND PRELIMINARY CLINICAL FINDINGS, IS TO DETERMINE THE IMPACT OF GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS (GLP-1RA) ON ASTHMA CONTROL AND AIRWAY AND ADIPOSE INFLAMMATION IN ADULTS WITH OBESE ASTHMA. OUR CENTRAL HYPOTHESIS IS THAT GLP-1RA IMPROVE ASTHMA CONTROL AND REDUCE AIRWAY INFLAMMATION DUE TO DIRECT EFFECTS ON THE RESPIRATORY TRACT IN OBESE ASTHMA. TO GENERATE THE PROOF-OF- CONCEPT DATA TO SUPPORT DEFINITIVE PHASE 3 CLINICAL TRIALS OF GLP-1RA IN THE OBESE ASTHMA PHENOTYPE AND TEST OUR CENTRAL HYPOTHESIS, WE PROPOSE THE FOLLOWING SPECIFIC AIMS: 1) DETERMINE THE EFFICACY OF GLP-1RA ON ASTHMA CONTROL AND ASSESS TOLERABILITY IN OBESE ASTHMA AND 2) DETERMINE THE TISSUE-SPECIFIC IMPACT OF GLP- 1RA ON INFLAMMATION IN THE AIRWAY AND ADIPOSE IN OBESE ASTHMA. IN A 12-WEEK DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED TRIAL OF ORAL SEMAGLUTIDE 7 MG ONCE DAILY IN ADULT SUBJECTS WITH OBESITY-RELATED, SYMPTOMATIC ASTHMA WITHOUT DMII, WE WILL TEST THE HYPOTHESES THAT SEMAGLUTIDE IMPROVES ASTHMA CONTROL (AIM 1A), IS TOLERATED (AIM 1B) AND REDUCES TYPE-2 AND NON-TYPE 2 AIRWAY INFLAMMATION INDEPENDENT OF WEIGHT LOSS (AIM 2). THE PRIMARY CLINICAL OUTCOME WILL BE CHANGE FROM BASELINE IN ACQ-7. THE PRIMARY MECHANISTIC OUTCOME WILL BE CHANGE FROM BASELINE IN SERUM PERIOSTIN. BECAUSE INSULIN RESISTANCE IS VARIABLE IN OBESITY AND BASELINE BLOOD EOSINOPHIL COUNTS ARE OFTEN PREDICTIVE OF RESPONSE TO ASTHMA THERAPEUTICS, THESE MARKERS WILL BE USED FOR PRESPECIFIED SUBGROUP ANALYSES. SUBCUTANEOUS ABDOMINAL ADIPOSE AND RESPIRATORY TRACT SAMPLES AT BASELINE AND 5 AND 12 WEEKS OF THERAPY WILL BE COMPARED USING RNA SEQUENCING TO TEST THE HYPOTHESIS THAT GLP-1RA REDUCE INFLAMMATION TO RESTORE HOMEOSTASIS IN THE RESPIRATORY TRACT OPPOSITE TO CHANGES IN ADIPOSE TISSUE IN OBESE ASTHMA. THIS PROPOSAL FACILITATES THE COLLECTION OF THE NECESSARY CLINICAL, MECHANISTIC, AND TOLERABILITY DATA TO INFORM THE DESIGN OF A DEFINITIVE PHASE III CLINICAL TRIAL OF A GLP-1RA IN ASTHMA. IT THEREBY SUPPORTS THE RAPID DEVELOPMENT OF A NOVEL THERAPEUTIC CLASS FOR ASTHMA AND REPRESENTS A PARADIGM SHIFT IN THE APPROACH TO THERAPEUTIC INTERVENTION IN ASTHMA THROUGH THE TARGETING OF A METABOLIC PATHWAY WHICH REGULATES UPSTREAM INFLAMMATION ACROSS MULTIPLE ORGAN SYSTEMS, MAY BE DISEASE MODIFYING, AND ULTIMATELY GLUCOCORTICOID SPARING.

MICROBIOME, METABOLITES, AND ALCOHOL IN HIV TO REDUCE CVD (META HIV CVD) - THE OVERARCHING THEME FOR THIS PROGRAM PROJECT GRANT (PPG) IS THAT ALCOHOL ASSOCIATED GUT DYSBIOSIS AND GUT DYSBIOTIC METABOLITES ARE CARDIOVASCULAR DISEASE (CVD) RISK FACTORS AMONG PEOPLE LIVING WITH HIV INFECTION (PLWH) WHO ARE HEAVY DRINKERS. THE GOALS OF THIS RESEARCH ARE (1) TO DETERMINE IF A TAILORED PROBIOTIC (I.E., CONTAINS BACTERIA SUPPORTING BUTYRATE SYNTHESIS) CAN MITIGATE ALCOHOL ASSOCIATED GUT DYSBIOSIS AND LOWER LEVELS OF MICROBIAL TRANSLOCATION, INFLAMMATION, AND IMPROVE HARMFUL DYSBIOTIC METABOLITE PROFILES (E.G. TRIMETHYLAMINE N OXIDE, TMAO) AND (2) TO DETERMINE IF THESE METABOLITES ARE ASSOCIATED WITH INCIDENT CVD AND DEATH AMONG PLWH. WE HYPOTHESIZE THAT, AMONG PLWH, A PROBIOTIC VS. PLACEBO CAN MITIGATE ALCOHOL ASSOCIATED GUT DYSBIOSIS AND LOWER LEVELS OF MICROBIAL TRANSLOCATION, INFLAMMATION, AND IMPROVE METABOLITE PROFILES (PROJECT 1 RCT, N=250); AND THAT HARMFUL ALTERATIONS OF THESE METABOLITES WILL BE ASSOCIATED WITH HIGHER RISK OF INCIDENT CVD AND DEATH (PROJECT 2 COHORT, N=2,900). PROJECT 1 WILL BE CONDUCTED AT PAVLOV STATE MEDICAL UNIVERSITY IN ST. PETERSBURG, RUSSIA, THE SAME SITE AS OUR GUT MICROBIOME AND METABOLITE STUDIES (ACME HIV AND TMAO HIV). PROJECT 2 WILL LEVERAGE THE VETERANS AGING COHORT STUDY, AN OBSERVATIONAL COHORT OF VETERANS LIVING WITH AND WITHOUT HIV. THE PROJECTS WILL BE SUPPORTED BY OUR ADMINISTRATIVE CORE AT VANDERBILT UNIVERSITY MEDICAL CENTER AND THE INTEGRATED METAGENOMICS AND METABOLOMICS CORE AT THE UNIVERSITY OF LOUISVILLE'S ALCOHOL RESEARCH CENTER (ULARC). THE LATTER IS THE CORE FOR ACME HIV AND WILL GENERATE THE METAGENOMICS AND METABOLOMICS FOR THIS PPG. THE FORMER WILL COORDINATE ALL STUDY PROJECTS/CORES AND INTEGRATE THE VANDERBILT SCHOLARS IN HIV AND HEART, LUNG, BLOOD, AND SLEEP RESEARCH NIH K12 TRAINING PROGRAM INTO THE PPG. OUR PRELIMINARY DATA: (1) HIV INFECTION IS A CVD RISK FACTOR; (2) INFLAMMATION IS ASSOCIATED WITH INCREASED RISK OF CVD AMONG PLWH; (3) AMONG PLWH, HEAVY DRINKING IS ASSOCIATED WITH INCREASED CVD RISK AND CORRELATED WITH MEASURES OF GUT DYSBIOSIS, CHARACTERIZED BY LOSS OF BUTYRATE PRODUCING BACTERIA; (4) GUT DYSBIOSIS AMONG PLWH WHO ARE HEAVY DRINKERS IS CORRELATED WITH HIGHER LEVELS OF INFLAMMATION, TMAO, AND ADVERSE BILE ACID METABOLITE PROFILES; AND (5) ULARC DATA IN MURINE MODELS SHOW HEAVY DRINKING CAUSES DYSBIOSIS, THAT DYSBIOSIS LEADS TO INCREASED BIOMARKER LEVELS OF INFLAMMATION, AND THAT PROBIOTIC ADMINISTRATION TARGETING ALCOHOL-ASSOCIATED GUT DYSBIOSIS ATTENUATES THE RISE IN THESE INFLAMMATORY BIOMARKERS EVEN IN THE PRESENCE OF ALCOHOL CONSUMPTION. CROSS PROJECT VALIDATION: BIOSPECIMENS FROM PROJECT 1 WILL BE USED TO VALIDATE SIGNIFICANT FINDINGS IN PROJECT 2. METABOLITES SIGNIFICANTLY ASSOCIATED WITH ALCOHOL AND CVD IN PROJECT 2, WILL BE EXPLORED IN PROJECT 1 TO SEE IF PROBIOTICS FAVORABLY IMPACT THE LEVELS OF THOSE METABOLITES. THE MICROBIOME, METABOLITES, AND ALCOHOL IN HIV TO REDUCE CVD (META HIV CVD) PPG WILL INFORM PROBIOTICS' ROLE AS STANDARD ADJUNCTIVE THERAPY COMPLEMENTING ALCOHOL INTERVENTIONS AMONG PLWH WHO ARE HEAVY DRINKERS AND ADVANCE THE UNDERSTANDING OF HOW ALCOHOL ASSOCIATED GUT DYSBIOSIS AND ITS METABOLITES CONTRIBUTE TO CVD AND DEATH.

ROLE OF MT-MMPS IN RENAL DEVELOPMENT

INTEGRATED PROGRAM FOR HUMAN PANCREAS PROCUREMENT AND ANALYSIS

INTEGRATED APPROACH TO STUDY EARLY AND LATE EVENTS IN COLONIC NEOPLASIA: MOUSE TO MAN

OVERALL: EUNICE KENNEDY SHRIVER INTELLECTUAL AND DEVELOPMENTAL DISABILITIES RESEARCH CENTER AT VANDERBILT

HOST-MEDIATED ZINC SEQUESTRATION DURING ACINETOBACTER BAUMANNII INFECTION

SYSTEMATICALLY MAPPING VARIANT EFFECTS FOR CARDIOVASCULAR GENES - CARDIOVASCULAR DISEASES ARE LEADING GLOBAL CAUSES OF DEATH AND DISABILITY, PRESENTING AS INTERRELATED PHENOTYPES OF ATHEROSCLEROTIC VASCULAR DISEASE, HEART FAILURE, AND ARRHYTHMIAS. THEY ARISE FROM INTERACTIONS BETWEEN ENVIRONMENTAL FACTORS AND COMMON AND RARE GENETIC VARIANTS, INCLUDING RELATIVELY COMMON MENDELIAN LIPID DISORDERS, CARDIOMYOPATHIES, AND ARRHYTHMIAS THAT COLLECTIVELY OCCUR IN AT LEAST 1/100 INDIVIDUALS. THE AVAILABILITY OF GENETIC SEQUENCING IS ALTERING CLINICAL MANAGEMENT, BUT A MAJOR BARRIER TO THE WIDESPREAD APPLICATION OF THIS PRACTICE IS THAT THE FUNCTION OF THE VAST MAJORITY OF VARIANTS IN KEY CARDIOVASCULAR DISEASE GENES IS UNKNOWN. VARIANT EFFECT MAPS THAT DEFINE FUNCTION FOR NEARLY ALL MISSENSE VARIANTS IN A TARGET SEQUENCE OFFER A WAY FORWARD. THIS PROJECT BRINGS TOGETHER SCIENTISTS AT THE FOREFRONT OF VARIANT EFFECT MAPPING IN DIVERSE CELLULAR SYSTEMS, ILLUMINATING UNDERLYING CARDIOVASCULAR BIOLOGY, ESTABLISHING RELATIONSHIPS BETWEEN VARIANT FUNCTION AND HUMAN PHENOTYPES, AND WORKING WITH OTHERS IN MULTI-INSTITUTIONAL COLLABORATIONS. OUR CARDIOVAR TEAM WILL GENERATE A COMPREHENSIVE ATLAS OF VARIANT EFFECT MAPS FOR KEY CARDIOVASCULAR DISEASE GENES. IN AIM 1, WE WILL DEVELOP, OPTIMIZE, AND VALIDATE A RANGE OF HIGH-THROUGHPUT CELLULAR ASSAYS. WE WILL USE A RANGE OF GENERALIZABLE (E.G. SURFACE ABUNDANCE) AND BESPOKE (E.G. ELECTROPHYSIOLOGICAL, LIPOPROTEIN UPTAKE) ASSAYS TO DIRECTLY MEASURE VARIANT FUNCTION IN DISEASE-RELEVANT CONTEXT. ASSAYS WILL BE ASSESSED BY THEIR ABILITY TO DISCRIMINATE PATHOGENIC FROM BENIGN VARIANTS. IN AIM 2, WE WILL USE IN SITU TARGETED MUTAGENESIS OR INSERTION OF VARIANT CONSTRUCTS AT A SAFE HARBOR SITE TO GENERATE POOLS OF CELLS CAPTURING ALL SINGLE-NUCLEOTIDE CHANGES IN TARGET GENES. WE WILL THEN DEPLOY EXISTING VALIDATED ASSAYS AND THOSE EMERGING FROM AIM 1 TO GENERATE AND VALIDATE VARIANT EFFECT MAPS AT SCALE. FUNCTIONAL SCORES AND UNCERTAINTY ESTIMATES WILL BE DERIVED AND EVALUATED, BOTH BY PERFORMANCE ON PATHOGENIC AND BENIGN VARIANTS AND ON CORRELATION WITH DISCRETE AND QUANTITATIVE PHENOTYPES IN CLINICAL COHORTS. IN AIM 3, WE WILL DERIVE BIOLOGICAL AND CLINICAL INSIGHTS FROM VARIANT EFFECT MAPS. DISCORDANT CASES, WHERE VARIANT SCORES DIVERGE FROM CLINICAL ANNOTATION, WILL BE FURTHER INVESTIGATED IN ZEBRAFISH, IPSC-CARDIOMYOCYTES, AND AUTOMATED PATCH CLAMPING SYSTEMS. THROUGH A COMBINATION OF HYPOTHESIS-DRIVEN ANALYSIS AND MACHINE LEARNING MODELS, WE WILL REVEAL RELATIONSHIPS AMONG VARIANT EFFECTS, PROTEIN STRUCTURE, PROTEIN FUNCTION, AND HUMAN PHENOTYPES. TO OPTIMIZE USE OF THE ATLAS, WE WILL PROVIDE A PORTAL SERVING AS A VARIANT-CENTRIC DECISION SUPPORT SYSTEM FOR EVALUATING FUNCTIONAL EVIDENCE OF PATHOGENICITY. WE WILL RELEASE VARIANT EFFECT MAP DATA PRE- PUBLICATION VIA MAVEDB (THAT WE CO-DEVELOPED) AND SHARE ALL RENEWABLE VARIANT ASSAY REAGENTS. THE CARDIOVAR ATLAS OF MISSENSE VARIANT EFFECTS, COVERING KEY CARDIOVASCULAR DISEASE GENES, WILL BE AN ESSENTIAL AND INTERPRETABLE COMMUNITY RESOURCE FOR CLINICAL AND MECHANISTIC STUDIES OF CARDIOVASCULAR DISEASE.

GENETIC PRIVACY AND IDENTITY IN COMMUNITY SETTINGS - GETPRECISE

INTEGRATED, INDIVIDUALIZED, AND INTELLIGENT PRESCRIBING (I3P) CLINICAL TRIAL NETWORK

H. PYLORI RELATIONSHIP TO DIGESTIVE DISEASES AND CANCER

OPTIMIZING CARDIOVASCULAR STEM CELLS FOR CARDIAC REPAIR AND REGENERATION

VANDERBILT-COORDINATED HUMAN VIROME COLLABORATIVE CENTER (V2C2) - VIRUSES ARE RESPONSIBLE FOR SIGNIFICANT MORBIDITY/MORTALITY AT THE HEART OF MOST OF GLOBAL PANDEMICS OF THE 21ST CENTURY. RECENT DEVELOPMENTS IN TECHNICAL AND BIOINFORMATIC CAPABILITIES TO ADDRESS VIRAL SEQUENCE DIVERSITY IN A HIGH-THROUGHPUT CONTEXT ALONGSIDE INTEGRATED HOST RESPONSES HAVE USHERED IN THE POTENTIAL FOR INVESTIGATING VIRAL PRESENCE AND CONSEQUENCES AT EPIDEMIOLOGIC SCALE. HERE, WE ESTABLISH THE VANDERBILT-COORDINATED VIRUS CHARACTERIZATION CENTER (V2C2) TO RESPOND TO RFA-RM-23-019 TO ADDRESS THE CENTRAL CALL OF THE HUMAN VIROME PROGRAM (HVP)—TO PROVIDE A COMPREHENSIVE, ANNOTATED, HOST-CONTEXTUALIZED VIROME. THE CENTRAL THEME/HYPOTHESIS OF V2C2 IS THAT UNRECOGNIZED EUKARYOTIC/PROKARYOTIC VIRUSES IN HUMAN ECOLOGY (1) EXHIBIT IMPORTANT INTERACTIONS WITH HOST BIOLOGY AND FLORA, WITH PREVALENCE OF VIRAL PERSISTENCE OR INTEGRATION RELATED TO VARIATION IN BIOLOGICALLY RELEVANT PHENOTYPES IN HEALTHY INDIVIDUALS (E.G., OBESITY, INFLAMMATION). TO ADDRESS THIS HYPOTHESIS, WE WILL STUDY (1) ≈2250 HISPANIC/LATINX INDIVIDUALS AT THE US-MEXICO BORDER (AGES 8-90; 1750 WITH 2 SERIAL SAMPLES ALREADY COLLECTED WITH UP TO ≈20 YEARS FOLLOW-UP; 500 WITH 3 SERIAL SAMPLES TO BE PROSPECTIVELY COLLECTED OVER ≈4 YEARS); (2) ≈200 CHILDREN (AGES 0-5, CANOE-VU) WITH SERIAL SAMPLES (SOME ALREADY COLLECTED). WE PROPOSE A BROAD SAMPLING SCHEME FOR PROSPECTIVE SAMPLES, SPANNING OCULAR, NASAL, OROPHARYNGEAL, PLASMA, BLOOD (EXTRACELLULAR VESICLES, PBMCS, PLATELETS), URINE, AND STOOL SAMPLES, AND ACCOMPANYING PLACENTAL AND BREAST MILK SAMPLES (PEDIATRIC COHORT), AND WILL PRIORITIZE PLASMA (ALL SAMPLES) AND 3 ADDITIONAL SAMPLE TYPES (PROSPECTIVE ONLY) BASED ON CONSORTIUM DISCUSSION. OUR HOST-CONTEXTUALIZED VIRAL CHARACTERIZATION APPROACH (AIM 1) WILL INCLUDE VIRAL WHOLE METAGENOMIC/METATRANSCRIPTOMIC SEQUENCING (TO ASSESS VIRAL PRESENCE, FUNCTION) WITH TARGETED CAPTURE-BASED CONFIRMATION. WITH OTHER HVP MEMBERS (E.G., FUNCTIONAL INTERACTION AWARDEES), WE WILL STUDY HOST-VIRAL INTERACTIONS (AIM 2) VIA (1) HOST GENOMICS (FOR INTEGRATION); (2) VIRAL TROPISM STUDIES (USING SINGLE CELL AND IN VITRO INFECTION STUDIES); (3) HOST RESPONSE CHARACTERIZATION (AT THE CELLULAR AND ORGANISM-WIDE LEVEL WITH PROTEOMICS/TRANSCRIPTOMICS). IN AIM 3, WE WILL ESTABLISH A REPOSITORY OF HARMONIZED METADATA AND MOLECULAR INFORMATION FOR DATA SHARING IN AN ETHICALLY RESPONSIBLE MANNER TO ALLOW MULTI-OMIC CONNECTIONS BETWEEN LONGITUDINAL PHENOTYPES AND HOST-VIRAL CHARACTERISTICS. WE WILL EXECUTE THIS VISION COLLABORATIVELY WITHIN THE HVP VIA (1) A CORE STRUCTURE (LED BY ADMINISTRATIVE) THAT ADDRESSES BIOSPECIMEN COLLECTION, ASSAY, DATA ANALYSIS/SUBMISSION, AND ETHICAL/LEGAL/SOCIAL IMPLICATIONS THAT (2) FOLLOW A PRE-DETERMINED SERIES OF MILESTONES (PREDICATED ON ESTABLISHING CONSORTIUM-WIDE PROTOCOLS IN THE INITIAL 6 MONTH PLANNING PHASE). V2C2 LEADERSHIP HAS (1) PUBLISHED EXPERTISE IN LARGE SAMPLE VIRAL CHARACTERIZATION/BIOLOGICAL DISCOVERY, WITH EXTENSIVE PRELIMINARY DATA BEARING DIRECTLY ON HVP; (2) COHORT EPIDEMIOLOGY; (3) EXTENSIVE CONSORTIUM EXPERIENCE IN NIH, CDC, AND COMMON FUND INITIATIVES. THE EFFECTIVENESS OF V2C2 IS AUGMENTED BY STRONG COMMUNITY ENGAGEMENT (CCHC), INSTITUTIONAL SUPPORT, AND PROGRAM MANAGEMENT STAFF WITH EXPERIENCE AT THE SCALE OF HVP.

DEVELOPING THE VUMC MICRO FACILITY TO ADVANCE INNOVATIVE BSL3 RESEARCH - PROJECT ABSTRACT IN RESPONSE TO THE GLOBAL INCREASE AND SPREAD OF INFECTIOUS DISEASE AND ITS IMPACT ON HUMAN HEALTH, VANDERBILT UNIVERSITY MEDICAL CENTER (VUMC) HAS ESTABLISHED A TRANS-INSTITUTIONAL STRATEGIC FRAMEWORK FOR INFECTION AND IMMUNOLOGY RESEARCH, INCLUDING SIGNIFICANT INVESTMENTS IN RESEARCH FOCUSED ON HIGHLY VIRULENT PATHOGENS. VANDERBILT INVESTIGATORS ARE RAPIDLY ADVANCING DISCOVERY IN THE FIELDS OF MICROBIAL PATHOGENESIS, THERAPEUTIC DEVELOPMENT, AND VACCINE DESIGN INCLUDING CRITICAL RESEARCH COMBATTING COVID-19. VANDERBILT’S GROWING LEADERSHIP IN MICROBIAL PATHOGENESIS MAKES RESEARCH AT BIOSAFETY LEVEL 3 (BSL3) CRITICAL TO ENABLING BREAKTHROUGHS. HOWEVER, VANDERBILT’S TWO SMALL BSL3 LABORATORIES SERVE INDIVIDUAL INVESTIGATORS AND OPERATE AT CAPACITY. MOST VANDERBILT RESEARCHERS THEREFORE HAVE NO ACCESS TO BSL3 FACILITIES. THE PROPOSED MICROBIAL INFECTIOUS DISEASE CORE RESOURCE (MICRO) WILL BE A MODERN, COMPREHENSIVE BSL3 SHARED RESEARCH FACILITY THAT SIGNIFICANTLY EXPANDS CAPACITY FOR BSL3 RESEARCH AT VANDERBILT. REGIONAL PARTNERSHIPS WITH INSTITUTIONS SUCH AS THE UNIVERSITY OF TENNESSEE AND MEHARRY MEDICAL COLLEGE WILL ADVANCE BSL3 WORK ACROSS THE SOUTHEASTERN UNITED STATES TO MAXIMIZE THE MICRO’S BENEFIT AND IMPACT. KEY PROJECT GOALS WILL BE ACCOMPLISHED THROUGH THE RENOVATION OF 3,587 NET SQUARE FEET (NSF) OF SPACE IN THE HEART OF VANDERBILT’S BIOMEDICAL RESEARCH ZONE. THE MICRO WILL BE FLEXIBLY CONFIGURED TO MEET STRINGENT ISOLATION REQUIREMENTS FOR BSL3 AND SELECT AGENT PATHOGENS AND CAN BE RAPIDLY MODIFIED AS RESEARCH AND PUBLIC HEALTH NEEDS EVOLVE. THE MICRO WILL CONTAIN THREE BSL3 SUITES WITH A TOTAL OF SEVEN PROCEDURE ROOMS AND WILL BE SERVED BY NEW AND/OR REROUTED MECHANICAL AND PLUMBING SYSTEMS THAT COMPLETELY ISOLATE THE BSL3 SPACE. A 1,038 NSF BSL3-DEDICATED SPACE WILL BE CONSTRUCTED TO ENCLOSE NEW MECHANICAL EQUIPMENT, INCLUDING DEDICATED AIR HANDLING UNITS AND AN EXHAUST FILTRATION SYSTEM. THE PROJECT WILL BE DESIGNED TO MEET LEED SILVER STANDARDS AS WELL AS NATIONAL INSTITUTES OF HEALTH AND CENTERS FOR DISEASE CONTROL AND PREVENTION GUIDELINES. THE MICRO WILL BE DEVELOPED AND MANAGED BY AN EXPERIENCED PROJECT MANAGER AND BSL3 FACILITY MANAGER WORKING WITH THE VANDERBILT INSTITUTE OF INFECTION, IMMUNOLOGY AND INFLAMMATION, OFFICE OF RESEARCH, AND SCIENTIFIC ADVISORY BOARD TO ENSURE EFFECTIVE PLANNING, OPERATION, AND SHARED ACCESS TO THE NEW FACILITY. OVERALL, THE REQUESTED RENOVATIONS WILL ENABLE SUBSTANTIAL IMPROVEMENTS IN INFRASTRUCTURE, CAPACITY, AND CAPABILITIES FOR BSL3 EXPERIMENTATION. THIS FACILITY WILL ENHANCE INFECTION AND IMMUNOLOGY RESEARCH THAT WILL LEAD TO SCIENTIFIC BREAKTHROUGHS IN THESE FIELDS AT THE NEXUS OF BASIC RESEARCH, CLINICAL CARE, AND PUBLIC HEALTH.

INTERACTIONS OF INTRARENAL DOPAMINE AND CYCLOOXYGENASE-2

BIOPHYSICAL BASIS OF FUNCTIONAL CONNECTIVITY BY MRI

BUILDING INTERDISCIPLINARY RESEARCH CAREERS IN WOMEN'S HEALTH

2/2-DOPAMINERGIC DYSFUNCTION IN LATE-LIFE DEPRESSION (THE D3 STUDY)

THE MIND USA STUDY

VANDERBILT INTEGRATED CENTER OF EXCELLENCE IN MATERNAL AND PEDIATRIC PRECISION THERAPEUTICS (VICE-MPRINT) - PROJECT SUMMARY / ABSTRACT - OVERALL THERE IS A RAPIDLY EXPANDING KNOWLEDGE BASE ENABLING PRECISION THERAPEUTICS FOR A NUMBER OF HUMAN DISEASES, BUT THERE ARE SIGNIFICANT UNMET NEEDS IN EVIDENCE GENERATION TO SUPPORT TRANSLATION TO THE TREATMENT OF CHILDREN AND PREGNANT/POST-PARTUM WOMEN. THE RECENT WIDESPREAD ADOPTION OF ELECTRONIC HEALTH RECORDS (EHRS) AND THE LINKAGE OF THESE DATA TO OTHER LARGE DATASETS REPRESENTS AN UNPRECEDENTED OPPORTUNITY FOR CLINICAL RESEARCH AND DISCOVERY. THE GOALS OF THIS CENTER OF EXCELLENCE IN MATERNAL AND PEDIATRIC PRECISION THERAPEUTICS ARE: TO ADDRESS KEY KNOWLEDGE GAPS AND PERFORM CLINICAL RESEARCH IN PHARMACOGENOMICS AND NEONATAL OPIOID WITHDRAWAL SYNDROME; TO LEVERAGE DATA SCIENCE METHODOLOGIES AND DEVELOP NOVEL TOOLS THAT SUPPORT MATERNAL AND PEDIATRIC PRECISION THERAPEUTICS RESEARCH; AND TO ENHANCE TRAINING FOR MATERNAL AND PEDIATRIC PRECISION THERAPEUTICS AT THE LOCAL, REGIONAL, AND NATIONAL LEVELS. WE BRING TO THIS EFFORT A UNIQUE COLLECTION OF INVESTIGATORS, INSTITUTIONAL SUPPORT, TOOLS, AND RESOURCES THAT ENABLE A PARADIGM-SHIFT FROM CURRENT NORMS OF SLOW, INCREMENTAL PROGRESS. PROJECT 1 WILL: USE A COMMUNITY ENGAGED APPROACH TO ILLUMINATE KNOWLEDGE OF, ATTITUDES ABOUT, AND PRIORITIES FOR PHARMACOGENOMICS; VALIDATE PHARMACOGENOMIC ASSOCIATIONS FOR MATERNAL AND PEDIATRIC POPULATIONS USING THE INNOVATIVE AND GENERALIZABLE STRATEGY OF EHR PHENOTYPING; AND IDENTIFY AND QUANTIFY VARIANTS WITH UNKNOWN FUNCTIONAL CONSEQUENCE IN DIVERSE INDIVIDUALS TO INFORM FUTURE RESEARCH EFFORTS AND REDUCE DISPARITIES. PROJECT 2 WILL: DEVELOP AND VALIDATE EHR-BASED ALGORITHMS TO IDENTIFY A COHORT OF OPIOID- EXPOSED INFANTS AND THEIR MOTHERS (DYADS) AND CREATE A NOVEL LINKAGE OF THESE DATA TO STATE-WIDE DATA; TEST THE HYPOTHESIS THAT USE OF MEDICATIONS FOR OPIOID USE DISORDER IS ASSOCIATED WITH IMPROVED EARLY OUTCOMES; AND TEST THE HYPOTHESIS THAT OPIOID USE DISORDER TREATMENT IS ASSOCIATED WITH IMPROVEMENTS IN THE NOVEL LONGITUDINAL OUTCOME OF DYADIC STABILITY. THESE PROJECTS ARE LED BY MULTIDISCIPLINARY TEAMS THAT INCLUDE INVESTIGATORS IN PEDIATRICS AND OBSTETRICS, AND WHO ARE NATIONALLY RECOGNIZED LEADERS IN THEIR RESPECTIVE FIELDS. BOTH PROJECTS WILL BE SUPPORTED BY A SCIENTIFIC CORE – THE PHENOTYPING SUPPORT CORE - WHICH ENHANCES EACH PROJECT WITH EXPERT PHENOTYPING, MACHINE LEARNING/ARTIFICIAL INTELLIGENCE, AND EXPERIENCE IN GENERALIZING AND DISSEMINATING PHENOTYPING APPROACHES. AN ADMINISTRATIVE CORE WILL PROVIDE LOGISTICAL SUPPORT FOR THE CENTER, SUPERVISE TRAINING OPPORTUNITIES, AND ENSURE SCIENTIFIC INTERCHANGE WITHIN THE CET AND WITH THE MPRINT HUB. THIS WORK WILL CONTRIBUTE TO INNOVATIVE APPROACHES TO PRECISION THERAPEUTICS FOR MOTHERS AND CHILDREN AND WILL DEVELOP THE EDUCATIONAL INFRASTRUCTURE TO SUPPORT THE TRAINING OF PHYSICIAN-SCIENTISTS TO SUPPORT FURTHER ADVANCES WELL INTO THE FUTURE.

RETINAL GANGLION CELL REPLACEMENT IN CLINICALLY RELEVANT MODELS OF OPTIC NEUROPATHY

SOUTHERN ENVIRONMENTAL HEALTH STUDY - SUMMARY APPROXIMATELY 80% OF HUMAN CANCERS ARE CAUSED BY ADVERSE ENVIRONMENTAL EXPOSURES, UNHEALTHY LIFESTYLES AND/OR THEIR INTERACTIONS WITH HOST SUSCEPTIBILITY FACTORS. PREVIOUS STUDIES HAVE MOSTLY FOCUSED ON EVALUATING BEHAVIORAL RISK FACTORS, SUCH AS TOBACCO SMOKING, PHYSICAL INACTIVITY, UNHEALTHY DIETS AND OBESITY. WHILE MORE THAN 80,000 CHEMICALS HAVE BEEN REGISTERED BY THE EPA, VERY FEW OF THEM HAVE BEEN ADEQUATELY INVESTIGATED IN RELATION TO HUMAN CANCERS IN EPIDEMIOLOGIC STUDIES. THERE ARE CONSIDERABLE CHALLENGES IN STUDYING ENVIRONMENTAL EXPOSURES IN EPIDEMIOLOGIC STUDIES. HUMANS ARE EXPOSED TO LARGE NUMBERS OF CHEMICAL AND PHYSICAL SUBSTANCES AND THEIR MIXTURES, TYPICALLY AT LOW LEVELS OVER EXTENDED PERIODS OF TIME. PREVIOUS ENVIRONMENTAL EPIDEMIOLOGIC STUDIES HAVE MOSTLY EVALUATED EXPOSURES ONE AT A TIME. HOWEVER, BECAUSE OF A TYPICALLY WEAK ASSOCIATION OF A GIVEN EXPOSURE WITH DISEASE RISK, COUPLED WITH LIMITED TOOLS AND BIOMARKERS FOR ENVIRONMENTAL ASSESSMENTS, MOST STUDIES HAVE FAILED TO PROVIDE CONVINCING EVIDENCE TO LINK ENVIRONMENTAL EXPOSURES TO CANCER RISK. TO OVERCOME THESE CHALLENGES, WE PROPOSE TO ESTABLISH A LARGE COHORT STUDY INCLUDING ~50,000 PARTICIPANTS WITH AN EXTENSIVE COLLECTION OF SURVEY AND GEOSPATIAL EXPOSURE DATA, AS WELL AS BIOLOGICAL AND ENVIRONMENTAL SAMPLES, TO ADDRESS CRITICAL ISSUES IN THE ENVIRONMENTAL ETIOLOGY OF CANCER. UTILIZING A FRAMEWORK OF COMMUNITY-ENGAGEMENT TO HELP INFORM RESEARCH, ENHANCE RECRUITMENT AND RETENTION EFFORTS, AND DISSEMINATE RESULTS, WE WILL FOCUS ON RECRUITING LOW-INCOME AND MINORITY POPULATIONS WHO ARE MORE LIKELY TO LIVE IN RESOURCE DEPRIVED AND HEAVILY POLLUTED COMMUNITIES. WE PROPOSE TO INCLUDE 1,500 OF THE STUDY PARTICIPANTS IN A DEEP-EXPOSOME STUDY TO COMPREHENSIVELY ASSESS THE EXPOSOME, IDENTIFY KEY BIOMARKERS OF EXTERNAL EXPOSURES, EXAMINE ASSOCIATIONS OF EXTERNAL AND INTERNAL METRICS WITH CANCER-RELATED BIOLOGICAL RESPONSES, AND DEVELOP CUMULATIVE EXPOSOME RISK SCORES. THE PROPOSED STUDY WILL ENABLE DIRECT EVALUATION OF ASSOCIATIONS OF ENVIRONMENTAL EXPOSURES WITH CANCER OUTCOMES IN THE LONG TERM, AND ASSOCIATIONS WITH CANCER INTERMEDIATE BIOMARKERS IN THE SHORT TERM. BY INTEGRATING ENVIRONMENTAL EXPOSURE DATA FROM MULTIPLE SOURCES, INCLUDING PERSONAL EXPOSURE ASSESSMENTS AND BIOLOGIC MARKERS OF ENVIRONMENTAL EXPOSURE AND RESPONSES, THIS PROPOSED STUDY WILL ALLOW US TO SYSTEMATICALLY AND RIGOROUSLY INVESTIGATE ENVIRONMENTAL EXPOSURES IN RELATION TO CANCER RISK AND PROVIDE SUBSTANTIAL NOVEL DATA TO IMPROVE THE UNDERSTANDING OF BOTH EXTERNAL AND INTERNAL EXPOSOMES, WHICH WILL PAVE THE WAY FOR FUTURE REMEDIATION OF ENVIRONMENTALLY INDUCED CANCER.

TOWARD A MECHANISM-BASED APPROACH TO TREATING CARDIAC ARRHYTHMIA

THE ELECTRONIC MEDICAL RECORDS AND GENOMICS (EMERGE) NETWORK PHASE III - COORDINATING CENTER (U01)

VANDERBILT GENOME-ELECTRONIC RECORDS (VGER) PROJECT

LONG-TERM NICOTINE TREATMENT OF MILD COGNITIVE IMPAIRMENT - PRECURSOR CONDITIONS TO ALZHEIMER’S DISEASE (AD) SUCH AS MILD COGNITIVE IMPAIRMENT (MCI) ARE NOW A TARGET OF PATIENT IDENTIFICATION AND POTENTIAL TREATMENT, AS STUDIES CLEARLY SHOWING THAT THE RISK OF PROGRESSION TO DEMENTIA IS VERY HIGH. DESPITE ATTEMPTS TO DEVELOP NEW TREATMENTS FOR AD AND ITS PRECURSOR, MCI, METHODS OF INTERRUPTING THE COURSE OF ILLNESS AND PREVENTING PROGRESSION HAVE PROVEN ELUSIVE. TREATMENT STRATEGIES FOR AD OR MCI BASED ON MOLECULAR PATHOLOGIES (SUCH AS ASS) HAVE THUS FAR PRODUCED EQUIVOCAL OR NEGATIVE RESULTS. LOSSES OF CHOLINERGIC NEURONS AND PARTICULARLY NICOTINIC CHOLINERGIC RECEPTORS HAVE BEEN SHOWN TO BE PRINCIPALLY RELATED TO COGNITIVE DECLINE IN AD. HOWEVER, CURRENTLY APPROVED TREATMENTS FOR AD HAVE NOT SIGNIFICANTLY IMPROVED MCI, DESPITE CLEAR EVIDENCE OF ALTERATION OF CHOLINERGIC FUNCTION AT THIS STAGE, THUS NONSPECIFIC ENHANCEMENT OF CHOLINERGIC FUNCTION DOES NOT APPEAR TO BE A FRUITFUL STRATEGY FOR EITHER ENHANCING LONG-TERM COGNITIVE FUNCTIONING IN MCI, NOR RETARDING THE PROGRESSION TO AD. THERE IS A CONTINUING SEARCH FOR NEW TREATMENTS THAT WILL IMPROVE COGNITIVE SYMPTOMS WHILE POTENTIALLY BE DISEASE MODIFYING. NICOTINE MAY BE ONE OF THOSE MOLECULES AND IS EASILY AVAILABLE, INEXPENSIVE, AND EASY TO USE. WE HAVE PREVIOUSLY PERFORMED A DOUBLE-BLIND 6-MONTH PILOT TRIAL SHOWING THAT NICOTINE TREATMENT SIGNIFICANTLY IMPROVED COGNITIVE PERFORMANCE IN THE AREAS OF ATTENTION AND EPISODIC MEMORY, SHOWED IMPROVING GLOBAL RATINGS OF FUNCTIONING AND SELF-RATED MEMORY PROBLEMS, AND WAS WELL TOLERATED WITH AN IMPRESSIVE SAFETY PROFILE AND NO ABUSE LIABILITY. IN THE PREVIOUS GRANT PERIOD, WE INITIATED A LARGER LONGER TRIAL, A DEFINITIVE 2-YEAR MULTI-CENTER CLINICAL TRIAL TO TEST WHETHER DAILY TRANSDERMAL NICOTINE WILL PRODUCE SUSTAINED COGNITIVE, CLINICAL, AND FUNCTIONAL BENEFITS IN PATIENTS WITH MCI AND TO TEST WHETHER NICOTINE WILL CHANGE THE UNDERLYING BIOLOGY RELATED TO DEVELOPING AD BY MONITORING BIOLOGICAL MARKERS INCLUDING STRUCTURAL AND FUNCTIONAL BRAIN IMAGING AND MEASURES OF AD PATHOLOGY IN SPINAL FLUID. IN THIS SUBSEQUENT GRANT PERIOD, WE WILL ENLARGE THE COHORT TO ACCOUNT FOR COVD-19 PANDEMIC ATTRITION, COMPLETE THE ENROLLMENT OF THE STUDY, AND TAKE ADVANTAGE OF NEW BIOMARKER APPROACHES (E.G. AMYLOID PET) TO EXPAND OUR ANALYSIS OF THE POTENTIAL IMPACT OF NICOTINE ON BRAIN PATHOLOGY OF MCI/AD. THIS PROPOSED STUDY HAS BROAD CLINICAL AND SCIENTIFIC SIGNIFICANCE. IF THE HYPOTHESES ARE VALIDATED, THESE FINDINGS WOULD SUPPORT A NOVEL, BROADLY AVAILABLE, AND INEXPENSIVE INTERVENTION FOR MCI. FURTHER, THE UNIQUE BIOLOGICAL INFORMATION WILL BE OBTAINED REGARDING THE EFFECTS OF NICOTINIC STIMULATION ON AD BIOMARKERS, BRAIN STRUCTURE/FUNCTION, AND BRAIN AMYLOID WILL MAKE AN INVALUABLE CONTRIBUTION TO AD RESEARCH. THIS WILL BE THE LONGEST TRIAL OF NICOTINIC STIMULATION ON BRAIN FUNCTION TO DATE AND IF SUCCESSFUL WOULD LEAD TO COMBINED TRIALS WITH OTHER SYMPTOMATIC AGENTS AND/OR AGENTS THAT DIRECTLY INTERACT WITH ASS OR TAU-RELATED MECHANISMS.

SMALL GTP BINDING PROTEINS IN GASTROINTESTINAL MUCOSA

THE ROLE OF HB-EGF IN RENAL EPITHELIAL CELL INJURY

EUNICE KENNEDY SHRIVER INTELLECTUAL AND DEVELOPMENTAL DISABILITIES RESEARCH CENTER AT VANDERBILT UNIVERSITY

COMPARISON OF HIGH VS. STANDARD DOSE INFLUENZA VACCINE IN PEDIATRIC SOLID ORGAN TRANSPLANT RECIPIENTS - PROJECT SUMMARY INFLUENZA VIRUS IS A SIGNIFICANT PATHOGEN IN PEDIATRIC SOLID ORGAN TRANSPLANT (SOT) RECIPIENTS. HOWEVER, THESE INDIVIDUALS RESPOND POORLY TO STANDARD-DOSE (SD) INACTIVATED INFLUENZA VACCINE (IIV). RECENT STUDIES HAVE INVESTIGATED TWO STRATEGIES TO OVERCOME POOR IMMUNE RESPONSES IN SOT RECIPIENTS: (1) ADMINISTRATION OF HIGH- DOSE (HD)-IIV COMPARED TO SD-IIV AND (2) TWO DOSES OF SD-IIV COMPARED TO ONE DOSE OF SD-IIV IN THE SAME INFLUENZA SEASON. ONE STUDY COMPARED HD-IIV VS. SD-IIV IN ADULT SOT RECIPIENTS AND NOTED THAT HD-IIV WAS SAFE AND MORE IMMUNOGENIC; HOWEVER, THE MEDIAN POST-TRANSPLANT PERIOD WAS 38 MONTHS. A PHASE I PEDIATRIC STUDY COMPARING A SINGLE DOSE OF HD-IIV VS. SD-IIV WAS SAFE WITH HIGHER IMMUNOGENICITY, BUT THE STUDY WAS LIMITED BY SMALL SAMPLE SIZE AND MEDIAN POST-TRANSPLANT VACCINE ADMINISTRATION WAS 26 MONTHS. IN ANOTHER PHASE II TRIAL OF ADULT SOT RECIPIENTS, TWO DOSES OF SD-IIV ONE MONTH APART COMPARED TO ONE-DOSE OF SD-IIV REVEALED MODESTLY INCREASED IMMUNOGENICITY WHEN GIVEN AT A MEDIAN OF 18 MONTHS POST-TRANSPLANT. THEREFORE, THESE STUDIES LACK BOTH EVALUATION IN THE EARLY POST-TRANSPLANT PERIOD AND SUBSTANTIVE PEDIATRIC POPULATIONS. ADDITIONALLY, THE ADMINISTRATION OF TWO-DOSES OF HD-IIV IN THE SAME INFLUENZA SEASON HAS NOT BEEN EVALUATED IN PEDIATRIC SOT RECIPIENTS. THUS, THE OPTIMAL IMMUNIZATION STRATEGY FOR PEDIATRIC SOT RECIPIENTS LESS THAN 24 MONTHS POST-TRANSPLANT IS UNKNOWN. IN ADDITION, IMMUNOLOGIC PREDICTORS AND CORRELATES OF INFLUENZA VACCINE IMMUNOGENICITY IN PEDIATRIC SOT RECIPIENTS HAVE NOT BEEN WELL-DEFINED. THE CENTRAL HYPOTHESIS OF OUR PROPOSAL IS THAT PEDIATRIC SOT RECIPIENTS 1-23 MONTHS POST-TRANSPLANT WHO RECEIVE TWO DOSES OF HD- QUADRIVALENT INACTIVATED INFLUENZA VACCINE (QIV) WILL HAVE SIMILAR SAFETY BUT HIGHER HAI GEOMETRIC MEAN TITERS (GMTS) TO INFLUENZA ANTIGENS COMPARED TO PEDIATRIC SOT RECIPIENTS RECEIVING TWO DOSES OF SD- QIV. TO TEST THIS HYPOTHESIS AND ADDRESS THE CRITICAL KNOWLEDGE GAPS OUTLINED ABOVE, WE PROPOSE TO CONDUCT A PHASE II, MULTI-CENTER, RANDOMIZED-CONTROLLED IMMUNOGENICITY AND SAFETY TRIAL COMPARING TWO DOSES OF HD-QIV TO TWO DOSES OF SD-QIV IN PEDIATRIC KIDNEY, HEART, AND/OR LIVER SOT RECIPIENTS 1-23 MONTHS POST-TRANSPLANT. THE RESULTS OF THIS STUDY WILL ADDRESS SIGNIFICANT KNOWLEDGE GAPS REGARDING INFLUENZA VACCINE STRATEGIES AND IMMUNE RESPONSES IN PEDIATRIC SOT RECIPIENTS AND WILL GUIDE VACCINE RECOMMENDATIONS IN THE EARLY POST- TRANSPLANT PERIOD.

ROLE OF RENAL MACROPHAGES IN RECOVERY FROM ACUTE KIDNEY INJURY

TYPE IV PROTEIN SECRETION IN HELICOBACTER PYLORI

OXGR1 IN RENAL INTERCALATED CELLS, SALT TRANSPORT AND DIURETIC EFFICACY

ADDRESSING HEALTH LITERACY AND NUMERACY TO PREVENT CHILDHOOD OBESITY

SHAPING OF THE MICROENVIRONMENT IN COLONIC PRE-CANCER BY EPITHELIA AND MICROBIOTA - THE VANDERBILT TBEL CENTER ASSEMBLES A MULTI-DISCIPLINARY TEAM OF FIELD-SPECIFIC EXPERTS TO COLLABORATIVELY INVESTIGATE THE BASIC AND TRANSLATIONAL PATHWAYS OF COLONIC PRE-CANCER PROGRESSION. OUR FOUNDATIONAL WORK ON TWO SUBTYPES OF COLONIC PRE-CANCERS, ADENOMAS (ADS) AND SESSILE SERRATED LESIONS (SSLS), DEPICTS THE EARLY ORIGINS OF TUMORIGENESIS THAT ARE SHAPED BY MODULATION OF THE IMMUNE MICROENVIRONMENT VIA NEOPLASTIC CELLS AND THE MICROBIOTA. WE HAVE SHOWN THAT SSLS ORIGINATE FROM GASTRIC METAPLASIA ARISING FROM THE MUCOSAL SURFACE IN A CYTOTOXIC IMMUNE MICROENVIRONMENT, WHEREAS ADS ARISE FROM STEM CELL-DERIVED WNT ACTIVATION AT THE CRYPT BASE. IN THIS CENTER, WE WILL EXTEND OUR INVESTIGATION OF SPECIFIC BIOLOGICAL MECHANISMS TOWARDS THE DEVELOPMENTAL TRAJECTORIES OF THESE PRE-MALIGNANT LESIONS INTO PROGRESSION OR INDOLENCE. BASIC PROJECT 1 INVESTIGATES THE CONTRIBUTION OF NEUTROPHIL-AD CROSSTALK, LARGELY VIA DIPEPTIDASE 1 (DPEP1) BOTH AT THE CELL SURFACE AND RELEASED IN SMALL EXTRACELLULAR VESICLES, IN THE COURSE OF AD PROGRESSION. TRANSLATIONAL PROJECT 2 INVESTIGATES, IN HUMAN PROSPECTIVE STUDIES, THE ASSOCIATION OF PKS+ ESCHERICHIA COLI THAT INDUCES GENOTOXIC STRESS WITH PRE-CANCER PROGRESSION, AS WELL AS COLON EPITHELIAL CELL AND MUCOSA MECHANISMS THAT MAY CONTRIBUTE TO A POLYP-PROMOTING MICROENVIRONMENT. BASIC PROJECT 3 INVESTIGATES ACQUISITION OF STEMNESS IN MODULATING ANTIGEN PRESENTATION TO CYTOTOXIC T CELLS IN THE CONTEXT OF CO-EVOLUTION BETWEEN NEOPLASTIC CELLS AND THE IMMUNE SYSTEM. JOINT ANALYSIS OF COMMON COLORECTAL PRE-CANCER TISSUES WILL FACILITATE AN ONGOING PROCESS OF ITERATION AND INTEGRATION ACROSS ALL PROJECTS. OUR TBEL CENTER OFFERS A COMPLEMENTARY BLEND, FROM REDUCTIONIST AND SYSTEMS BIOLOGY APPROACHES, TO INVESTIGATE CRITICAL FACTORS INVOLVED IN THE PROGRESSION OF PRE-CANCEROUS TUMORS OF THE COLON TO CRC. THE WORK WILL UTILIZE CUTTING-EDGE TECHNOLOGIES ON HUMAN TISSUES, INCLUDING SINGLE-CELL AND SPATIAL TRANSCRIPTOMICS, SMALL EXTRACELLULAR VESICLE PROFILING, MULTIPLEX IMAGING, LONGITUDINAL DATA ANALYSIS, AND NEXT-GENERATION COMPUTATIONAL ALGORITHMS. IN ADDITION, SUBSTANTIAL HUMAN POLYP RESOURCES PREVIOUSLY ESTABLISHED BY THE VANDERBILT GI SPECIALIZED PROGRAMS OF RESEARCH EXCELLENCE AND THE NCI MOONSHOT HUMAN TUMOR ATLAS NETWORK WILL BE LEVERAGED BY THE SAME TEAM OF INVESTIGATORS IN THE TBEL CENTER. IN ADDITION, AN INNOVATIVE CO-CULTURE SYSTEM WILL BE EMPLOYED BY EACH PROJECT, WHERE POLARIZING PRE-CANCER ORGANOIDS CAN BE CO-CULTURED WITH KEY MICROENVIRONMENT ELEMENTS EXPOSED TO NEOPLASTIC CELLS FROM THE LUMINAL OR BASAL SIDE. THIS WORK WILL INFORM THE MODELING OF TUMOR DEVELOPMENT TRAJECTORIES AND IDENTIFY MECHANISMS OF PROGRESSION THAT WILL ENABLE IMPROVEMENTS IN RISK STRATIFICATION, PRECISION PREVENTION, AND INTERCEPTION FOR INDIVIDUALS WITH COLORECTAL PRE- CANCERS.

INTERVENTIONS AGAINST THE MOLECULAR ETIOLOGY OF BMPR2-INDUCED PAH

REVISION ACL RECONSTRUCTIONS: A COMPARATIVE EFFECTIVENESS TREATMENT STUDY

HUMAN PANCREAS ANALYSIS PROGRAM-T2D

VANDERBILT-EMORY-CORNELL-DUKE CONSORTIUM FOR GLOBAL HEALTH FELLOWS (VECDOR)

VANDERBILT CENTER FOR DIABETES TRANSLATION RESEARCH

NOVEL INTEGRATED ANALYSES OF HUMAN DIABETIC NEPHROPATHY

IMAGING HIPPOCAMPAL FUNCTION IN PSYCHOSIS

IDENTIFYING A DISEASE GENE CAUSING PRIMARY OPEN ANGLE GLAUCOMA

STRUCTURE-FUNCTION ANALYSIS OF H. PYLORI VACA

CAUSAL: COHORT TO AUGMENT THE UNDERSTANDING OF SARCOMA SURVIVORSHIP ACROSS THE LIFESPAN - PROJECT SUMMARY SARCOMAS REPRESENT A RARE AND HIGHLY HETEROGENEOUS SUBTYPE OF TUMORS THAT MAY DEVELOP ACROSS THE LIFESPAN. IN THE UNITED STATES (US), THERE ARE APPROXIMATELY 14,000 NEW CASES ANNUALLY, WITH APPROXIMATELY 65% SURVIVAL. ASIDE FROM THOSE INCLUDED IN PEDIATRIC CANCER SURVIVOR COHORT STUDIES, THERE ARE NO SARCOMA SURVIVOR COHORTS IN WHICH TO SYSTEMATICALLY STUDY RECURRENCE, ORGAN TOXICITY, FUNCTION, QUALITY OF LIFE, AND SURVIVAL AS WELL AS THEIR PREDICTORS. WE PROPOSE TO ADDRESS THESE CRITICAL GAPS IN KNOWLEDGE BY ESTABLISHING A COHORT OF APPROXIMATELY 2100 SARCOMA SURVIVORS THROUGH THE VANDERBILT UNIVERSITY MEDICAL CENTER (VUMC) SARCOMA TREATMENT CENTER, WHICH IS AMONGST THE LARGEST SARCOMA PROGRAMS IN THE US, IN EXISTENCE SINCE 1987. IN THIS COHORT, WE WILL SYSTEMATICALLY COLLECT REPEATED INFORMATION ON DISEASE, TREATMENT, RESPONSE, RELAPSE, TREATMENT-RELATED TOXICITY, SOCIODEMOGRAPHICS, LIFESTYLE, FUNCTIONAL STATUS, QUALITY OF LIFE, PHYSICAL HEALTH OUTCOMES, AND SURVIVAL, TOGETHER WITH BIOSPECIMENS (TUMOR TISSUE AND PERIPHERAL BLOOD SAMPLES). WE HYPOTHESIZE THAT: 1) EXTRINSIC FACTORS, TUMOR BIOLOGY, AND GERMLINE GENOMICS CONTRIBUTE TO ONCOLOGIC OUTCOMES AND LONG-TERM ORGAN TOXICITY; 2) HEALTHY LIFESTYLE, E.G., HIGH QUALITY OF DIET, EXERCISE, ABSTINENCE FROM CIGARETTE SMOKING AND ALCOHOL DRINKING MITIGATE THE ADVERSE HEALTH CONSEQUENCES, IMPROVE SURVIVAL AND QUALITY OF LIFE AMONG SARCOMA SURVIVORS; AND 3) LIQUID BIOPSY TOOLS, DEVELOPED THROUGH IDENTIFYING GENOMIC DRIVERS OF SARCOMA, WILL BE OF PREDICTIVE AND PROGNOSTIC UTILITY. OUR AIMS FOR CURRENT GRANT PERIOD ARE TO EVALUATE1) THE IMPACT OF DISEASE, TREATMENT, SOCIODEMOGRAPHIC AND LIFESTYLE CONTRIBUTORS ON ADVERSE ONCOLOGIC AND NON-ONCOLOGIC OUTCOMES AND MORTALITY IN THE COHORT; 2) THE ROLE OF DRUG METABOLISM AND DNA REPAIR GENE FUNCTIONAL POLYMORPHISMS, GENETICALLY PREDICTED GENE EXPRESSION LEVELS, AND POLYGENIC RISK SCORES, ON TREATMENT EFFICACY AND THERAPY-INDUCED NORMAL TISSUE TOXICITY; AND 3) GENOMIC DRIVERS OF SARCOMA TO DEVELOP PERSONALIZED LIQUID BIOPSY ASSAYS FOR MONITORING TREATMENT RESPONSE, RECURRENCE, AND MINIMAL RESIDUAL DISEASE. ESTABLISHMENT OF A PROSPECTIVE COHORT OF SARCOMA SURVIVORS ACROSS THE LIFESPAN, WITH EXTENSIVE AND WELL CHARACTERIZED CLINICAL AND EPIDEMIOLOGIC DATA, PATIENT REPORTED OUTCOMES, TUMOR TISSUE AND SERIAL BLOOD SAMPLES BUILDS A FOUNDATION FOR A LONG-TERM PROSPECTIVE INVESTIGATION ON LIFE AFTER SARCOMA. THIS EFFORT IS CRITICALLY IMPORTANT TO IMPROVE THE UNDERSTANDING OF A RARE TUMOR AFFECTING THE LIFESPAN BUT SERIOUSLY UNDERREPRESENTED IN RESEARCH. IDENTIFICATION OF HEALTH OUTCOMES AND THEIR PREDICTIVE AND PROGNOSTIC FACTORS CAN LEAD TO PRECISION TREATMENT AND SURVIVORSHIP CARE, WHICH ARE CURRENTLY CLINICALLY UNMET NEEDS.

DETERMINANTS OF CORONAVIRUS FIDELITY IN REPLICATION AND PATHOGENESIS

CLINICAL AND TRANSLATIONAL RESEARCH TRAINING PROGRAM IN PULMONARY MEDICINE

MOLECULAR PHYSIOLOGY OF A VOLUME-SENSITIVE CIC CHANNEL

VANDERBILT ANTIBODY AND ANTIGEN DISCOVERY FOR CLOSTRIDIOIDES DIFFICILE VACCINES - OVERALL PROJECT SUMMARY VANDERBILT ANTIBODY AND ANTIGEN DISCOVERY FOR CLOSTRIDIOIDES DIFFICILE VACCINES VANDY-CDV CLOSTRIDIOIDES DIFFICILE IS A SPORE-FORMING ANAEROBIC BACTERIUM THAT IS THE LEADING CAUSE OF HOSPITAL- ACQUIRED GASTROINTESTINAL INFECTION IN THE UNITED STATES. THE RISING INCIDENCE OF COMMUNITY- ACQUIRED C. DIFFICILE INFECTION (CDI) IN OTHERWISE HEALTHY ADULTS IS LINKED TO INCREASED ANTIBIOTIC USE AND THE EMERGENCE OF NEW STRAINS. CDI SYMPTOMS AND PATHOLOGY ARE MEDIATED BY TWO LARGE HOMOLOGOUS TOXINS, TCDA AND TCDB, AND THEREFORE THE TOXINS REPRESENT ATTRACTIVE TARGETS FOR PREVENTION AND THERAPEUTIC STRATEGIES. WHILE EFFORTS CENTERED AROUND THE USE OF TOXOIDS FOR IMMUNIZATION HAVE SHOWN PROMISE IN REDUCING THE SEVERITY OF SYMPTOMS, THE TOXOID APPROACH HAS NOT RESULTED IN A DECREASED INCIDENCE OF CDI IN CLINICAL TRIALS. THERE ARE SEVERAL OPPORTUNITIES TO IMPROVE UPON EXISTING VACCINE STRATEGIES. FIRST, LARGE SCALE GENOMIC STUDIES SHOW THAT TCDB IS UNDERGOING RAPID EVOLUTIONARY CHANGE; THE IDENTIFICATION OF CONSERVED TOXIN EPITOPES CAN BE USED TO DIRECT THE IMMUNE RESPONSE TOWARD THE PRODUCTION OF BROADLY NEUTRALIZING RESPONSES. SECOND, THE IDENTIFICATION OF CONSERVED ANTIGENS ON THE SURFACE OF THE VEGETATIVE BACTERIA OR SPORES THAT CAN SERVE AS IMMUNOGENS WILL ALLOW THE HOST TO ELICIT MUCOSAL IMMUNE RESPONSES THAT PREVENT BACTERIAL COLONIZATION. THE INCLUSION OF MUCOSAL IMMUNIZATION ROUTES IS EXPECTED TO FURTHER ENHANCE VACCINE EFFICACY AND DURABILITY. THE OVERARCHING GOAL OF THE VANDY-CDV PROGRAM IS TO IDENTIFY TOXIN SUBUNITS AND NOVEL CELL SURFACE ANTIGENS THAT, WHEN COMBINED, PROMOTE DURABLE PROTECTION AGAINST C. DIFFICILE INFECTION AND SYMPTOMS. AMONG MANY INNOVATIVE STRENGTHS, THE APPROACH INCLUDES THE USE OF HUMAN CDI PATIENT SAMPLES AS A RESOURCE FOR UNDERSTANDING WHAT ANTIGENS PROMOTE IGG, IGA, AND SIGA RESPONSES IN NATURAL INFECTION. THE APPROACH ALSO INCLUDES THE USE OF POWERFUL SINGLE B CELL SORTING AND SEQUENCING METHODS. THE ABILITY TO IDENTIFY PAIRED HEAVY AND LIGHT CHAIN SEQUENCES FROM INDIVIDUAL MEMORY B CELLS BINDING TOXINS AND/OR BACTERIA ALLOWS FOR THE PRODUCTION OF UNIQUE ANTIBODIES THAT CAN THEN BE USED AS TOOLS FOR EPITOPE MAPPING AND NOVEL ANTIGEN DISCOVERY. A THIRD HIGHLIGHT OF THE APPROACH INVOLVES THE USE OF A NEWLY CREATED C. DIFFICILE TRANSPOSON LIBRARY WHICH WILL BE USED TO IDENTIFY NOVEL ANTIGENS IN AN IN VIVO VACCINATION/CHALLENGE EXPERIMENT. OTHER INNOVATIONS INCLUDE A STRUCTURE-GUIDED APPROACH TO IDENTIFYING POTENT, NEUTRALIZING EPITOPES AND A SYSTEMATIC EVALUATION OF HOW INTESTINAL LYMPHOCYTE RESPONSES VARY WITH ROUTES OF IMMUNIZATION. VACCINE EFFICACY AND THE MUCOSAL CORRELATES OF PROTECTION WILL BE EVALUATED IN PRE-CLINICAL MODELS OF COLONIZATION, INFECTION, AND RECURRENCE. AT THE END OF FIVE YEARS, WE EXPECT TO HAVE THE PRE-CLINICAL DATA NEEDED TO ADVANCE A NOVEL ANTIGEN COCKTAIL AND IMMUNIZATION STRATEGY FORWARD INTO HUMAN SAFETY AND EFFICACY TRIALS.

FROM GWAS TO PHEWAS: SCANNING THE EMR PHENOME FOR GENE-DISEASE ASSOCIATIONS

ENHANCED SURVEILLANCE FOR NEW VACCINE PREVENTABLE DISEASES

DISCOVERY OF PANCREATIC SIGNATURES IN TYPE 2 DIABETES MELLITUS

TRAINING GRANT IN GASTROENTEROLOGY

RESEARCH TRAINING IN DIABETES AND ENDOCRINOLOGY

STRUCTURE BASED DESIGN OF TRIMER INTERFACE EPITOPE FOCUSED UNIVERSAL INFLUENZA VACCINES

HELICOBACTER PYLORI AND GASTROINTESTINAL BIOLOGY

OUTCOME DEPENDENT SAMPLING STUDIES OF LONGITUDINAL DATA: DESIGN AND ANALYSIS

SELECTION AND REGULATION OF B LYMPHOCYTES IN IDDM

INDUCTION AND EVOLUTION OF METAPLASIA IN THE STOMACH

PATHOBIOLOGY OF A HEME INDUCIBLE TRANSPORTER IN STAPHYLOCOCCUS AUREUS

IMPLEMENTATION OF RAPID HIV TESTING AND LINKAGE TO HIV TREATMENT OR PREVENTION AMONG VULNERABLE POPULATIONS IN TENNESSEE

NEUROPROTECTIVE EFFECTS OF VASCULAR ENDOTHELIAL GROWTH FACTOR IN ALZHEIMER'S DISEASE

VANDERBILT O'BRIEN KIDNEY CENTER

SHANGHAI WOMENS HEALTH STUDY

INTERDISCIPLINARY TRAINING PROGRAM IN LUNG RESEARCH

IMPROVING DIAGNOSTIC ACCURACY FOR ACUTE HEART FAILURE - PROJECT SUMMARY/ABSTRACT ACUTE HEART FAILURE (HF) IS HIGHLY MORBID, LETHAL, AND COSTLY. IT IS A DIFFICULT DIAGNOSIS TO MAKE GIVEN ITS SYMPTOMS AND SIGNS OVERLAP WITH OTHER CARDIAC AND NON-CARDIAC CONDITIONS. IN THE EMERGENCY DEPARTMENT (ED), MISDIAGNOSIS OF ACUTE HF IS COMMON AND ASSOCIATED WITH ADVERSE OUTCOMES. BIOMARKER TESTING CAN FACILITATE ACCURATE DIAGNOSIS; HOWEVER, NATRIURETIC PEPTIDES (NP) ARE THE ONLY GUIDELINE RECOMMEND BIOMARKER OF HF FOR DIAGNOSTIC TESTING, AND ARE BETTER FOR RULING-OUT, RATHER THAN RULING-IN, ACUTE HF. EVEN WITH NP TESTING, IN CONTEMPORARY CLINICAL PRACTICE MISDIAGNOSIS OF ACUTE HF STILL OCCURS IN 10 TO 45% OF PATIENTS PRESENTING TO THE ED WITH DYSPNEA. CLINICAL PREDICTION MODELS INCLUDING MULTIPLE BIOMARKERS HOLD PROMISE FOR IMPROVING DIAGNOSTIC ACCURACY. THE FEW PRIOR STUDIES INVESTIGATING A MULTIPLE BIOMARKER APPROACH FOR DIAGNOSING ACUTE HF WERE LIMITED BY CONSTRAINT TO HIGHLY CORRELATED MARKERS FROM KNOWN BIOLOGIC PATHWAYS, RELATIVELY SMALL SAMPLE SIZES, LACK OF INCLUSION OF ALL A PRIORI SELECTED BIOMARKERS INTO A SINGLE MODEL, AND ABSENCE OF VALIDATION COHORTS. OUR STUDY DESIGN ADDRESSES THESE LIMITATIONS. RECENT ADVANCES IN “OMICS” ENABLE NOVEL BIOMARKER DISCOVERY ON A LARGER SCALE AND INVESTIGATIONS LESS “BIASED” BY EXISTING KNOWLEDGE. THUS, OUR OVERARCHING HYPOTHESIS IS A MULTI-MARKER MODEL INCORPORATING NOVEL PROTEINS DISCOVERED WITH PLASMA PROTEOMICS IMPROVES DIAGNOSTIC ACCURACY FOR ACUTE HF. IN PRELIMINARY WORK, WE PERFORMED A PROOF OF CONCEPT STUDY UTILIZING PLASMA PROTEOMICS TO DISCOVER A MULTI-MARKER PANEL OF 21 BIOMARKERS WHICH IMPROVED DIAGNOSTIC ACCURACY FOR ACUTE HF BEYOND CURRENT CLINICAL PRACTICE USING CLINICAL DATA AND NP LEVELS. OUR PROMISING PRELIMINARY DATA MOTIVATE BROADER DISCOVERY IN A LARGER SAMPLE SIZE WITH SUBSEQUENT DERIVATION AND VALIDATION OF A MULTI-MARKER MODEL FOR DIAGNOSING ACUTE HF IN INDEPENDENT SAMPLES OF ADEQUATE SIZE. OUR SPECIFIC AIMS ARE TO: 1) EXPAND THE DISCOVERY COHORT AND REFINE THE MULTI-MARKER PANEL OF 21 BIOMARKERS TO IMPROVE DIAGNOSTIC ACCURACY FOR ACUTE HF, 2) DERIVE A MODEL FOR DIAGNOSING ACUTE HF INCORPORATING THE 21-BIOMARKER PANEL, 3) TEST PERFORMANCE OF THE MULTI-MARKER MODEL IN A PROSPECTIVE VALIDATION COHORT, AND 4) ASSESS THE INCREMENTAL VALUE OF THE MULTI- MARKER MODEL FOR DIAGNOSING ACUTE HF. IN AIM 1, EXISTING PLASMA SAMPLES FROM 989 PATIENTS WILL BE USED TO ASSAY 925 PROTEINS TO DISCOVER A SMALLER SET OF NOVEL BIOMARKERS MOST STRONGLY ASSOCIATED WITH AN ADJUDICATED ACUTE HF DIAGNOSIS. IN AIM 2, WE WILL UTILIZE AN EXISTING PROSPECTIVE OBSERVATIONAL COHORT, EMROC-AHF, TO DERIVE THE MULTI-MARKER MODEL IN 1,000 PATIENTS WHO PRESENTED TO THE ED WITH ACUTE DYSPNEA. IN AIM 3, FROM FOUR EDS IN DETROIT, MI AND NASHVILLE, TN WE WILL PROSPECTIVELY RECRUIT A NEW SAMPLE OF 1,000 PATIENTS PRESENTING WITH ACUTE DYSPNEA AND ADJUDICATE THE PRESENCE OF ACUTE HF BY CARDIOLOGIST PANEL REVIEW. IN AIM 4, WE WILL COMPARE OUR MULTI-MARKER MODEL AGAINST THE CURRENT CLINICAL APPROACH FOR DIAGNOSING ACUTE HF USING THE COHORTS FOR AIMS 2 AND 3. GIVEN THE BURDEN OF HF, THE FREQUENCY OF INACCURATE DIAGNOSIS AND ITS ADVERSE CONSEQUENCES, WE WILL ADDRESS A SIGNIFICANT UNMET NEED BY IMPROVING DIAGNOSTIC ACCURACY FOR ACUTE HF.

BRIDGING THE CHILDHOOD EPILEPSY TREATMENT GAP IN AFRICA (BRIDGE)

EARLY INTERVENTION SERVICES

VANDERBILT-EMORY-CORNELL-DUKE CONSORTIUM FOR GLOBAL HEALTH FELLOWS (VECDOR)

CONVERGENT SCIENCE CANCER CONSORTIUM FOR IMMUNE CELL ENGINEERING

NEURAL CORRELATES OF RECOVERY FROM APHASIA AFTER ACUTE STROKE

VANDERBILT ALZHEIMER'S DISEASE RESEARCH CENTER

ROLE OF CHX10 IN EMBRYONIC RETINAL PROGENITOR CELLS

PREVENTION OF VEIN GRAFT FAILURE

BIOCHEMISTRY AND PATHOPHYSIOLOGY OF FACTOR XI AND CONTACT ACTIVATION

ROLE OF GENDER IN TH17-MEDIATED INFLAMMATION IN SEVERE ASTHMA

POSTDOCTORAL TRAINING IN BIOMEDICAL MRI AND MRS

IMPROVING IDENTIFICATION AND HEALTHCARE FOR PATIENTS WITH INHERITED CANCER SYNDROMES: EVIDENCE-BASED EMR IMPLEMENTATION USING A WEB-BASED COMPUTER PLATFORM

CELLULAR, MOLECULAR AND QUANTITATIVE IMAGING ANALYSIS OF SCREENING-DETECTED LUNG ADENOCARCINOMA

PRIMARY PREVENTION OF STROKE IN CHILDREN WITH SCD IN SUB-SAHARAN AFRICA II

RURAL LEADERSHIP ED FOR NDRP & FAMILIES BASED IN MID-TN

RESTING STATE CONNECTIVITY IN PRIMATE SPINAL CORD

1/3-RECURRENCE MARKERS, COGNITIVE BURDEN AND NEUROBIOLOGICAL HOMEOSTASIS IN LATE-LIFE DEPRESSION (REMBRANDT)

CELL PLASTICITY IN THE ORIGIN OF GASTRIC CARCINOGENESIS - ABSTRACT GASTRIC CANCER IS THE 4TH LEADING CAUSE OF CANCER-RELATED DEATH WORLDWIDE AND IT MOST COMMONLY DEVELOPS WITHIN A CARCINOGENIC CASCADE FROM PRE-CANCEROUS METAPLASIA TO DYSPLASIA AND ADENOCARCINOMA. METAPLASIAS FIRST ARISE AS A RESPONSE TO INJURY THROUGH THE CHIEF CELL TRANSDIFFERENTIATION INTO SPASMOLYTIC POLYPEPTIDE- EXPRESSING METAPLASIA (SPEM) CELLS. WHILE THIS INITIAL PROCESS IS POSSIBLY REVERSIBLE, ONCOGENIC GENE ACTIVATION OR CHRONIC INFLAMMATION CAN ACTIVATE SPEM CELL PLASTICITY, WHICH PROMOTES SPEM CELL PROGRESSION TO INTESTINAL METAPLASIA (IM) AND DYSPLASIA. THIS NEOPLASTIC PROCESS MAY ALSO LEAD TO TRANSCRIPTIONAL AND EPIGENETIC CHANGES, AND INCITE CELL LINEAGE CONVERSION, WHERE MULTIPLE INTERMEDIATE CELL TYPES ARE PRODUCED THAT CAN EVOLVE INTO CANCEROUS CELLS, INCLUDING DYSPLASTIC STEM CELLS WHICH MAY ARISE DURING THE NEOPLASTIC TRANSITION. FURTHERMORE, THE ONCOGENIC GENE MUTATION BURDEN MAY BE ASSOCIATED WITH THE CELL LINEAGE CONVERSION AND DIVERSIFICATION OF THE DYSPLASTIC STEM CELLS TO CANCEROUS CELLS. HOWEVER, IT IS NOT CLEAR WHETHER THE SPEM CELL PLASTICITY IS RESPONSIBLE FOR THE CELL HETEROGENEITY AND EVOLUTION OF PRE-CANCEROUS METAPLASIA TO INCOMPLETE IM, WHICH CARRIES A HIGHER RISK OF PATIENT PROGRESSION TO DYSPLASIA AND WHAT MECHANISMS ARE INVOLVED IN THE CARCINOGENIC PROCESS. WE THEREFORE HYPOTHESIZE THAT SPEM CELLS ARE KEY GASTRIC CANCER PRECURSOR CELLS, WHICH DISPLAY FUNCTIONAL PROPERTIES AND CELL LINEAGE CONVERSION CAPACITY TO DRIVE METAPLASIA PROGRESSION TO DYSPLASIA. OUR OVERARCHING GOAL IS TO DEFINE MECHANISMS THAT CONTROL THE CELL LINEAGE CONVERSION OF REPARATIVE SPEM CELLS TOWARDS INCOMPLETE IM AND MORE CANCEROUS CELL LINEAGES, WHICH DISPLAY A HIGHER MUTATIONAL BURDEN. TO ADDRESS THESE QUESTIONS DIRECTLY, WE HAVE ESTABLISHED NOVEL IN VIVO TRANSGENIC MOUSE MODELS AND IN VITRO METAPLASTIC OR DYSPLASTIC ORGANOID MODELS DERIVED FROM TRANSGENIC MOUSE STOMACHS FOLLOWING INDUCTION OF ACTIVE KRAS OR FROM HUMAN PATIENT SAMPLES WITH METAPLASIA OR DYSPLASIA. USING THESE NOVEL MODELS, WE WILL ASSESS CRITICAL SPEM CELL LINEAGE DERIVATION AND DEFINE CELL POPULATIONS THAT ACCOUNT FOR THE KEY TRANSCRIPTIONAL AND EPIGENETIC CHANGES ARISING DURING METAPLASIA PROGRESSION. WE WILL PURSUE THREE SPECIFIC AIMS: FIRST WE WILL ASSESS FUNCTIONAL PROPERTIES OF SPEM CELLS DURING MUCOSAL RECOVERY OR NEOPLASTIC PROGRESSION FOLLOWING MUCOSAL INJURY. SECOND, WE WILL EXAMINE REGULATORY MECHANISMS OF CELL LINEAGE DIVERSIFICATION AND CONVERSION DURING METAPLASIA PROGRESSION. THIRD, WE WILL INVESTIGATE MOLECULAR MECHANISMS DRIVING CELL LINAGE DIVERSIFICATION AND CLONAL EVOLUTION OF DYSPLASTIC STEM CELLS TO ADENOCARCINOMA. OUR STUDIES WILL DEFINE CRITICAL TRANSITION POINTS WHICH LEAD TO NEOPLASTIC TRANSITIONS FOR SPEM CELLS AS THE ORIGIN OF GASTRIC CARCINOGENESIS. AN UNDERSTANDING OF REGULATORY MECHANISMS IN CELL PLASTICITY AND THE ABILITY TO REVERSE SUCH TRANSITIONS COULD LEAD TO THERAPEUTIC INTERVENTIONS TO PREVENT GASTRIC CANCER.

MECHANISMS OF IMMUNE ACTIVATION IN HYPERTENSION

SECRETED RNA DURING CRC PROGRESSION BIOGENESIS FUNCTION AND CLINICAL MARKERS

PMI PARTICIPANTS PREPARATORY/PROTOTYPING INITIATIVE

HISPANIC LATINO LIPID CONSORTIUM

MOLECULAR MAPPING OF MICROBIAL COMMUNITIES AT THE HOST-PATHOGEN INTERFACE BY MULTI-MODAL 3-DIMENSIONAL IMAGING MASS SPECTROMETRY

LANGUAGE PROCESSING IN CONTEXT FOLLOWING TRAUMATIC BRAIN INJURY

IMPACT OF ACUTE KIDNEY INJURY ON KIDNEY DISEASE PROGRESSION

GENOMIC AND CIRCULATING PREDICTORS OF PAH RESPONSE

INSULIN REGULATION OF MONOAMINE SIGNALING: PATHWAY TO OBESITY

STATISTICAL METHODS FOR ORDINAL VARIABLES IN HIV/AIDS STUDIES

SHANGHAI MEN'S HEALTH STUDY

SURGICAL ONCOLOGY TRAINING GRANT

GLUCOSE MODIFICATION OF PROTEINS IN DIABETIC NEPHROPATHY

CHRONIC GRAFT DESTRUCTION: INTERPLAY OF ALLO- AND AUTOANTIBODIES AND NONADHERENCE

MECHANISM AND FUNCTION OF HEME-IRON ACQUISITION IN STAPHYLOCOCCAL PATHOGENESIS

VGER, THE VANDERBILT GENOME-ELECTRONIC RECORDS PROJECT

VANDERBILT UNIVERSITY: CLINICAL CENTER APPLICATION, TYPE 1 DIABETES TRIALNET

COMPARISON OF HIGH VS. STANDARD DOSE FLU VACCINE IN PEDIATRIC STEM CELL TRANSPLANT RECIPIENTS

CANCER RISK REDUCTION AND DIET: A COHORT STUDY OF WOMEN

USDHUB: COMMUNITY RESOURCE FOR URINARY STONE DISEASE RESEARCH - ABSTRACT URINARY STONE DISEASE (USD) IS HIGHLY PREVALENT AND CONTRIBUTES A SUBSTANTIAL PROPORTION OF HEALTHCARE COSTS RELATED TO KIDNEY AND UROLOGIC DISEASE. APPROXIMATELY HALF OF CHILDREN AND ADULTS SUFFER RECURRENT SYMPTOMATIC STONE EVENTS, RESULTING IN EMERGENCY DEPARTMENT VISITS AND SURGERY. MORE THAN A CONDITION WITH EPISODIC OCCURRENCE OF DEBILITATING EVENTS, USD IS A DISORDER OF MINERAL METABOLISM WITH SUBSTANTIAL MORBIDITY, INCLUDING INCREASED FUTURE RISK OF CHRONIC KIDNEY DISEASE, FRACTURE, HYPERTENSION, AND CARDIOVASCULAR DISEASE. DESPITE THE HIGH PREVALENCE AND BURDEN OF USD, ADVANCES IN THE UNDERSTANDING, TREATMENT, AND PREVENTION OF USD HAVE STALLED DUE TO DEFICIENCIES IN AVAILABLE DATA RESOURCES. THESE CRITICAL GAPS INCLUDE LACK OF CLINICALLY IMPORTANT INFORMATION, LACK OF LONGITUDINAL DATA, RELIANCE ON SINGLE-CENTER DESIGNS THAT SEGREGATE PEDIATRIC AND ADULT PATIENTS, AND EXCLUSION OF KEY STAKEHOLDERS IN DATABASE DESIGN. TO ADDRESS THIS NEED, THIS PROPOSAL CREATES THE URINARY STONE DISEASE HUB (USDHUB), A READILY ACCESSIBLE RESEARCH RESOURCE FOR THE BROAD RESEARCH COMMUNITY THAT WOULD SUPPORT A WIDE RANGE OF IMPACTFUL CLINICAL INVESTIGATION TO IMPROVE THE HEALTH OF CHILDREN AND ADULTS WITH USD. USDHUB WILL GENERATED FROM 10 HEALTH SYSTEMS IN THE UNITED STATES THAT PARTICIPATE IN STAR AND PEDSNET, TWO PCORNET CLINICAL RESEARCH NETWORKS THAT HAVE STANDARDIZED ELECTRONIC HEALTH RECORD DATA. WE WILL ENSURE THAT THE CONTENT AND STRUCTURE OF USDHUB HAS VALUE TO THE USD RESEARCH COMMUNITY BY INCLUDING STAKEHOLDERS, INCLUDING PATIENTS AND CAREGIVERS. THIS WORK WILL INCLUDE THE FOLLOWING THREE AIMS: FIRST, WE WILL CREATE A RESEARCH COHORT OF >230,000 INDIVIDUALS ACROSS THE LIFESPAN WITH USD. WE WILL LINK EXTANT STRUCTURED DATA FROM THE PCORNET COMMON DATA MODEL TO 24-HOUR URINE RESULTS AND STONE COMPOSITION DATA. SECOND, WE WILL ENRICH USDHUB WITH INFORMATION EXTRACTED FROM CT IMAGES AND CLINICAL NOTES USING NATURAL LANGUAGE PROCESSING AND MACHINE LEARNING METHODS. THIRD, WE WILL BROADLY DISSEMINATE USDHUB TO RESEARCHERS USING SUSTAINABLE DATA ACCESS MODEL. WE WILL PARTNER THE USD RESEARCH COMMUNITY TO USER TEST AND REFINE THE DATA ACCESS PROCESS. TO MAXIMIZE USDHUB’S IMPACT, WE WILL PROVIDE PILOT GRANTS, CLINICS TO ORIENT RESEARCHERS TO USDHUB DATA, AND PARTNER WITH PROFESSIONAL ORGANIZATIONS TO DISSEMINATE USDHUB TO THE BROADER USD RESEARCH COMMUNITIES. THE OUTCOME OF THIS WORK WILL BE A NEW RESEARCH ECOSYSTEM FOR INVESTIGATORS TO GENERATE IMPACTFUL REAL-WORLD KNOWLEDGE THAT WILL TRANSFORM THE WAY USD RESEARCH IS CONDUCTED AND THEREBY IMPROVE CARE AND OUTCOMES FOR THE GROWING NUMBER OF INDIVIDUALS LIVING WITH THE DISEASE. THIS RESOURCE WILL SPUR AND ACCELERATE HYPOTHESIS-TESTING RESEARCH AND LEAD TO IMPACTFUL AND CLINICALLY MEANINGFUL DISCOVERIES THAT IMPROVE THE HEALTH OF INDIVIDUALS AND POPULATIONS WITH USD ACROSS THE LIFESPAN.

PROBIOTICS-DERIVED SOLUBLE PROTEINS REGULATE INTESTINAL INFLAMMATION

MOLECULAR BASIS OF INFECTIOUS DISEASES TRAINING PROGRAM

APPLYING INNOVATIVE LUNG MAPPING STRATEGIES TO UNDERSTAND ALVEOLAR CAPILLARY BARRIER PERMEABILITY IN ARDS

ASTHMA AND NOCTURNAL HYPOXEMIA IN SICKLE CELL ANEMIA

RATIONAL INTEGRATION OF POLYGENIC RISK SCORES (RIPS) - PROJECT SUMMARY THERE HAS BEEN EXTRAORDINARY GROWTH IN NEW TECHNIQUES TO PREDICT COMMON, COMPLEX DISEASE BASED ON POLYGENIC RISK SCORES (PRS). WITHOUT AN UNDERSTANDING GROUNDED IN EVIDENCE, IT IS UNLIKELY THAT THE CLINICAL USE OF PRS WILL PROPAGATE FROM HIGHLY SPECIALIZED APPLICATIONS AND ENVIRONMENTS TO BECOME ADOPTED MORE BROADLY AND PROVIDE GREATER BENEFIT TO THE US POPULATION. CRITICAL CHALLENGES INCLUDE: 1) UNDERSTANDING THE IMPACT OF CLINICAL PRS FOR MULTIPLE DISEASES ON LONG-TERM PATIENT OUTCOMES, 2) IDENTIFYING RISK THRESHOLDS FOR RETURN OF RESULTS THAT OPTIMIZE PATIENT OUTCOMES AND PROVIDE COST-EFFECTIVE CARE, 3) UNDERSTANDING HOW PRS PERFORMANCE ACROSS DIVERSE POPULATIONS MAY AFFECT EXISTING DISPARITIES AND SUBSEQUENT PATIENT OUTCOMES. WE PROPOSE TO ADDRESS THESE CHALLENGES USING DECISION ANALYTIC MODELING AND BY BUILDING ON OUR EXTENSIVE WORK IN THIS AREA TO CREATE A NOVEL FRAMEWORK CAPABLE OF ASSESSING PRSS IN THE CONTEXT OF MONOGENIC AND CLINICAL RISKS. WE HAVE ALREADY CREATED CLINICAL-ECONOMIC MODELS TO PROJECT LIFETIME CLINICAL IMPACT AND COST-EFFECTIVENESS FOR POPULATION-LEVEL GENOMIC SCREENING WITH RETURN OF MONOGENIC DISEASE RISKS ASSOCIATED WITH THREE CDC TIER 1 CONDITIONS: HEREDITARY BREAST AND OVARIAN CANCER, LYNCH SYNDROME, AND FAMILIAL HYPERLIPIDEMIA. AS PART OF THIS PROPOSAL, TITLED RATIONAL INTEGRATION OF POLYGENIC RISK SCORES (RIPS), WE WILL CREATE MODELS TO ASSESS THE CLINICAL OUTCOMES AND ECONOMIC VALUE OF POPULATION SCREENING USING PRS IN REAL- WORLD SETTINGS AND APPLIED TO LARGE AND DIVERSE POPULATIONS. THE AIMS OF THE PROPOSAL INCLUDE 1) TO EVALUATE PUBLISHED AND REAL-WORLD EVIDENCE ON THE CLINICAL VALUE OF ADDING PRS TO INFORM COMPREHENSIVE GENOMIC RISK ASSESSMENT; 2) TO UNDERSTAND THE IMPACT OF PRS PERFORMANCE AND RETURN RISK THRESHOLDS ON INCREMENTAL CLINICAL BENEFIT AND COST EFFECTIVENESS FOR BREAST CANCER, ATHEROSCLEROTIC CARDIOVASCULAR DISEASE, AND COLORECTAL CANCER, AND 3) TO DEVELOP RESEARCH PRIORITIES FOR THE EQUITABLE DEVELOPMENT AND IMPLEMENTATION OF PRS ACROSS UNDERSERVED AND UNDERREPRESENTED POPULATIONS.

COGNITIVE AND PHYSICAL EXERCISE TO IMPROVE OUTCOMES AFTER SURGERY IN THE ELDERLY

ROLE OF EGFR LIGANDS IN NEOPLASIA

RENAL BIOLOGY AND DISEASE TRAINING PROGRAM

NRSA TRAINING CORE

INTEGRATED, INDIVIDUALIZED, INTELLIGENT PRESCRIBING (I3P)

ANVIL CLINICAL ENVIRONMENT FOR INNOVATION AND TRANSLATION (ACE-IT) - PROJECT SUMMARY THE ANALYSIS, VISUALIZATION, AND INFORMATICS LAB-SPACE (ANVIL) PLATFORM IS A SCALABLE CLOUD-BASED COMPUTING RESOURCE THAT AIMS TO ACCELERATE GENOMICS RESEARCH BY PROVIDING BROAD ACCESS TO GENOMICS DATASETS AND THE INFRASTRUCTURE NECESSARY TO IMPROVE ANALYSIS WORKFLOWS AND ENHANCE COLLABORATION. THE ANVIL CLINICAL ENVIRONMENT FOR INNOVATION AND TRANSLATION (ACE-IT) PROJECT WILL BRING TOGETHER A NETWORK OF EXPERTISE TO ADDRESS A MAJOR GAP IN CLINICAL GENOMICS RESEARCH AND OPERATIONALIZE A KEY MISSION OF THE ANVIL PROJECT BY EXPANDING ITS EXISTING ECOSYSTEM TO INCLUDE A COMPREHENSIVE SUITE OF CLINICAL GENOMICS RESEARCH TOOLS AND SERVICES. THE NEWLY DEVELOPED ANVIL CLINICAL RESOURCE WILL BRING TOGETHER DATA, TOOLS, AND SUPPORT RESOURCES MEANT TO AMPLIFY THE BENEFITS OF THE EXISTING PLATFORM AND PROVIDE A CRITICAL FOUNDATION FOR THE CLINICAL GENOMICS RESEARCH COMMUNITY TO BETTER LEVERAGE THIS INNOVATIVE RESOURCE. DEVELOPMENT OF THE ACE-IT WILL BE GUIDED BY THREE KEY AIMS: 1. ENGAGEMENT WITH DIVERSE COMMUNITY AND RESEARCH PARTNERS TO CHARACTERIZE BARRIERS AND FACILITATORS TO ADOPTING FEDERALLY- SUPPORTED, CLOUD-CONNECTED CLINICAL GENOMICS RESEARCH SERVICES; 2. DEVELOPMENT AND DEPLOYMENT APPROACHES TO INGEST, INDEX, AND SEARCH DATA TO SUPPORT CLINICAL GENOMICS RESEARCH WITH AN EMPHASIS ON POPULATIONS HISTORICALLY UNDERREPRESENTED IN BIOMEDICAL RESEARCH; AND 3. INTEGRATION OF TOOLS, APIS, AND WORKFLOWS THAT ENABLE CLINICAL GENOMICS RESEARCH METHODS ON THE ANVIL, INCLUDING RARE DISEASE DIAGNOSIS AND GENOMIC RISK SCORES AS USE CASES. THE ACE-IT TEAM CONSISTS OF EXPERTISE ACROSS MULTIPLE HEALTH CARE CENTERS, INCLUDING VANDERBILT UNIVERSITY MEDICAL CENTER, BRIGHAM AND WOMEN'S HOSPITAL, MASSACHUSETTS GENERAL HOSPITAL, AND THE AMERICAN HEART ASSOCIATION. THIS TEAM WILL DEVELOP INFRASTRUCTURE ON ANVIL'S CLOUD ENVIRONMENT TO MEET CLINICAL GENOMICS RESEARCHERS' NEEDS OVER TIME AND INTEGRATE WITH EXISTING ANVIL WORKING GROUPS AND MEETINGS AS TEAM MEMBERS AND STAKEHOLDERS WHERE APPROPRIATE. THE TOOLS AND RESOURCES WE DEVELOP WILL SUPPORT CLINICAL GENOMICS RESEARCH BY FOCUSING ON BOTH RARE AND COMMON DISEASES AND INTEGRATION INTO TRANSLATIONAL RESEARCH.

PARVALBUMIN INTERNEURONS REGULATE NUCLEUS ACCUMBENS SYNAPSES AND BEHAVIOR

NEUTRALIZATION FINGERPRINTING ANALYSIS OF POLYCLONAL ANTIBODY RESPONSES AGAINST HIV-1

CONTEMPORARY CLASSIFICATION OF MYOCARDIAL INJURY EVENTS IN MESA: DEFINING DISTINCT RISK FACTOR ASSOCIATIONS WITH MYOCARDIAL INFARCTION TYPE 1-5 AND ACUTE NON-ISCHEMIC MYOCARDIAL INJURY - PROJECT SUMMARY/ABSTRACT DESPITE MARKED DECLINES, ATHEROSCLEROTIC CARDIOVASCULAR DISEASE (ASCVD) IS THE LEADING CAUSE OF DEATH WORLDWIDE. FATAL OR NON-FATAL ACUTE MYOCARDIAL INFARCTION (MI) REMAINS THE INITIAL PRESENTATION IN AT LEAST HALF OF THESE PATIENTS. IN RECENT YEARS, REFLECTIVE OF THE GREATER UNDERSTANDING OF THE MANY DIVERSE CAUSES OF MYOCARDIAL INJURY, INTERNATIONAL CONSENSUS DEFINITION NOW INCLUDES NON-ISCHEMIC CAUSES OF MYOCARDIAL INJURY AND SEVERAL ETIOLOGICALLY DISTINCT SUBTYPES OF MYOCARDIAL INJURY, INCLUDING SUBTYPES OF MI. HOWEVER, THE BASIC EPIDEMIOLOGY OF MI SUBTYPES AND NON-ISCHEMIC MYOCARDIAL INJURY AND HOW RISK FACTORS DIFFER BETWEEN THESE CATEGORIES IS CONSPICUOUSLY LACKING AND CRITICALLY NEEDED. A FUNDAMENTAL UNDERSTANDING OF THE EPIDEMIOLOGY OF MYOCARDIAL INJURY EVENTS, INCLUDING DIFFERENTIAL RELATIONSHIP OF TRADITIONAL AND NONTRADITIONAL RISK FACTORS TO THE DIFFERENT MI SUBTYPES, IS NEEDED TO ADVANCE THE PREDICTION, PREVENTION, AND TREATMENT OF THESE LEADING CAUSES OF DEATH. THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) IS A GENDER BALANCED CONTEMPORARY NHLBI CARDIOVASCULAR COHORT WITH EXTENSIVE BASELINE PARTICIPANT PHENOTYPING AND EVENT SURVEILLANCE. IN THIS PROPOSAL, WE AIM TO SYSTEMATICALLY RE-ADJUDICATE MORE THAN 18,000 CLINICAL EVENTS COLLECTED IN MESA OVER 14 YEARS. WE HAVE DEVELOPED INNOVATIVE TOOLS TO ENHANCE ACCURACY AND EFFICIENCY OF THE ADJUDICATION PROCESS. WE WILL USE THIS DATA TO ASCERTAIN THE INCIDENCE OF SPECIFIC ACUTE MI SUBTYPES. WE WILL DELINEATE THE SIZE AND STRENGTH OF ASSOCIATION BETWEEN BASELINE TRADITIONAL AND NOVEL CARDIOVASCULAR RISK FACTORS WITH INDIVIDUAL ACUTE MI SUBTYPES AND ACUTE NON-ISCHEMIC MYOCARDIAL INJURY. IN ADDITION TO ANALYZING THE IMPACT OF INDIVIDUAL RISK FACTORS ON SPECIFIC MYOCARDIAL INJURY SUBTYPES, WE WILL UTILIZE FACTOR ANALYSES TO LEVERAGE INFORMATION GAINED FROM HOW MULTIPLE RISK FACTORS WITHIN A DOMAIN (E.G., THROMBOGENICITY, ATHEROSCLEROSIS AND MYOCARDIAL DAMAGE) INTERACT WITH EACH OTHER TO IMPACT SPECIFIC MYOCARDIAL INJURY SUBTYPE. SUCCESSFUL COMPLETION OF THE PROPOSED STUDY WILL DEFINE THE TYPE AND FREQUENCY OF ACUTE MI EVENTS IN A COHORT REPRESENTATIVE OF THE US TARGET PREVENTION POPULATION. BY FIRST CHARACTERIZING AND QUANTIFYING THE RISK FACTOR PROFILE, WE EXPECT THE FINDINGS OF THIS PROJECT TO ENABLE DEVELOPMENT OF MORE SPECIFIC INDIVIDUAL PATIENT RISK PREDICTION AND EFFECTIVE TAILORING OF PREVENTION EFFORTS (PRECISION MEDICINE). SUCH KNOWLEDGE WILL RESULT IN THE EVALUATION OF MORE JUDICIOUS APPLICATION OF CURRENT THERAPIES—E.G., LIMITING AGGRESSIVE ANTI-THROMBOTIC THERAPY FOR THOSE AT GREATEST RISK FOR TYPE 1 VERSUS TYPE 2 MI TO MAXIMIZE BENEFIT AND LIMIT RISK WHILE MORE EFFICIENTLY UTILIZING HEALTHCARE RESOURCES. FURTHERMORE, IDENTIFICATION OF NEW RISK FACTORS WILL SUPPORT EXPLORATION OF NOVEL THERAPEUTIC AVENUES THAT SPECIFICALLY TARGET INDIVIDUAL MYOCARDIAL INJURY SUBTYPES.

TRANSLATING AN MR-GUIDED FOCUSED ULTRASOUND SYSTEM FOR FIRST-IN-HUMAN PRECISION NEUROMODULATION OF PAIN CIRCUITS - THIS PROPOSAL RESPONDS TO PAR-21-315 BLUEPRINT MEDTECH TRANSLATOR AND AIMS TO TRANSLATE A NEXT-GENERATION NONINVASIVE NEUROMODULATION SYSTEM THAT SUPPORTS A DEVICE-BASED STRATEGY FOR NON-ADDICTIVE PAIN TREATMENTS. SPECIFICALLY, WE HAVE DEVELOPED AN INTEGRATED MAGNETIC RESONANCE (MR) IMAGE-GUIDED FOCUSED ULTRASOUND (MRGFUS) STIMULATION SYSTEM FOR TARGETED AND HIGH PRECISION MODULATION OF DEEP BRAIN REGIONS WITH REAL-TIME TARGETING FEEDBACK AND FUNCTIONAL MONITORING BY FMRI. ALTHOUGH THERE ARE SEVERAL DEVICES AVAILABLE ON THE MARKET TO TREAT PAIN, THEIR EFFICACY IS LIMITED BY IMPRECISE TARGETING RESULTING FROM INSUFFICIENT MECHANISTIC DATA ABOUT “DEVICE-ABLE” TARGETS, AND FROM LACK OF FEEDBACK OF EFFECTS TO MODULATE THE THERAPY. REVERSIBLE FUS STIMULATION UNDER MRI GUIDANCE (MRGFUS) COMBINES THE DUAL NEUROMODULATION CAPACITY OF LOW FREQUENCY FOCAL ULTRASOUND WITH SIMULTANEOUS MONITORING OF NEUROMODULATION IN ACTION USING FMRI. MRGFUS OVERCOMES THE LIMITATIONS OF EXISTING PAIN-TREATMENT DEVICES AND HAS GREAT POTENTIAL TO IMPROVE PATIENT OUTCOMES THROUGH FUS AND MRI TECHNOLOGIES THAT ENABLE TARGETING AND CONTROL. OUR GROUP HAS DEVELOPED AN MRGFUS SYSTEM FOR NON-HUMAN PRIMATE (NHP) USE AND SUCCESSFULLY MODULATED NEURAL ACTIVITY IN THE BRAIN REGIONS RESPONSIBLE FOR NOCICEPTIVE INFORMATION PROCESSING VALIDATED BY FMRI. AS PART OF PREVIOUSLY FUNDED WORK, WE HAVE SCALED THE DEVICE TO FUNCTION WITH A HUMAN SKULL, AND HERE WE PROPOSE TO TRANSLATE THIS EARLY-STAGE TECHNOLOGY INTO A NEW NON-ADDICTIVE PAIN THERAPY. WE HAVE DESIGNED THE HUMAN DEVICE TO USE FUS TO STIMULATE PAIN TARGETS (THALAMIC NUCLEI, ACC, AND PAG/PVG) THAT ARE CURRENTLY USED IN CLINICAL PAIN TREATMENTS WITH THE ABILITY TO VALIDATE THE LOCATION OF STIMULATION AND TO MONITOR BRAIN ACTIVITY USING BLOOD OXYGENATION LEVEL DEPENDENT FMRI. OUR EXPERIMENTAL PLAN NAVIGATES BARRIERS TO DEPLOYING FUS, INCLUDING 1) OPTIMIZING MR-BASED METHODS TO VISUALIZE THE ULTRASOUND BEAM WITH HIGH PRECISION WHILE USING SAFE ULTRASOUND EXPOSURE TO THE BRAIN, 2) ASSESSING DEVICE SAFETY IN NON-HUMAN PRIMATES, AND 3) OBTAINING REGULATORY APPROVAL FOR USE OF THE PROPOSED DEVICE FOR A FIRST-IN-HUMAN TRIAL OF HIGH PRECISION MRGFUS IN PATIENTS WITH MEDICALLY-REFRACTORY ESSENTIAL TREMOR AND INTRACTABLE CHRONIC CENTRAL POST-STROKE PAIN. THE UG3-PHASE IS DESIGNED TO PREPARE THE DEVICE FOR HUMAN USE AND HAS QUANTITATIVE GO/NO-GO MILESTONES FOR ESTABLISHING SAFE USE OF HIGH PRECISION MRGFUS IN HUMANS WITH REGULATORY APPROVAL. SUCCESSFUL COMPLETION OF THE UG3 MILESTONES WILL PLACE THIS GROUNDBREAKING TECHNOLOGY INTO THE HANDS OF TREATING PHYSICIANS AND LEAD TO THE FIRST CLINICAL TRIAL OF HIGH PRECISION MRGFUS NEUROMODULATION IN PATIENTS WITH MOVEMENT DISORDERS AND CHRONIC PAIN. THE PROPOSED WORK WILL DELIVER A SYSTEM THAT OVERCOMES TECHNICAL BARRIERS IN TRANSCRANIAL ULTRASOUND AND IS READY FOR PILOT CLINICAL TRIALS IN VARIOUS PAIN MANAGEMENT APPLICATIONS.

GENETIC DRIVERS OF RESILIENCE TO ALZHEIMER'S DISEASE

IMMUNOGENETIC PREDICTORS OF ACTIVE AND INCIPIENT TB IN HIV-NEGATIVE AND -POSITIVE CLOSE TB CONTACTS

THE GENERAL FACTOR OF PSYCHOPATHOLOGY IN PSYCHOSIS AND SEVERE MENTAL ILLNESS

THE ADAPT TRIAL: ADAPTING EVIDENCE-BASED OBESITY INTERVENTIONS IN COMMUNITY SETTINGS - PROJECT SUMMARY EVIDENCE-BASED OBESITY TREATMENT IS INACCESSIBLE TO MOST CHILDREN IN THE UNITED STATES. THIS LACK OF ACCESS IS A SOURCE OF HEALTH INEQUITY, WHEREBY CHILDREN FROM RURAL AND MINORITY COMMUNITIES, WHO HAVE THE HIGHEST RATES OF CHILDHOOD OBESITY, ARE ALSO THE LEAST LIKELY TO RECEIVE AN EVIDENCE-BASED INTERVENTION. DEVELOPING STRATEGIES TO IMPROVE ACCESS TO EVIDENCE-BASED OBESITY INTERVENTIONS COULD REDUCE HEALTH DISPARITIES BY IMPROVING REACH TO THESE UNDERSERVED COMMUNITIES. THE PREMISE OF THIS STUDY IS THAT USING A SYSTEMATIC FRAMEWORK TO ADAPT A COMMUNITY-BASED BEHAVIORAL INTERVENTION FOR CHILDHOOD OBESITY THAT ACCOUNTS FOR INDIVIDUAL, FAMILY, AND COMMUNITY FACTORS WILL INCREASE REACH AND EFFECTIVENESS AMONG LOW-INCOME, MINORITY, AND RURAL POPULATIONS. COACH IS A MULTI-LEVEL OBESITY INTERVENTION THAT SUPPORTS 1) THE INDIVIDUAL CHILD THROUGH DEVELOPMENTALLY APPROPRIATE HEALTH BEHAVIOR CURRICULUM, 2) THE FAMILY BY DIRECTLY ADDRESSING PARENT WEIGHT LOSS AND ENGAGING PARENTS AS AGENTS OF CHANGE FOR THEIR CHILDREN, AND 3) THE COMMUNITY BY BUILDING THE CAPACITY OF LOCAL COMMUNITY CENTERS TO OFFER PARENT-CHILD PROGRAMMING. COACH HAS BEEN TESTED IN A PRIOR RCT AND DEMONSTRATED EFFECTIVENESS AT REDUCING CHILD BMI AT 1-YEAR FOLLOW-UP. WE PROPOSE TESTING THE PROCESS OF ADAPTING COACH IN A CLUSTER-RANDOMIZED TRIAL. IN AIM 1, WE WILL CONDUCT A COMMUNITY READINESS ASSESSMENT FOR COACH IN 50 COMMUNITY CENTERS SERVING RURAL, MINORITY, AND LOW-INCOME FAMILIES IN MIDDLE TN. THIS ASSESSMENT WAS DEVELOPED AND PILOT-TESTED BY OUR TEAM AND ASSESSES BARRIERS TO STUDY IMPLEMENTATION IN MULTIPLE DOMAINS. IN 25 RANDOMLY SELECTED COMMUNITY CENTERS, WE WILL USE A SYSTEMATIC PROCESS TO ADAPT THE INTERVENTION PROTOCOL BASED ON THE ASSESSMENT RESULTS, WHILE MAINTAINING FIDELITY TO COACH’S CORE COMPONENTS. IN AIM 2, IN A CLUSTER-RANDOMIZED TRIAL, WE WILL TEST THE COMPARATIVE EFFECTIVENESS OF EACH IMPLEMENTATION STRATEGY (ADAPTATION VS. ORIGINAL PROGRAM) ON THE IMPLEMENTATION OUTCOMES OF REACH, ADOPTION, IMPLEMENTATION, AND MAINTENANCE. IN AIM 3, WE WILL TEST THE COMPARATIVE EFFECTIVENESS OF THE ADAPTED AND ORIGINAL INTERVENTION ON CHILD BMI-Z AT 6-MONTH FOLLOW-UP. CHILDREN WITH OBESITY (BMI PERCENTILE =95TH) AGES 6-11 AND THEIR FAMILIES (N=750; 15 INDEX CHILDREN/CENTER) WILL BE RECRUITED FROM COMMUNITIES SERVED BY EACH CENTER. THIS RESEARCH IS INNOVATIVE BECAUSE IT USES ADAPTATION SCIENCE AS A POTENTIAL SOLUTION TO REDUCE HEALTH DISPARITIES IN CHILDHOOD OBESITY. BY TESTING THIS INTERVENTION IN A COMMUNITY RESOURCE AVAILABLE TO 230 MILLION AMERICANS (COMMUNITY CENTERS), WE WILL CREATE A SCALABLE OBESITY INTERVENTION THAT COULD BE IMPLEMENTED IN TRADITIONALLY UNDERSERVED POPULATIONS ACROSS THE COUNTRY. THIS STUDY WILL ALSO DEVELOP AND TEST A THEORY-BASED PROCESS FOR ADAPTING BEHAVIORAL INTERVENTIONS FOR BOTH OBESITY AND OTHER HEALTH OUTCOMES AMONG DIVERSE RURAL AND URBAN COMMUNITIES. THIS RESEARCH ALIGNS WITH THE NHLBI’S MISSION TO IDENTIFY THE BEST STRATEGIES FOR ENSURING SUCCESSFUL INTEGRATION OF EVIDENCE-BASED INTERVENTIONS WITHIN PUBLIC HEALTH SETTINGS.

GENETICS OF AFRICAN AMERICAN TYPE 2 DIABETES

MOLECULAR MECHANISMS OF RENAL INJURY

GENOME SEQUENCING TO IDENTIFY NOVEL GENETIC FACTORS FOR BREAST CANCER RISK

SOCIAL PERCEPTION AND SOCIAL COMMUNICATION IN ADULTS WITH TRAUMATIC BRAIN INJURY

CHILDHOOD INFECTION RESEARCH PROGRAM

PHOSPHATASE AND TENSIN HOMOLOG PTEN ACTIONS IN POLYMICROBIAL SEPSIS