Washington University

CENTER FOR LARGE-SCALE GENOME SEQUENCING & ANALYSIS

GLYCEMIA REDUCTION APPROACHES IN DIABETES: A COMPARATIVE EFFECTIVENESS STUDY

DATA COORD. CENTER - NICHD COOPERATIVE MULTICENTER MATERNAL FETAL MEDICINE UNITS

STATISTICS CENTER FOR PEDIATRIC TYPE 2 DIABETES THERAPY

WU ICTS - RESOURCE DEVELOPMENT TO FACILITATE SIRB REVIEW FOR MULTI-SITE RESEARCH

THE LONG LIFE FAMILY STUDY

CANCER CENTER SUPPORT GRANT

DIAN-TU: TAU NEXT GENERATION PREVENTION TRIAL

DIAN-TU PRIMARY PREVENTION TRIAL

A PLATFORM FOR LARGE-SCALE DISCOVERY IN COMMON DISEASE

AIDS AND CANCER SPECIMEN RESOURCE (ACSR)

DATA COORDINATING CENTER (DCC) FOR COMPLETION OF ONGOING MFMU NETWORK PROTOCOLS (U24 CLINICAL TRIAL OPTIONAL) - PROJECT SUMMARY/ABSTRACT THE EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT MATERNAL-FETAL MEDICINE UNITS (MFMU) NETWORK WAS CREATED IN 1986 TO CONDUCT CLINICAL RESEARCH STUDIES IN OBSTETRICS AND PERINATAL MEDICINE. THE MFMU NETWORK CONSISTS OF A NUMBER OF MAJOR ACADEMIC CLINICAL CENTERS, A DATA COORDINATING CENTER (DCC), AND THE NICHD. THE RESEARCH STUDIES, RANDOMIZED TRIALS AND OBSERVATIONAL STUDIES, ARE AIMED AT REDUCING MATERNAL, FETAL AND INFANT MORBIDITY RELATED TO PRETERM BIRTH, FETAL GROWTH ABNORMALITIES AND MATERNAL COMPLICATIONS, AND TO PROVIDE THE RATIONALE FOR EVIDENCE-BASED, COST-EFFECTIVE, OBSTETRIC PRACTICE. THE MFMU NETWORK STRUCTURE ALLOWS STUDIES TO BE COMPLETED IN A MORE RIGOROUS FASHION AND MORE EFFICIENTLY THAN INDIVIDUAL MULTI-CENTER PROJECTS. TO FULFILL THIS MISSION, THE MFMU NETWORK IS CURRENTLY CONDUCTING SIX RANDOMIZED TRIALS, THREE OBSERVATIONAL STUDIES, AND TWO LONG-TERM FOLLOW-UP STUDIES OF CHILDREN. THESE STUDIES ARE A REFLECTION OF THE URGENT CLINICAL ISSUES OF TODAY INCLUDING PREMATURITY, MATERNAL PREGNANCY RELATED MORBIDITY, THE OPIOID CRISIS AND THE COVID- 19 PANDEMIC. THE DCC IS A CRITICALLY IMPORTANT PART OF THIS COLLABORATIVE EFFORT AND A VITAL PART OF ENSURING THESE STUDIES ARE COMPLETED ON TIME AND WITH INTEGRITY. THE OVERALL PURPOSE OF THE DCC IS TO MAKE SURE THAT THE STUDIES ARE DESIGNED TO MINIMIZE BIAS, ARE CONDUCTED USING RIGOROUS PROTOCOLS, AND THE RESULTS ANALYZED AND INTERPRETED APPROPRIATELY TO ENSURE THE VALIDITY OF THE CONCLUSIONS. THE AIMS OF THE DCC ARE TO PROVIDE SCIENTIFIC AND BIOSTATISTICAL EXPERTISE IN MATERNAL FETAL MEDICINE, EPIDEMIOLOGY AND BIOSTATISTICS TO ADDRESS THE KEY SCIENTIFIC QUESTIONS. THE DCC WILL CONDUCT INTERIM ANALYSES FOR THE DATA AND SAFETY MONITORING BOARD, COLLABORATE WITH MFMU INVESTIGATORS ON STATISTICAL ANALYSES AND THE DISSEMINATION OF STUDY RESULTS, AND SHARE DATASETS AND RESOURCES. THE DCC WILL PROVIDE A FLEXIBLE DATA MANAGEMENT SYSTEM AND COLLABORATE WITH THE MFMU INVESTIGATORS ON THE CONDUCT AND MONITORING OF EACH STUDY INCLUDING TRAINING, MAINTENANCE OF STUDY DOCUMENTS, AND REPORTING TO THE STEERING COMMITTEE AND FOOD AND DRUG ADMINISTRATION. LASTLY, THE DCC WILL COORDINATE COMMUNICATION THROUGH BOTH PRIVATE AND PUBLIC WEBSITES, AND PROVIDE THE LOGISTICAL AND ADMINISTRATIVE SUPPORT TO THE OVERALL NETWORK ORGANIZATION NECESSARY TO RUN EFFICIENT AND PRODUCTIVE STUDIES. THROUGH EFFECTIVE ORGANIZATION, COMMUNICATION, AND LOGISTICAL, TECHNICAL AND SCIENTIFIC SUPPORT, THE DCC WILL CONTINUE TO PROVIDE THE FRAMEWORK FOR THE MFMU NETWORK TO ADDRESS THE KEY SCIENTIFIC QUESTIONS OF THE ONGOING STUDIES.

POST DPP FOLLOW UP STUDY: DATA COORDINATING CENTER

MRCE FOR BIODEFENSE AND EMERGING INFECTIOUS DISEASES

GENOMICS OF ACUTE MYELOGENOUS LEUKEMIA

FLAVIVIRUS AND ALPHAVIRUS REVAMPP (FLARE) - SUMMARY. THE FLAVIVIRUS AND ALPHAVIRUS REVAMPP (FLARE) CENTER WILL DEVELOP AND OPTIMIZE PROTEIN NANOPARTICLE, VIRION-BASED, AND MRNA VACCINE PLATFORMS, AND MONOCLONAL ANTIBODY (MAB)-BASED TREATMENTS TO RAPIDLY RESPOND TO EMERGING FLAVIVIRUSES AND ALPHAVIRUSES WITH PANDEMIC POTENTIAL. A KEY GOAL IS TO PAIR SPECIFIC ANTIGEN DESIGNS AND VACCINE PLATFORMS SO THAT SUCCESSFUL PARADIGMS CAN BE RAPIDLY ADAPTED IN A “PLUG AND PLAY” MANNER TO EMERGING VIRUSES WITHIN THE SAME FAMILY. OUR SUITE OF ANTIGEN DESIGN STRATEGIES, VACCINE PLATFORMS, STATE-OF-THE-ART VIROLOGICAL AND IMMUNOLOGICAL ASSAYS, EXTENSIVE ANIMAL MODEL EXPERIENCE, DETAILED ANALYSIS OF CORRELATES OF PROTECTION, AND EXPERIENCED INDUSTRY PARTNERS (E.G., MODERNA) WILL ENABLE US TO GENERATE INNOVATIVE VACCINES AND MAB COMBINATIONS AGAINST KEY TARGETED PROTOTYPE FLAVIVIRUSES AND ALPHAVIRUSES, WHICH THEN CAN BE APPLIED TO RELATED NEW THREATS. MOREOVER, WITH OUR COLLECTIVE ACADEMIC EXPERIENCE IN VACCINOLOGY AND COLLABORATIVE EXPERIENCE WITH INDUSTRY PARTNERS, WE CAN MAKE INFORMED GO/NO-GO DECISIONS TO FOCUS ON ANTIGENS AND VACCINES WITH THE GREATEST CHANCE FOR CLINICAL EFFICACY AND SAFETY. OUR FLARE CENTER INTEGRATES THE WORK OF MULTIPLE ACADEMIC GROUPS, WITH PROVEN RECORDS OF COLLABORATION, THAT HAVE THE HIGHEST LEVELS OF EXPERTISE IN FLAVIVIRUS AND ALPHAVIRUS BIOLOGY, ANTIGEN DESIGN, STRUCTURAL BIOLOGY, ANTIBODY STRUCTURE AND FUNCTION, MAB GENERATION AND CHARACTERIZATION, VACCINE DEVELOPMENT, B AND T CELL IMMUNITY, FC EFFECTOR FUNCTIONS, AND ANIMAL CHALLENGE STUDIES, ALL WORKING TOWARD THE GOAL OF DESIGNING OPTIMIZED IMMUNOGENS FOR INCORPORATION INTO LIPID-ENCAPSULATED MRNA, NANOPARTICLES, OR OTHER VECTORS TO CREATE VACCINES THAT CAN PROTECT AGAINST INFECTION AND DISEASE CAUSED BY EXISTING AND FUTURE FLAVIVIRUS AND ALPHAVIRUS THREATS. OUR FLARE CENTER IS COMPOSED OF FIVE PRIMARY RESEARCH PROJECTS: TWO VACCINE PROJECTS THAT COLLECTIVELY FOCUS ON PROTOTYPE FLAVIVIRUSES INCLUDING WEST NILE (WNV), TICK-BORNE ENCEPHALITIS (TBEV), AND DENGUE (DENV) VIRUSES; TWO VACCINE PROJECTS, THAT FOCUS ON PROTOTYPE ALPHAVIRUSES INCLUDING CHIKUNGUNYA (CHIKV) AND VENEZUELAN EQUINE ENCEPHALITIS (VEEV) VIRUSES; AND A MAB THERAPY PROJECT THAT FOCUSES ON BOTH FLAVIVIRUSES (WNV AND DENV) AND ALPHAVIRUSES (CHIKV). THESE PROJECTS ARE SERVED BY AN ADMINISTRATIVE CORE, A DATA MANAGEMENT CORE, AND THREE SCIENTIFIC CORES THAT PERFORM STRUCTURAL BIOLOGY AND PROTEIN ENGINEERING, ANIMAL VACCINATION AND CHALLENGE, AND CORRELATES OF IMMUNE PROTECTION EXPERIMENTS IN COLLABORATION WITH MULTIPLE PROJECTS. OUR NETWORK OF EXPERT INVESTIGATORS, INNOVATIVE PROJECT AND CORES, AND STATE-OF-THE ART VIROLOGICAL AND IMMUNOLOGICAL APPROACHES WILL ENABLE US TO DEVELOP VACCINE AND MAB THERAPEUTICS AGAINST PROTOTYPE FLAVIVIRUSES AND ALPHAVIRUSES THAT CAN BE READILY AND RAPIDLY APPLIED TO OTHER CONTEMPORARY AND NEWLY EMERGING RELATED VIRAL THREATS.

DOMINANTLY INHERITED ALZHEIMER NETWORK

VACCINES AND THERAPEUTIC ANTIBODIES TO RESPIRO, RUBULA, PERIBUNYA AND PHENUIVIRIDAE (R2P2)-REVAMPP - SUMMARY. THE VACCINES AND THERAPEUTIC ANTIBODIES TO RESPIROVIRUS, RUBULAVIRUS, PERIBUNYAVIRUS AND PHENUIVIRUS (R2P2) REVAMPP CENTER WILL UTILIZE BOTH WELL-DEFINED AND NOVEL APPROACHES TO DEVELOP PROTOTYPE VACCINES AND HUMAN MONOCLONAL ANTIBODY (MAB)-BASED TREATMENTS FOR RAPID RESPONSE TO VIRUSES FROM THE PARAMYXOVIRIDAE, PERIBUNYAVIRIDAE AND PHLEBOVIRIDAE FAMILIES. R2P2 IS COMPOSED OF FOUR PRIMARY RESEARCH PROJECTS: TWO THAT COLLECTIVELY FOCUS ON PROTOTYPE VIRUSES OF THE PARAMYXOVIRIDAE FAMILY INCLUDING HUMAN PARAINFLUENZA VIRUSES 3 AND 1 (HPIV3, HPIV1), AND HUMAN AND BAT MUMPS VIRUS (MUV, BATMUV); AND TWO THAT FOCUS ON PROTOTYPE VIRUSES OF THE BUNYAVIRALES ORDER INCLUDING THE PERIBUNYAVIRIDAE OROPOUCHE (OROV) AND LA CROSSE (LACV) AND THE PHENUIVIRIDAE RIFT VALLEY FEVER VIRUS (RVFV) AND TOSCANA VIRUS (TOSV). EACH PROJECT IN R2P2 FOLLOWS A PARALLEL STRUCTURE AND MAKES USE OF THE PRINCIPLES OF REVERSE VACCINOLOGY, WHERE INSIGHTS FROM THE STRUCTURAL AND FUNCTION STUDIES WILL PROVIDE A FRAMEWORK TO UNDERSTAND THE MOLECULAR CORRELATES OF IMMUNITY AND ANTIGENICITY AND PROVIDE A ROADMAP FOR DESIGNING OPTIMIZED IMMUNOGENS. THE FOUNDATIONAL STUDIES CARRIED OUT IN THIS REVAMPP CENTER WILL FILL GAPS IN BASIC UNDERSTANDING OF VIRAL ENTRY AND WILL ALSO INFORM HOW TO EXTEND THE STABILIZATION APPROACHES SUCCESSFULLY USED TO ADVANCE VACCINES AGAINST AGENTS WITH CLASS I FUSOGENS (E.G., RSV), TO THOSE WITH CLASS II. A KEY R2P2 FEATURE IS THAT ALL FOUR PROJECTS COMPARE THE SAME THREE VACCINE PLATFORMS: PROTEIN SUBUNIT, MRNA, AND CHIMERIC VSV, ALLOWING FOR CROSS COMPARISONS THAT WILL RAPIDLY YIELD INFORMATION ABOUT PLATFORM PERFORMANCE IN TRANSLATING TO RELATED PATHOGENS. THE QUESTIONS OF WHICH ANTIGEN STABILIZATION PARADIGMS, AND WHICH VACCINE PLATFORMS ARE MOST AMENABLE TO GENERALIZING FROM THE PROTOTYPE PATHOGENS WILL BE ANSWERED IN DEPTH AND BREADTH BY THESE COMPARISONS ACROSS VIRUS FAMILIES. WE ASSEMBLED A COLLABORATIVE TEAM OF WORLD-RENOWNED EXPERTS ON VIRAL ENVELOPE PROTEIN STRUCTURE AND FUNCTION, LEADING IMMUNOLOGISTS, VACCINOLOGISTS WITH EXTENSIVE EXPERIENCE IN INDUSTRY AND REGULATORY ISSUES, AND INDUSTRY PARTNERS (E.G., MODENA, GSK). THE INCLUSION OF JUNIOR INVESTIGATORS WITH EXCEPTIONAL PROMISE IS DESIGNED TO ENSURE THE ENGAGEMENT OF THE NEXT GENERATION OF LEADERS IN VIRAL GLYCOPROTEIN BIOLOGY, VIRAL IMMUNOLOGY AND VACCINOLOGY IN PANDEMIC PREPAREDNESS. THESE PROJECTS ARE SERVED BY AN ADMINISTRATIVE CORE (CORE A), A DATA MANAGEMENT CORE (CORE B), AND THREE SCIENTIFIC CORES THAT PERFORM STRUCTURAL BIOLOGY, BIOPHYSICS AND PROTEIN ENGINEERING (CORE C), ANTIBODY ISOLATION AND ASSESSMENT (CORE D), AND CORRELATES OF IMMUNE PROTECTION (CORE E) EXPERIMENTS IN COLLABORATION WITH MULTIPLE PROJECTS. THE KNOWLEDGE ACCUMULATED IN THIS PROJECT AND THE ROBUSTNESS OF THE APPROACHES IMPLEMENTED TO DEVELOP PROTOTYPE VACCINES WILL BE EXPANDED TO DIFFERENT VIRUSES OF THE SAME FAMILIES TO EVALUATE THEIR POTENTIAL AND BROAD APPLICABILITY AGAINST EMERGING VIRUSES OF THE BUNYAVIRALES ORDER AND PARAMYXOVIRIDAE FAMILY.

ANTEDECENT BIOMARKERS FOR AD: THE ADULT CHILDREN STUDY BIOMARKERS CORE

WASHINGTON UNIVERSITY INSTITUTE OF CLINICAL AND TRANSLATIONAL SCIENCES

PHOTOSYNTHETIC ANTENNA RESEARCH CENTER (PARC) -- EFRC

AGING EYES AND AGING BRAINS IN STUDYING ALZHEIMER'S DISEASE: MODERN OPHTHALMIC DATA COLLECTION IN THE ADULT CHANGES IN THOUGHT (ACT) STUDY

NATIONAL RESEARCH SCIENCE AWARD - MEDICAL SCIENTIST

HEALTHY AGING AND SENILE DEMENTIA

THE DC COHORT: A LONGITUDINAL POPULATION-BASED COHORT STUDY OF PEOPLE LIVING WITH HIV IN WASHINGTON, DC

CPCRA CLINICAL TRIALS UNIT

WASHINGTON UNIVERSITY INSTITUTE OF CLINICAL AND TRANSLATIONAL SCIENCES (UL1)

DIAN-TU: NEXT GENERATION PREVENTION TRIAL

THE ALLIANCE NCTN BIOREPOSITORY AND BIOSPECIMEN RESOURCE

MAPPING THE HUMAN CONNECTOME: STRUCTURE FUNCTION AND HERITABILITY

HIGHER EDUCATION EMERGENCY RELIEF FUND, INSTITUTIONAL PORTION

VULNERABILITY AND RESILIENCY IN THE AGING ADULT BRAIN CONNECTOME (AABC) - ABSTRACT FOR OVERVIEW THE AGING ADULT BRAIN CONNECTOME (AABC) LEVERAGES THE EXISTING INFRASTRUCTURE DEVELOPED BY THE HUMAN CONNECTOME PROJECT FOR AGING (HCP-A) BY OBTAINING LONGITUDINAL FOLLOW-UP DATA (NEUROIMAGING, COGNITIVE TESTING, AND BLOOD) USING A STANDARDIZED PROTOCOL FROM A WELL CHARACTERIZED COHORT OF OVER 1,000 HEALTHY INDIVIDUALS TO GENERATE WITHIN-PARTICIPANT BRAIN TRAJECTORIES FOR UP TO 10 YEARS. AT INITIAL RECRUITMENT, INDIVIDUALS ENROLLED IN THE HCP-A WERE GENERALLY PHYSICALLY AND COGNITIVELY HEALTHY BUT OVER TIME SOME WILL DEVELOP PRECLINICAL AD OR EARLY COGNITIVE CHANGES DUE TO AD OR ADRD. THE AABC IS COMPRISED OF FOUR PROJECTS: PROJECT 1 EXAMINE THE EFFECTS OF STRESS AND ALLOSTATIC LOAD, INCLUDING INFLAMMATION, DURING THE EARLY ADULT PERIOD. PROJECT 2 EXAMINES THE EFFECTS OF LIFESTYLE BEHAVIORS ON THE TRAJECTORY OF COGNITIVE AND BRAIN CHANGES DURING THE MID ADULT PERIOD. PROJECT 3 EXAMINE THE EFFECTS OF MENOPAUSE TRANSITION/VASOMOTOR SYMPTOMS DURING THE MID ADULT PERIOD. PROJECT 4 EXAM- INE THE CLINICAL AND NEURAL INDICATORS OF RESILIENCY AND RESISTANCE TO AD AND ADRD IN THE LATER DECADES OF ADULT- HOOD. THE AABC ALSO CONSISTS OF 4 CORES: THE ADMINISTRATION CORE (AC) WILL PROVIDE ESSENTIAL CORE AND SITE LEADERSHIP TO CARRY OUT THE SCIENTIFIC MISSION OF THE AABC. THE DIVERSITY RECRUITMENT AND RETENTION UNIT (DRRU) WILL BE LOCATED WITHIN THIS CORE AND WILL ENSURE THAT THE AABC CONTINUES TO RECRUIT AND RETAIN AN ADEQUATE DISTRI- BUTION OF RACES THAT IS CURRENTLY SEEN IN THE US. THE INTEGRATED DATA ACQUISITION CORE (IDAC) PROVIDES EXPERTISE AND PERSONNEL FROM EACH SITE TO ACQUIRE HIGH QUALITY NEUROIMAGING, DEEP PHENOTYPING OF NON-IMAGING DATA, AND BIOSAMPLES FROM EACH SITE.THE INFORMATICS, DATA ANALYSIS, AND STATISTICS CORE (IDASC) WILL HOUSE PROJECT IMAG- ING DATA USING THE INTRADB DATABASE, WILL PERFORM QUALITY CONTROL OF RAW AND ANALYZED DATA, WILL DEVELOP AND RUN CROSS-SECTIONAL AND LONGITUDINAL PIPELINES TO PRODUCE MULTI-MODAL IMAGING DATA PHENOTYPES FOR EACH PROJECT, WILL PROVIDE DIMENSION-REDUCED SUMMARIES, WILL IMPUTE MISSING DATA; AND WILL DEVELOP AND RUN STATISTICAL MODELS FOR EACH PROJECT. THE IDASC WILL ALSO BE RESPONSIBLE FOR DATA SHARING WITH THE GENERAL PUBLIC. THE GENETICS AND MULTI-OMICS SPECIMENS CORE (GMSC) WILL PROVIDE GENETIC INFORMATION ON PARTICIPANTS EVALUATED THROUGH THE AABC WHO HAVE BEEN CHARACTERIZED USING A UNIFORM PROTOCOL. MULTI-OMIC DATA AND AD BIOMARKER DATA WILL BE GENERATED BY THE GMSC.

AUTOPHAGY MODULATORS AS NOVEL BROAD-SPECTRUM ANTI-INFECTIVE AGENTS

INSTITUTIONAL SUPPORT

EPIDEMIOLOGY OF DIABETES INTERVENTIONS AND COMPLICATIONS DATA COORDINATING CENTER

ALZHEIMER'S DISEASE RESEARCH CENTER

HEALTHY BRAIN AND CHILD DEVELOPMENT NATIONAL CONSORTIUM DATA COORDINATING CENTER - PROJECT SUMMARY THE LANDMARK HEALTHY BRAIN AND CHILD DEVELOPMENT (HBCD) STUDY WILL PROVIDE A REPRESENTATIVE REFERENCE DATA RESOURCE TO THE SCIENTIFIC COMMUNITY ENABLING UNPRECEDENTED INVESTIGATION OF NEURODEVELOPMENT AND THE IMPACT OF ENVIRONMENTAL, GENETIC, AND BIOLOGICAL FACTORS ON BRAIN AND BEHAVIORAL HEALTH AND DEVELOPMENTAL TRAJECTORIES FROM INFANCY THROUGH CHILDHOOD. THROUGH THIS STUDY, THE HEALTHY BRAIN AND CHILD DEVELOPMENT NATIONAL CONSORTIUM (HBCD-NC) WILL RECRUIT AND RETAIN A SOCIODEMOGRAPHICALLY DIVERSE COHORT OF 7,500 PREGNANT WOMEN FROM 24 SITES ACROSS THE U.S. AND FOLLOW THESE FAMILIES AND THEIR CHILDREN THROUGH THE FIRST DECADE OF LIFE. CHILDREN WILL UNDERGO RIGOROUS DATA COLLECTION ACROSS MODALITIES INCLUDING NEUROIMAGING, NEUROPHYSIOLOGY, BEHAVIORAL AND COGNITIVE ASSESSMENTS, AND COLLECTION OF BIOSPECIMENS VIA A BALANCED PROTOCOL DEVELOPED BY FIELD-LEADING EXPERTS. BUILDING UPON THE SUBSTANTIVE COMPLEMENTARY EXPERIENCE AND EXPERTISE OF ITS MULTIDISCIPLINARY TEAM AND LEVERAGING MULTIPLE POPULATION-SPECIFIC TECHNICAL INNOVATIONS, THE HEALTHY BRAIN AND CHILD DEVELOPMENT NATIONAL CONSORTIUM DATA COORDINATING CENTER (HDCC) WILL PROVIDE THE LEADERSHIP, MANAGEMENT, AND OVERSIGHT OF DATA COLLECTION, QUALITY CONTROL, CURATION, PROCESSING, MANAGEMENT, SHARING, AND ANALYTICS TO FACILITATE AND SUPPORT THE ACTIVITIES OF THE HBCD-NC AND ENSURE ITS SUCCESS. INCLUDED IS DEVELOPMENT AND IMPLEMENTATION OF AN OPTIMIZED, STATE-OF-THE-ART MRI PROTOCOL HARMONIZED FOR THE FIRST TIME IN INFANTS/TODDLERS ACROSS ALL THREE MAJOR VENDORS WHICH LEVERAGES THE LATEST INNOVATIONS IN SCANNER TECHNOLOGY WITH AGE-SPECIFIC STRUCTURAL, MICROSTRUCTURAL, QUANTITATIVE, FUNCTIONAL, AND SPECTROSCOPY SEQUENCES. ALSO DETAILED IS A TARGETED EEG PROTOCOL LINKED WITH A FIELD-LEADING AUTOMATED PROCESSING PIPELINE FOR DEVELOPMENTAL EEG WHICH PROVIDES INNOVATIVE DERIVATIVE MEASURES. DATA AND PROJECT MANAGEMENT WILL OCCUR THROUGH A CENTRALIZED TRACKING AND DISTRIBUTION PLATFORM LINKED TO A HIGH-THROUGHPUT COMPUTE BACKBONE WHICH OVERCOMES LIMITS OF COMMERCIALLY-AVAILABLE SYSTEMS FOR MANAGEMENT AND INTEGRATED PROCESSING OF MULTIMODALITY DATA FROM LARGE, MULTI-SITE STUDIES. HIGH PERFORMANCE COMPUTING WILL BE SUPPORTED THROUGH UNIQUE ACCESS TO A COMBINATION OF FIELD-LEADING RESOURCES. DETAILED PROCEDURES ARE OUTLINED FOR SECURE COLLECTION, MANAGEMENT, AND ANALYSIS OF PERSONALLY IDENTIFIABLE INFORMATION (PII) DATA, INCLUDING FLEXIBLE METHODS DESIGNED TO ACCOMMODATE HETEROGENEITY IN ELECTRONIC HEALTH RECORD SYSTEMS ACROSS SITES. FINALLY, SUBSTANTIVE HBCD-SPECIFIC ENHANCEMENTS TO THE DATA EXPLORATION AND ANALYSIS PORTAL (DEAP 2.0) WILL PRODUCE A CRUCIAL TOOL FOR DATA ACCESS TO AUTHENTICATED USERS WHILE PROMOTING BEST PRACTICES IN REPRODUCIBLE STATISTICAL ANALYSIS AND PROVIDING FLEXIBLE COMPUTATION WITHOUT THE NEED TO DOWNLOAD RESTRICTED-ACCESS DATA. THE RESULT OF THIS FIELD- LEADING COMBINATION OF HDCC RESOURCES WILL BE A STATE-OF-THE-ART, LONGITUDINAL DATA SET OF UNPARALLELED SCALE WHICH PROVIDES DEEP UNDERSTANDING OF THE BIOLOGICAL AND ENVIRONMENTAL FACTORS THAT AFFECT A CHILD’S HEALTH, BRAIN, AND BEHAVIORAL DEVELOPMENT AND SHAPES RESEARCH, CLINICAL CARE, AND PUBLIC POLICY FOR DECADES TO COME.

WASHU-VAI SOMATIC MOSAICISM ACROSS HUMAN TISSUES (SMAHT) PROGRAM GENOME CHARACTERIZATION CENTER - PROJECT SUMMARY THE SOMATIC MOSAICISM ACROSS HUMAN TISSUES (SMAHT) NETWORK AIMS TO PROPEL DISCOVERY OF NEW BIOLOGICAL PROCESSES IN HUMAN HEALTH AND DISEASE THAT ARE MEDIATED BY GENOMIC VARIATION IN SOMATIC TISSUES. WE PROPOSE TO ESTABLISH THE WASHU-VAI SOMATIC MOSAICISM ACROSS HUMAN TISSUES (SMAHT) PROGRAM GENOME CHARACTERIZATION CENTER (SMAHT-GCC). A FUNDAMENTAL GOAL OF OUR PROPOSED GCC IS TO GENERATE HIGH THROUGHPUT, HIGH QUALITY, AND HIGH CONSISTENCY GENOMIC DNA AND RNA SEQUENCING DATA, AND TO CONSTRUCT A COMPREHENSIVE CATALOGUE OF THE HUMAN SOMATIC VARIATION TOGETHER WITH OTHER MEMBERS OF THE NETWORK. FIRST, WE WILL ESTABLISH AND MANAGE A COLLABORATIVE, EFFICIENT, TRANSPARENT, AND FLEXIBLE GCC AS AN INTEGRAL COMPONENT OF THE SMAHT NETWORK. WE WILL LEVERAGE OUR EXPERIENCE IN PARTICIPATING AND LEADING MANY PAST AND CURRENT GENOMICS CONSORTIA TO DESIGN AND IMPLEMENT OUR GCC. THE GCC WILL MANAGE CENTER ADMINISTRATION, MAINTAIN HIGH QUALITY, SUSTAINABLE, AND ON-TIME DATA PRODUCTION, DEVELOP AND IMPLEMENT DATA MANAGEMENT PLANS, CONDUCT DATA QUALITY ASSURANCE AND INTEGRATIVE DATA ANALYSIS, AND FULLY ENGAGE WITH THE ENTIRE SMAHT NETWORK. SECOND, WE WILL GENERATE HIGH QUALITY, HIGH THROUGHPUT, COMPREHENSIVE AND SUSTAINABLE GENOMICS DATASETS FOR THE CHARACTERIZATION OF HUMAN SOMATIC MOSAICISM, USING STATE-OF-THE-ART TECHNOLOGIES. WE CAPITALIZE ON OUR PAST EXPERIENCE IN GENERATING HIGH QUALITY SEQUENCING-BASED GENOMIC RESOURCES, TO DESIGN AND IMPLEMENT OUR DATA PRODUCTION PLAN. WE RECOMMEND A COLLECTION OF HUMAN TISSUE TYPES, AND WILL IMPLEMENT FOUR CORE GENOMICS ASSAYS TO PROFILE SAMPLE RECEIVED FROM SMAHT TISSUE PROCUREMENT CENTER. WE AIM TO DELIVER HIGH THROUGHPUT, HIGH QUALITY, AND HIGH CONSISTENCY GENOMIC DNA AND RNA SEQUENCING DATA TO THE SMAHT DATA ANALYSIS CENTER. THIRD, WE WILL DEVELOP AND MAINTAIN A MODERN, EFFICIENT, SCALABLE, AND INTERACTIVE DATA MANAGEMENT AND PROCESSING SYSTEM THAT SEAMLESSLY INTERFACES WITH THE SMAHT DATA ANALYSIS CENTER. WE WILL LEVERAGE OUR EXPERIENCE IN SCIENTIFIC COMPUTING, INFORMATION TECHNOLOGY SYSTEM, LARGE GENOMIC DATA MANAGEMENT AND INTEGRATION, AND COMMUNITY ENGAGEMENT TO DESIGN AND IMPLEMENT OUR DATA MANAGEMENT PLAN. WE WILL BUILD A STREAMLINED, EFFICIENT DATA INFRASTRUCTURE TO MANAGE GCC DATA AND COLLABORATE WITH SMAHT DAC. FOURTH, WE WILL DEVELOP AND IMPLEMENT DATA ANALYSIS AND VISUALIZATION SOLUTIONS FOR THE SMAHT-GCC DATA. WE WILL LEVERAGE OUR EXTENSIVE EXPERIENCE IN GENOMIC DATA ANALYSIS AND INTEGRATION, BIOINFORMATICS TOOL DEVELOPMENT AS WELL AS DATA VISUALIZATION IN THE IMPLEMENTATION OF OUR DATA ANALYSIS AND VISUALIZATION PLAN. WE WILL ALSO BRING IN UNIQUE EXPERTISE IN ANALYZING TRANSPOSABLE ELEMENTS AND EPIGENOMICS DATA. WE WILL CONTRIBUTE TO THE NETWORK-WIDE DATA ANALYSIS, AND FACILITATE THE CHARACTERIZATION OF A FULL SPECTRUM OF THE HUMAN SOMATIC MOSAICISM.

WESTERN WASHINGTON UNIVERSITY: CARES ACT HIGHER EDUCATION EMERGENCY RELIEF FUND - IHE

NORTH AMERICAN PRODROMAL SYNUCLEINOPATHY CONSORTIUM FOR RBD, STAGE 2 (NAPS2) - MOST INDIVIDUALS WITH RAPID EYE MOVEMENT (REM) SLEEP BEHAVIOR DISORDER (RBD) DEVELOP ADDITIONAL NEUROLOGICAL SYMPTOMS AND ARE SUBSEQUENTLY DIAGNOSED WITH OVERT SYNUCLEINOPATHIES, INCLUDING DEMENTIA WITH LEWY BODIES (DLB), PARKINSON’S DISEASE (PD), AND MULTIPLE SYSTEM ATROPHY (MSA), INDICATING THAT RBD REPRESENTS A PRODROMAL STAGE OF SYNUCLEINOPATHY. RBD THEREFORE OFFERS A WINDOW OF OPPORTUNITY TO INTERVENE WITH NEUROPROTECTIVE TREATMENTS AT THE EARLIEST STAGES OF DISEASE WHEN TREATMENT IS MOST LIKELY TO BE EFFECTIVE. RECOGNIZING THE IMPORTANCE OF EARLY INTERVENTION, KEY FEDERAL AGENCIES FOCUSED ON NEURODEGENERATIVE DISEASE HAVE PROPOSED HIGH PRIORITY RECOMMENDATIONS FOR PRODROMAL ASPECTS OF SYNUCLEINOPATHIES, INCLUDING SPECIFICALLY RBD, TO PREPARE FOR CLINICAL TRIALS. THE NORTH AMERICAN PRODROMAL SYNUCLEINOPATHY (NAPS) CONSORTIUM BEGAN IN 2018 TO PLAN FOR NEUROPROTECTIVE CLINICAL TRIALS IN RBD. THE NAPS CONSORTIUM, CURRENTLY AT 10 SITES, HAS THUS FAR ENROLLED 215 PARTICIPANTS WITH POLYSOMNOGRAM-CONFIRMED RBD, AND HAS SUCCESSFULLY PERFORMED COMPREHENSIVE AND STANDARDIZED ASSESSMENTS AND BIOFLUIDS COLLECTION. THE NORTH AMERICAN PRODROMAL SYNUCLEINOPATHY CONSORTIUM FOR RBD, STAGE 2 (NAPS2) PROGRAM REPRESENTS AN INTEGRATED EXPANSION OF NAPS TO SUPPORT A LONGITUDINAL, PROSPECTIVE STUDY OF RBD, TO ADDRESS KEY GAPS CURRENTLY PROHIBITING NEUROPROTECTIVE CLINICAL TRIALS IN RBD. NAPS2 WILL ESTABLISH ENHANCED INFRASTRUCTURE TO SUPPORT LONG-TERM RESEARCH IN PRODROMAL SYNUCLEINOPATHIES. WE WILL INSTITUTE 8 CORES—ADMINISTRATIVE; CLINICAL; BIOFLUID; NEUROIMAGING; POLYSOMNOGRAM (PSG); GENETICS; DATA MANAGEMENT AND STATISTICS (DMS); AND RECRUITMENT, EDUCATION, AND OUTREACH (REO)—TO AUGMENT OUR PROTOCOL AND TO SUPPORT A PROJECT TO PREDICT PHENOCONVERSION TO OVERT SYNUCLEINOPATHY. NAPS2 WILL PROSPECTIVELY ASSESS >300 PARTICIPANTS WITH RBD FOR COMPREHENSIVE CLINICAL EVALUATION AND COLLECTION OF PSG/NEUROPHYSIOLOGICAL, BIOFLUID (BLOOD AND CEREBROSPINAL FLUID), GENETIC, AND NEUROIMAGING (MRI AND DATSCAN) BIOMARKERS. THE OVERARCHING GOAL OF NAPS IS TO ENABLE NEUROPROTECTIVE CLINICAL TRIALS TO PREVENT OR DELAY SYNUCLEINOPATHIES. TOWARD THIS GOAL, THE NAPS2 AIMS ARE: 1) TO CONDUCT RESEARCH ON RBD AS A PRODROMAL MANIFESTATION OF DLB, PD, AND MSA; 2) TO EXPAND OUR COHORT OF RBD PARTICIPANTS AND ADD MATCHED CONTROL PARTICIPANTS FOR LONGITUDINAL, STANDARDIZED COLLECTION OF CLINICAL, PSG, GENETIC, BIOFLUID, AND NEUROIMAGING DATA; 3) TO ANALYZE COLLECTED DATA AGAINST LONGITUDINAL CLINICAL OUTCOMES TO REFINE SCALES AND DEVELOP BIOMARKERS TO OPTIMALLY DESIGN CLINICAL TRIALS; 4) TO SHARE DATA, SAMPLES, AND METHODS FOR USE BY THE SCIENTIFIC COMMUNITY; 5) TO INTERACT WITH NIH, OTHER SCIENTIFIC GROUPS ON RBD AND OVERT SYNUCLEINOPATHIES, INDUSTRY PARTNERS, PATIENTS, AND OTHER GROUPS; AND 6) TO PREPARE FOR LARGE-SCALE CLINICAL TRIALS. ULTIMATELY, SYNUCLEINOPATHY BIOMARKERS AND NEUROPROTECTIVE TREATMENTS DEVELOPED IN THE RBD POPULATION COULD BE APPLIED TO THE LARGER POPULATION AT RISK FOR SYNUCLEINOPATHIES, TO DELAY OR PREVENT DLB, PD, AND MSA.

DISTRICT OF COLUMBIA CENTER FOR AIDS RESEARCH (DC CFAR)

SPECIALIZED PROGRAM OF RESEARCH EXCELLENCE (SPORE) IN LEUKEMIA

CPCRA CLINICAL TRIALS UNIT

STRUCTURAL AND FUNCTIONAL CHARACTERIZATION OF THE EBOLA VIRUS REPLICATION COMPLEX

DOMINANTLY INHERITED ALZHEIMER'S NETWORK TRIALS UNIT - ADAPTIVE PREVENTION TRIAL

CARES ACT EMERGENCY FINANCIAL AID GRANT FUNDING

DIABETES RESEARCH CENTER

CWU - INSTITUTIONAL PORTION OF THE HIGHER EDUCATION EMERGENCY RELIEF FUND

EMERGENCY FINANCIAL AID GRANTS TO STUDENTS UNDER THE CARES ACT

EXTREME LONGEVITY FAMILY STUDY - DMCC

ALZHEIMER'S DISEASE RESEARCH CENTER

WASHINGTON UNIVERSITY CLINICAL NUTRITION RESEARCH UNIT

CARES ACT EMERGENCY FINANCIAL AID GRANT FUNDING

DOMINANTLY INHERITED ALZHEIMER NETWORK

REGULATORY FACTORS IN THE GI TRACT

EARLY LIFE ADVERSITY, BIOLOGICAL EMBEDDING, AND RISK FOR DEVELOPMENTAL PRECURSORS OF MENTAL DISORDERS

CWU - HIGHER EDUCATION EMERGENCY RELIEF FUND

THE WASHU-UCSC-EBI HUMAN GENOME REFERENCE CENTER

MAPPING THE HUMAN CONNECTOME DURING TYPICAL AGING

NEW THERAPIES FOR LIVER FIBROSIS AND HYPERPROLIFERATION IN ALPHA1-AT DEFICIENCY

PATHWAYS REGULATING LUNG TRANSPLANT TOLERANCE

COMPREHENSIVE REGIONAL ASSISTANCE CENTERS - COMPREHENSIVE REGIONAL ASSISTANCE CENTERS

MAPPING THE HUMAN CONNECTOME DURING TYPICAL DEVELOPMENT

SEQUENCING THE MAIZE GENOME

GAINING EARLY AWARENESS AND READINESS FOR UNDERGRADUATE PROGRAMS (GEAR UP PARTNERSHIP)

OPER & MAINT OF FHWA AND NHTSA NATL CRASH A C

BLOOD AMYLOID, TAU, AND NEURODEGENERATION BIOMARKERS AND PREDICTION OF CLINICAL ONSET, COGNITIVE DECLINE, AND DEMENTIA DIAGNOSIS - PROJECT SUMMARY IN ORDER TO ACCELERATE OBSERVATIONAL CLINICAL STUDIES AND TRIALS AND TO IDENTIFY APPROPRIATE PATIENTS FOR TREATMENTS, HIGHLY ACCURATE AND ACCESSIBLE DIAGNOSTIC TESTS FOR ALZHEIMER'S DISEASE (AD) ARE NEEDED. CLINICAL ASSESSMENTS ALONE ARE INSUFFICIENT FOR ACCURATE DIAGNOSES, AND THE CURRENT GOLD STANDARD TESTS FOR AD (CSF AND PET) ARE COSTLY, LIMITED TO SPECIALIZED MEDICAL CENTERS, AND PERCEIVED TO BE INVASIVE. IN OUR ONGOING PROSPECTIVE STUDY TO EVALUATE AMYLOID IN BLOOD AND IMAGING RELATED TO DEMENTIA (SEABIRD), WE DISCOVERED THAT DECREASED BLOOD PLASMA AΒ42/40 RATIO IS AN ACCURATE BIOMARKER OF AMYLOID PLAQUES AND CONFIRMED THIS IN A DIVERSE COMMUNITY- BASED POPULATION, ALSO DEMONSTRATING THAT BLOOD TESTS ARE FEASIBLE TO SCREEN THE GENERAL POPULATION. WE HAVE DISCOVERED AND REPORTED THE MOST ACCURATE AΒ42/40 AND PHOSPHORYLATED-TAU BLOOD BIOMARKERS (%PTAU217, %PTAU205, AND %PTAU181) AND DISCOVERED NOVEL FORMS OF NEUROFILAMENT LIGHT (NFL) THAT PROMISE TO QUANTIFY THE MAJOR DOMAINS OF AD PATHOPHYSIOLOGY. WITH DEMONSTRATION THAT REMOVAL OF AMYLOID PLAQUES LEADS TO DISEASE-MODIFYING TREATMENT CLINICAL BENEFITS, ACCESS TO ANTI-AMYLOID THERAPIES WILL DEPEND ON ACCURATE DIAGNOSIS, AND BLOOD BIOMARKERS WILL BE CRITICAL TOOLS FOR DOCTORS AND PATIENTS IN UNDERREPRESENTED POPULATIONS. HOWEVER, THERE ARE MULTIPLE QUESTIONS THAT NEED TO BE ADDRESSED TO INFORM ABOUT THE BIOLOGY, USE, AND INDICATIONS OF THESE RAPIDLY DEVELOPING AND UTILIZED BLOOD-BASED BIOMARKERS. THESE QUESTIONS INCLUDE: `WHAT ARE THE DIAGNOSTIC AND PROGNOSTIC PROPERTIES OF BLOOD AΒ, TAU, AND NEURODEGENERATION (A/T/N) BIOMARKERS TO MEASURE AMYLOID AND TAU PATHOLOGY, CLINICAL COGNITIVE DECLINE, AND DIAGNOSIS IN A REAL-WORLD CLINICAL PATIENT POPULATION?', AND `WHICH DEMOGRAPHIC, CLINICAL, OR GENETIC FACTORS INFLUENCE THE RELATIONSHIP OF BLOOD A/T/N BIOMARKERS TO THE GOLD STANDARDS OF CLINICAL COGNITIVE DECLINE, DEMENTIA, AND PET TESTS OF PATHOLOGY?' OUR PROPOSED STUDY, CALLED SUNBIRD (STUDY TO UNDERSTAND NOVEL BIOMARKERS IN RESEARCHING DEMENTIA), WILL ENROLL 1000 NEW PARTICIPANTS FROM PRIMARY AND SPECIALTY CARE CLINICS AND FOLLOW THE EXISTING ~1000 SEABIRD PARTICIPANTS. WE WILL INCORPORATE HIGH PERFORMANCE BLOOD-BASED BIOMARKERS TRACKING AMYLOID, TAU AND NEURODEGENERATION AND ASSESS THEIR RELATIONSHIP WITH TAU PET, AMYLOID PET, AND OTHER CLINICAL AD TESTS. WE WILL FOLLOW THESE COHORTS LONGITUDINALLY USING BLOOD SAMPLES, EHR DATA, AND IN-PERSON AND REMOTE COGNITIVE TESTING. WE AIM TO UNDERSTAND HOW BLOOD-BASED BIOMARKERS CAN IDENTIFY THOSE WITH CLINICAL SYMPTOMS DUE TO AD PATHOLOGY, DETERMINE IF BLOOD-BASED BIOMARKERS CAN BE UTILIZED IN LIEU OF PET OR CSF MEASURES, AND ALSO DIAGNOSE AND STAGE PATIENTS TO ENABLE TREATMENT AND PREVENTION IN THE CLINIC. THE PROPOSED WORK BUILDS ON THE PRIOR PIONEERING APPROACH THAT DISCOVERED AND VALIDATED BLOOD AMYLOID BIOMARKERS, DISCOVERED NOVEL TAU PHOSPHORYLATION SITES. THESE STUDIES WILL LAY THE GROUNDWORK FOR RAPID DEPLOYMENT TO ACCELERATE ENROLLMENT OF AD TRIALS, CLINICAL DIAGNOSIS, AND EARLY AND ACCURATE DIAGNOSIS FOR THE WHOLE POPULATION.

TYPE 1 DIABETES TRIALNET: OPERATIONS COORD. CENTER

SEQUENCING THE HUMAN MICROBIOME

MULTI-ARM OPTIMIZATION OF STROKE THROMBOLYSIS (MOST) STROKE TRIAL

REMEDIATING AGE RELATED COGNITIVE DECLINE: MINDFULNESS-BASED STRESS REDUCTION AND EXERCISE

NEW TOOLS FOR COMPARATIVE SYSTEMS BIOLOGY OF THREAT AGENT ACTION MECHANISMS

NEUROIMMUNOLOGY OF AD AND CAA WITH FOCUS ON INNATE IMMUNITY AND LYMPHATICS - PROJECT SUMMARY/ABSTRACT ALZHEIMER’S DISEASE (AD) AND CEREBRAL AMYLOID ANGIOPATHY (CAA) ARE SIGNIFICANT CONTRIBUTORS TO AGE-RELATED DEMENTIA AND A MAJOR ECONOMIC BURDEN. CURRENT STRATEGIES TO ALLEVIATE AD AND CAA PATHOLOGY AND ASSOCIATED COGNITIVE DECLINE ARE LARGELY INEFFECTIVE, NECESSITATING THE NEED FOR ADDITIONAL THERAPEUTIC AVENUES TO BE EXPLORED, PARTICULARLY WITH A MULTI-DISCIPLINARY TEAM ABLE TO ACHIEVE A HOLISTIC UNDERSTANDING OF VASCULAR, NEURONAL, AND IMMUNE EVENTS THAT UNDERLIE DISEASE PROGRESSION. ONE PROMISING STRATEGY IS THE AUGMENTATION OF CLEARANCE PATHWAYS – INCLUDING MICROGLIA/MACROPHAGE PHAGOCYTOSIS OF AB AND MENINGEAL LYMPHATIC DRAINAGE OF CEREBRAL SPINAL FLUID (CSF) - THAT FACILITATE THE REMOVAL OF TOXIC, MISFOLDED PROTEIN AGGREGATES THAT REPRESENT PATHOLOGICAL HALLMARKS OF AD BRAINS. WHILE THE VAST MAJORITY OF PRIOR RESEARCH HAS FOCUSED ON PARENCHYMAL AB PATHOLOGY AND MICROGLIAL FUNCTIONS, MANY PATIENTS ALSO DISPLAY CAA, CONTRIBUTING TO VASCULAR DYSFUNCTION, AND IMPLICATING A ROLE FOR PARENCHYMAL BORDER MACROPHAGES (PBMS; PERIVASCULAR AND LEPTOMENINGEAL, COLLECTIVELY). THUS, WE WILL EXPLORE THE COMPLEX INTERACTIONS BETWEEN THE MENINGEAL LYMPHATIC SYSTEM, CSF FLOW, PBMS, AND PARENCHYMAL MICROGLIA IN AD AND CAA. THE OVERALL HYPOTHESIS OF THIS PPG IS THAT NEUROIMMUNE EVENTS, PARTICULARLY ASPECTS OF THE INNATE IMMUNE SYSTEM AND MENINGEAL LYMPHATICS, UNDERLIE AD AND CAA PATHOLOGY. WE FURTHER HYPOTHESIZE THAT DEVISING NEW THERAPEUTIC APPROACHES, HARNESSING THE FUNCTIONS OF MICROGLIA, PBMS, AND THE MENINGEAL LYMPHATICS MAY REPRESENT NOVEL TARGETS TO ALLEVIATE AD-RELATED COGNITIVE DECLINE. IN PARTICULAR, WE WILL EXPLORE HOW DYSFUNCTION IN CHOLESTEROL METABOLISM, APOE, AND DOWNSTREAM TREM2 SIGNALING CONTRIBUTE TO HOMEOSTATIC FUNCTIONS OR PROMOTE PATHOLOGICAL ROLES OF MICROGLIA, PBMS, AND THE MENINGEAL LYMPHATICS, PRECIPITATING AB PATHOLOGY. WORKING AS A HIGHLY COLLABORATIVE MULTIDISCIPLINARY TEAM, WE WILL UTILIZE NEWLY DEVELOPED INNOVATIVE TOOLS TO EXPLORE THESE HYPOTHESES, INCLUDING INTRA-VITAL IMAGING APPROACHES, IN-VIVO MICROANALYSIS, NEW TRANSGENIC MOUSE LINES AND UNIQUE SURGICAL APPROACHES. THE SPECIFIC PROJECTS AND CORES ARE AS FOLLOWS: PROJECT 1: KIPNIS, PI: PARENCHYMAL BORDER MACROPHAGES IN AD AND CAA. PROJECT 2: HOLTZMAN, PI: CAA: ROLE OF APOE, INNATE IMMUNITY, AND MENINGEAL LYMPHATICS. PROJECT 3: RANDOLPH, PI: INTERPLAY BETWEEN MENINGEAL LYMPHATICS, HIGH-DENSITY LIPOPROTEINS AND BORDER MACROPHAGES IN CAA AND AD. PROJECT 4: COLONNA, PI: THE PROTEIN TYROSINE KINASE SYK DRIVES INNATE IMMUNE RESPONSES AGAINST AD. CORE A: ADMINISTRATION (KIPNIS, PI); CORE B: IMAGING AND SURGERY CORE (RANDOLPH, PI).

UNDERSTANDING AND TARGETING THE PATHOPHYSIOLOGY OF YOUTH-ONSET TYPE 2 DIABETES - BIOSTATISTICS RESEARCH CENTER - PROJECT SUMMARY/ABSTRACT TYPE 2 DIABETES (T2D) IN YOUTH IS INCREASINGLY PREVALENT IN PARALLEL WITH THE OBESITY EPIDEMIC, YET EFFECTIVE TREATMENT AND PREVENTION STRATEGIES ARE LIMITED. THE PHYSIOLOGIC REDUCTION IN INSULIN SENSITIVITY OCCURRING DURING PUBERTY IN COMBINATION WITH OBESITY-RELATED INSULIN RESISTANCE ENHANCE THE RISK OF T2D. YET IT REMAINS UNCLEAR WHY SOME YOUTH EXPERIENCE NORMAL PUBERTAL PROGRESSION WITH INTACT SS-CELL FUNCTION, WHILE OTHERS DO NOT, DESPITE SIMILAR PHENOTYPIC AND METABOLIC CHARACTERISTICS. THE LOW INCIDENCE AND PREVALENCE OF T2D IN YOUTH COMPARED TO ADULT’S TURNS THE FOCUS TO IDENTIFYING AND CHARACTERIZING PATHOPHYSIOLOGICAL PRECURSORS TO T2D. MORE INFORMATION IS NEEDED REGARDING THE UNIQUE EVENTS DURING PUBERTY TO BETTER UNDERSTAND THE BASIC PATHOPHYSIOLOGY OF GLUCOSE CONTROL, INSULIN SENSITIVITY, SS-CELL FUNCTION, AND T2D RISK IN YOUTH, AS WELL AS DIFFERENCES BY SEX/GENDER AND RACE/ETHNICITY, AND THE POTENTIAL CONTRIBUTION OF HARMFUL ENVIRONMENTAL FACTORS THAT ARE CHARACTERISTIC OF THIS POPULATION. IMPORTANTLY, THIS RESEARCH NEEDS TO ADDRESS THE TIMELINE OF PATHOPHYSIOLOGICAL ACTIVITY FROM NORMOGLYCEMIA TO PREDIABETES TO YOUTH-ONSET T2D (YO-T2D). THE UNDERSTANDING AND TARGETING THE PATHOPHYSIOLOGY OF YOUTH-ONSET TYPE 2 DIABETES (UTP-T2D) CONSORTIUM PROVIDES A UNIQUE OPPORTUNITY TO CHARACTERIZE THE RISK PROGRESSION PROFILE AND MECHANISMS UNDERLYING THE DEVELOPMENT OF YO-T2D, AND EVALUATE THE EFFECTS OF MODIFIABLE AND NON-MODIFIABLE RISK FACTORS. ULTIMATELY, THE RESULTS OF THIS STUDY WILL ESTABLISH A BASIC PATHOPHYSIOLOGY TO INFORM FUTURE STUDIES AIMED AT ACHIEVING GLYCEMIC CONTROL, IMPROVING INSULIN SENSITIVITY, PRESERVING SS-CELL FUNCTION, AND/OR PREVENTING T2D IN YOUTH. TO ADDRESS THIS GOAL, THE UTP-T2D STUDY WILL RECRUIT, ENROLL, AND FOLLOW A LARGE RACIALLY AND ETHNICALLY DIVERSE COHORT OF 3,000 AT- RISK OBESE YOUTH IN EARLY PUBERTY, EXTENSIVELY PHENOTYPE THEM AS THEY TRANSITION THROUGH PUBERTY, AND CHARACTERIZE THE COURSE OF DECLINE AND DYSFUNCTION IN PATHOPHYSIOLOGICAL INDICATORS THAT LEAD TO T2D. THE EXPECTED DURATION OF THE UTP-T2D STUDY IS 5 YEARS, INCLUDING PLANNING, RECRUITMENT, FOLLOW-UP, ANALYSIS, AND REPORTING. IN ADDITION TO ADDRESSING THE AIMS WITH ANALYSES CONDUCTED AS PART OF THE PROPOSED STUDY, THE UTP- T2D CONSORTIUM WILL STORE LONGITUDINAL BIOSPECIMENS AND GENETIC MATERIAL WITH THE INTENTION OF ACQUIRING ADDITIONAL ANCILLARY FUNDING TO PURSUE ANALYSIS OF EMERGING INDICATORS. THE BIOSTATISTICS RESEARCH CENTER (BRC) WILL ENHANCE THE VALUE OF THE UTP-T2D CONSORTIUM BY 1) OVERSEEING ALL OPERATIONAL ASPECTS OF THE CONSORTIUM, 2) PROVIDING ADMINISTRATIVE RESOURCES AND LOGICAL SUPPORT OF THE CONSORTIUM, AND 3) PROVIDING SCIENTIFIC AND BIOSTATISTICAL EXPERTISE FOR THE CONSORTIUM. THROUGH EFFECTIVE ORGANIZATION, COMMUNICATION, AND SUPPORT, AND BY PROMOTING A COLLABORATIVE ENVIRONMENT, THE BRC WILL PROVIDE THE FRAMEWORK AND INFRASTRUCTURE FOR THE CONSORTIUM TO SUCCESSFULLY RECRUIT A COHORT OF EARLY PUBERTAL YOUTH AT RISK FOR DEVELOPING PREDIABETES AND T2D, DEEPLY PHENOTYPE THEM THROUGH PUBERTY, AND ULTIMATELY CONTRIBUTE TO A BETTER UNDERSTANDING OF THE PATHOPHYSIOLOGY OF YO-T2D.

SPACE RENOVATION FOR NEW RESEARCH CENTER FOR THE NEGLECTED DISEASES OF POVERTY

INNATE AND ADAPTIVE IMMUNE SIGNALING IN ASTHMA

CROSS SECTIONAL AND LONGITUDINAL RACIAL DISPARITY IN MOLECULAR BIOMARKERS OF ALZHEIMER DISEASE

METAGENOMIC STUDIES OF THE GUT MICROBIOMES OF OBESE AND LEAN TWINS

WASHINGTON UNIVERSITY MOLECULAR IMAGING CENTER

WASHINGTON UNIVERSITY PARTICIPANT ENGAGEMENT AND CANCER GENOMIC SEQUENCING CENTER (WU-PE-CGS) - PROJECT SUMMARY VISION. PARTICIPANT ENGAGEMENT AND SEQUENCING RESEARCH FROM THE WASHINGTON UNIVERSITY PARTICIPANT ENGAGEMENT AND CANCER GENOMIC SEQUENCING CENTER (WU-PE-CGS) WILL FILL CRITICAL GAPS IN KNOWLEDGE, METHODOLOGY, AND CHARACTERIZATION OF UNDERSTUDIED CANCER POPULATIONS, LEADING TO OPTIMAL APPROACHES TO PARTICIPANT ENGAGEMENT, OUTREACH, AND COMMUNICATION IN GENOMIC CHARACTERIZATION STUDIES. GOAL. THE OVERALL GOAL OF THE WU-PE-CGS IS TO BUILD A RIGOROUS, SCIENTIFIC EVIDENCE BASE FOR APPROACHES DIRECT ENGAGEMENT OF CANCER PATIENTS AND POST-TREATMENT CANCER SURVIVORS AS PARTICIPANTS IN CANCER RESEARCH. OUR FOCUS IS ON RARE AND UNDERSTUDIED CANCER POPULATIONS WITH SIGNIFICANT DISPARITIES INCLUDING CHOLANGIOCARCINOMA, MULTIPLE MYELOMA, AND COLORECTAL CANCER UNDER AGE 50. PARTICIPANT ENGAGEMENT STRATEGIES ARE MOST EFFECTIVE WHEN THEY ARE ADAPTED AND IMPLEMENTED IN REAL-WORLD SETTINGS IN PARTNERSHIP WITH COMMUNITY AND PATIENT ADVOCACY STAKEHOLDERS. SETTING. OUR CENTER WILL BE HOUSED IN AN EXCEPTIONAL ENVIRONMENT THAT FOSTERS TRANSDISCIPLINARY COLLABORATION, CATALYZES NEW IDEAS IN PATIENT ENGAGEMENT, AND ENSURES SUPPORT FOR PATIENT ENGAGEMENT AND GENOME SEQUENCING THAT FINDS SOLUTIONS FOR COMPLEX RECRUITMENT AND ENGAGEMENT CHALLENGES IN REAL-WORLD SETTINGS WITH UNDERREPRESENTED PATIENT POPULATIONS. SIGNIFICANT MATCHING CONTRIBUTIONS FROM WASHINGTON UNIVERSITY WILL ALLOW US TO QUICKLY AND STRATEGICALLY INVEST IN IDEAS. AIMS. THE SPECIFIC AIMS OF THE CENTER ARE TO: (1) ADVANCE THE FIELD OF PARTICIPANT ENGAGEMENT TO STUDY CANCER DISPARITIES AND RARE CANCERS BY CONDUCTING INNOVATIVE AND IMPACTFUL DIRECT STAKEHOLDER ENGAGEMENT WITH CONTINUOUS EVALUATION AND RESEARCH; (2) EXPAND AN EXCEPTIONAL, DIVERSE TEAM OF INVESTIGATORS, PATIENTS, AND ADVOCACY STAKEHOLDERS; (3) ADDRESS CANCER DISPARITIES BY UNDERSTANDING BARRIERS TO AND IMPROVING THE ABILITY FOR DISADVANTAGED AND UNDERSTUDIED POPULATIONS TO ENCOUNTER, USE, AND BENEFIT FROM GENOMIC SEQUENCING AND ANALYSIS; (4) ORGANIZE AND INTEGRATE CENTER UNITS TO FACILITATE TRANSDISCIPLINARY, TEAM SCIENCE WITHIN OUR CENTER AND ACROSS THE PE-CGS NETWORK. INNOVATIONS AND IMPACT. THE WU-PE-CGS BUILDS ON A LONG AND OUTSTANDING RECORD OF LEADERSHIP IN BOTH CANCER DISPARITIES AND GENOMIC RESEARCH ACROSS THE CANCER CONTINUUM. WE WILL BE PARTICULARLY INNOVATIVE AND ALLOW FOR A SIGNIFICANT RETURN ON THE SCIENTIFIC INVESTMENT IN SEVERAL WAYS. FIRST, OUR CENTER HAS DISTINCTIVE FEATURES THAT INCLUDE A COMBINED FOCUS ON CANCER DISPARITIES, THE APPLICATION OF STRATEGIES TO INCREASE PARTICIPANT ENGAGEMENT IN RESEARCH, SUCCESS IN BIOSPECIMEN ACQUISITION, AND EXCEPTIONAL GENOMIC SEQUENCING EXPERTISE. SECOND, WE HAVE ASSEMBLED A DIVERSE, WORLD CLASS TEAM WITH STRONG LINKAGES TO MULTIPLE RARE AND UNDERSTUDIED CANCERS. THIRD, WE ENGAGE INVESTIGATORS FROM DIFFERENT DISCIPLINES AND INVEST IN THE DEVELOPMENT OF EARLY CAREER SCHOLARS. FOURTH, WE WILL STRATEGICALLY AND CREATIVELY DISSEMINATE PRODUCTS IN WAYS THAT WILL BENEFIT RESEARCHERS, PRACTITIONERS, AND COMMUNITY MEMBERS. FIFTH, WE WILL PARTNER WITH EXCEPTIONAL PATIENT-CENTERED AND WIDE-REACHING ADVOCACY GROUPS TO ENGAGE PATIENTS, OPTIMIZE RECRUITMENT, AND SEAMLESSLY RETURN RESULTS. INPUT FROM THESE GROUPS, PATIENTS, AND THEIR FAMILIES IS A KEY STRENGTH THAT WILL LEVERAGE OUR TRACK RECORD OF STAKEHOLDER-ENGAGED RESEARCH. AND FINALLY, WE HAVE DEVELOPED A FOCUSED STRATEGY FOR COLLECTIVE INTEGRATION OF OUR UNITS. THESE SYNERGIES WILL ALLOW OUR CENTER TO BECOME A NATIONAL RESOURCE FOR OPTIMAL APPROACHES TO PARTICIPANT ENGAGEMENT, OUTREACH, AND COMMUNICATION IN GENOMIC CHARACTERIZATION STUDIES AND OTHER STUDIES AS TECHNOLOGIES ADVANCE THAT WILL ACCELERATE PROGRESS FOR BOTH THE SCIENTIFIC COMMUNITY, PATIENTS AND THEIR COMMUNITIES. IN SUMMARY, WE ARE UNIQUELY SITUATED TO ADVANCE A NETWORK OF PARTICIPANT ENGAGEMENT AND SEQUENCING RESEARCHERS, INTEGRATE RESEARCH WITH PATIENTS

ENABLING TECHNOLOGIES FOR PHOTONIC CHIPS-BASED OPTICAL COHERENCE TOMOGRAPHY - ARPA-H

A DATA CENTER FOR THE DISCOVERY OF THE GENETIC BASIS OF HUMAN DISEASE

WASHINGTON UNIVERSITY INSTITUTE OF CLINICAL AND TRANSLATIONAL SCIENCES (KL2)

CENTER: NSF ENGINEERING RESEARCH CENTER FOR CARBON UTILIZATION REDESIGN THROUGH BIOMANUFACTURING-EMPOWERED DECARBONIZATION (CURB) -THE CARBON UTILIZATION REDESIGN FOR BIOMANUFACTURING-EMPOWERED DECARBONIZATION (CURB) ENGINEERING RESEARCH CENTER WILL TRANSFORM U.S. MANUFACTURING BY CURBING CO2 EMISSIONS AND DECREASING THE HUMAN ECOLOGICAL FOOTPRINT. GLOBAL INDUSTRIAL AND ENERGY EMISSIONS TOPPED 36.8 BILLION TONS IN 2022, POTENTIALLY CAUSING $6.8 TRILLION IN SOCIAL COSTS. CURB WILL ADVANCE, DEPLOY, AND SCALE INNOVATIVE HYBRID ELECTRO-BIOMANUFACTURING ENGINEERED SYSTEMS TO EMPOWER A NEW CIRCULAR CARBON ECONOMY WHEREIN CO2 WILL SERVE AS VALUABLE FEEDSTOCK FOR MANUFACTURING A BROAD RANGE OF PRODUCTS MUCH MORE EFFICIENTLY THAN CURRENT STATE-OF-THE-ART AND NATURAL SYSTEMS. CURB WILL CREATE COST-EFFECTIVE AND EMISSIONS-FREE BIOMANUFACTURING TECHNOLOGIES, FACILITATING THE NEXT-GENERATION BIOECONOMY AND EMPOWERING INDUSTRIAL DECARBONIZATION. THE EMERGING DECARBONIZATION AND BIOECONOMY INDUSTRIES HAVE GROWN RAPIDLY TO $4.5 AND $4 TRILLION RESPECTIVELY, REPRESENTING UNPARALLELED OPPORTUNITIES FOR U.S. ECONOMIC GROWTH AND MILLIONS OF JOB OPPORTUNITIES. CURB UNIQUELY CONVERGES THESE TWO SECTORS TO TURN OUR MOST DAUNTING SUSTAINABILITY CHALLENGES INTO POWERFUL CATALYSTS FOR ECONOMIC GROWTH. ULTIMATELY, CURB WILL TRANSFORM U.S. MANUFACTURING TO ZERO- AND NEGATIVE EMISSIONS, VALORIZE WASTE CO2 FROM BROAD INDUSTRIES, MITIGATE CLIMATE CHANGE, REDUCE HAZARDOUS COMPOUNDS IN EMISSIONS, AND PRODUCE PLASTICS THAT ARE BIODEGRADABLE RATHER THAN POLLUTING. CURB WILL PRODUCE EVIDENCE-BASED PRACTICES FOR THE INCLUSION OF UNDERREPRESENTED GROUPS AND WORKFORCE PATHWAYS TO SUCCESS TO EMPOWER RAPID TECHNOLOGY DEPLOYMENT AND PROMOTE ENVIRONMENTAL JUSTICE. THROUGH PARTNERS RANGING FROM START-UPS TO MAJOR CORPORATIONS, CURB?S TECHNOLOGY COMMERCIALIZATION WILL EMPOWER A BILLION-TON LEVEL CARBON EMISSION REDUCTION AND TENS OF BILLIONS OF DOLLARS IN ECONOMIC GROWTH. IN ORDER TO ACHIEVE THESE IMPACTS, CURB WILL DEMONSTRATE THE CONVERSION OF CO2 AT A MUCH HIGHER CONVERSION RATE THAN THE STATE-OF-THE-ART USING HYBRID ELECTRO-BIO CO2 UTILIZATION SYSTEMS (HEBCUS). THE HEBCUS-ENGINEERED SYSTEMS WILL USE ELECTROCATALYSIS TO PRODUCE C2+ INTERMEDIATES (E.G., ETHANOL, ACETATE, AND PROPIONATE) THAT CAN ENTER PRIMARY METABOLISM WITH FEWER STEPS THAT C1 INTERMEDIATES AND ARE COMPATIBLE WITH MANY CELL OR CELL-FREE BIOMANUFACTURING SYSTEMS. THE DESIGN WILL ENABLE EFFICIENT CONVERSION INTO A BROAD RANGE OF PRODUCTS AT HIGHER TITER AND PRODUCTIVITY THAN PLATFORMS BASED ON C1 INTERMEDIATES. SOLUBLE C2+ INTERMEDIATES ALSO SUBSTANTIALLY IMPROVE MASS, ENERGY, AND ELECTRON TRANSFERS AND OVERCOME THE GAS-TO-LIQUID TRANSFER CHALLENGES OF HYDROGEN AND CO. CURB WILL FOCUS ON THREE INTERRELATED RESEARCH THRUSTS THAT CONVERGE SCIENTIFIC, ECONOMIC, ENVIRONMENTAL, AND SOCIAL APPROACHES WITH STAKEHOLDER NEEDS FOR COMPREHENSIVE SYSTEM DESIGN AND OPTIMIZED SOCIETAL IMPACTS WITHIN THREE DEMONSTRATION TESTBEDS: CO2 CONVERSION TO (1) PLATFORM CHEMICALS AND POLYMER PRECURSORS, (2) ENVIRONMENTALLY RESPONSIBLE MATERIALS AND BIOFERTILIZERS, AND (3) LIPIDS AND PROTEINS. CONVERGENT RESEARCH WILL DRIVE NEW TRANSDISCIPLINARY EDUCATIONAL AND TRAINING PATHWAYS FOR THE DECARBONIZATION AND BIOMANUFACTURING WORKFORCE OF TOMORROW, AN ESTIMATED 10 MILLION JOBS. CURB WILL BUILD A CULTURE OF INCLUSION EMBRACING DIVERGENT PERSPECTIVES, ENGAGING UNDERREPRESENTED POPULATIONS, AND PROMOTING CONVERGENCE. CURB?S INNOVATION ECOSYSTEM, WITH 18 COMMITTED INDUSTRY PARTNERS, WILL TRANSFORM INDUSTRIES AND COMMUNITIES, MITIGATE CLIMATE CHANGE, ADVANCE ENVIRONMENTAL JUSTICE, EMPOWER CURB SUSTAINABILITY BEYOND NSF FUNDING, CREATE AND FILL JOBS WITH A DIVERSE AND COMPETENT WORKFORCE, ACHIEVING MULTI-FACET AND TANGIBLE SOCIETAL IMPACTS. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.- SUBAWARDS ARE PLANNED FOR THIS AWARD.

21/21 ABCD-USA CONSORTIUM: RESEARCH PROJECT SITE AT WUSTL

A LONGITUDINAL MRI STUDY CHARACTERIZING VERY EARLY BRAIN DEVELOPMENT IN INFANTS WITH DOWN SYNDROME

COMBINING TESTOSTERONE THERAPY AND EXERCISE TO IMPROVE FUNCTION POST HIP FRACTURE

MEDICAL EDUCATION PARTNERSHIP INITIATIVE COORDINATING CENTER

TRAINING PROGRAM IN CELLULAR AND MOLECULAR BIOLOGY

WASHINGTON UNIVERSITY INTELLECTUAL AND DEVELOPMENTAL DISABILITIES RESEARCH CENTER

MRI BASED PRESYMPTOMATIC PREDICTION OF ASD

DIABETES AND RELATED METABOLIC DISEASES

PURPOSE: THE PURPOSE OF THIS COOPERATIVE AGREEMENT TO PROVIDE UNDERGRADUATE/GRADUATE RESEARCHERS, INDIVIDUALS WITH BACHELORS OR MASTER'S DEGREES, POST-DOCTORAL ASSOCIATES, SENIOR RESEARCH FELLOWS AND ACADEMIC AFFILIATES WITH FELLOWSHIP OPPORTUNITIES AND FINANCIAL ASSISTANCE TO OBTAIN LABORATORY EXPERIENCES AND AID IN DEVELOPING COLLABORATIVE RESEARCH RELATIONSHIPS WITH NIST STAFF WITHIN THE NIST GAITHERSBURG, MD LABORATORY.ACTIVITIES TO BE PERFORMED: PREP SEEKS TO ENCOURAGE THE GROWTH AND PROGRESS OF SCIENCE AND ENGINEERING IN THE UNITED STATES, INCLUDING THE ENCOURAGEMENT OF WOMEN AND MINORITY RESEARCHERS SEEKING TO FURTHER THEIR PROFESSIONAL DEVELOPMENT, AND TO NURTURE RESEARCHERS AND POST-DOCTORAL ASSOCIATES CONSIDERED TO BE POTENTIAL FUTURE NIST EMPLOYEES.EXPECTED OUTCOMES: THE OBJECTIVES OF THE PREP PROGRAM ARE TO: 1) ENCOURAGE THE GROWTH AND PROGRESS OF SCIENCE AND ENGINEERING IN THE UNITED STATES BY PROVIDING RESEARCH OPPORTUNITIES FOR PREP RESEARCHERS WITH NIST SCIENTISTS AND ENGINEERS AND EXPOSING THEM TO CUTTING-EDGE RESEARCH AND DEVELOPMENT (R&D); 2) PROMOTE THE PURSUIT OF DEGREES OR PROFESSIONAL DEVELOPMENT, AS APPLICABLE, FOR PREP RESEARCHERS; AND 3) PROMOTE DIVERSITY AND EQUITY IN STEM.INTENDED BENEFICIARIES: NIST AND NIST RESEARCHERS, AND UNDERGRADUATE/GRADUATE RESEARCHERS, INDIVIDUALS WITH BACHELORS OR MASTER'S DEGREES, POST-DOCTORAL ASSOCIATES, SENIOR RESEARCH FELLOWS AND ACADEMIC AFFILIATES, EMPLOYED BY OR AFFILIATED WITH THE UNIVERSITIES.SUBRECIPIENT ACTIVITIES: THE RECIPIENT DOES INTEND TO SUBAWARD SOUTHEAST UNIVERSITIES RESEARCH ASSOCIATION (SURA), A CONSORTIUM OF OVER 60 LEADING RESEARCH UNIVERSITIES IN THE U.S. AND CANADA WITH A DEMONSTRATED TRACK RECORD OF FILLING NEEDS FOR SKILLED RESEARCH STAFF IN FEDERAL LABS.

THE DISTRICT OF COLUMBIA CLINICAL TRIALS UNIT (DC CTU) - PROJECT SUMMARY THE DISTRICT OF COLUMBIA CLINICAL TRIALS UNIT (DC CTU) WILL CONDUCT CLINICAL TRIALS FOR PERSONS WITH AND AT RISK FOR HIV IN DC, WHERE 1.8% OF THE OVERALL POPULATION AND 2.7% OF THE AFRICAN-AMERICAN POPULATION ARE LIVING WITH HIV. THE DC CTU WILL UNITE TWO EXISTING, HIGH-PERFORMING DAIDS/NIAID CLINICAL RESEARCH SITES (CRS), THE WHITMAN-WALKER HEALTH CRS AND THE GEORGE WASHINGTON UNIVERSITY CRS, IN A NEW CTU, PARTICIPATING IN THE HIV/AIDS ADULT THERAPEUTICS AND HIV PREVENTION CLINICAL TRIALS NETWORKS. OUR INNOVATIVE AND GEOGRAPHICALLY- FOCUSED DC CTU WILL ENSURE EXEMPLARY CLINICAL TRIALS MANAGEMENT, RECRUITMENT, AND RETENTION OF A DIVERSE SAMPLE OF PARTICIPANTS, WITH A COMMUNITY ENGAGEMENT STRATEGY BUILT ON EXISTING PARTNERSHIPS AND GOOD PARTICIPATORY PRACTICES. THE DC CTU WILL ACHIEVE FOUR SPECIFIC AIMS: 1) PROVIDE SCIENTIFIC LEADERSHIP AND ADMINISTRATIVE INFRASTRUCTURE TO ALLOW HIGH-QUALITY CONDUCT OF THERAPEUTIC AND PREVENTION STUDIES AT TWO ESTABLISHED CRSS; 2) IMPLEMENT BEST PRACTICES TO ENSURE CONTINUED HIGH RECRUITMENT AND RETENTION RATES; PARTICIPANT SAFETY; AND LABORATORY, PHARMACY, DATA, AND REGULATORY EXCELLENCE; 3) ACTIVELY ENGAGE WITH THE LOCAL COMMUNITY TO ENSURE OPTIMAL ENROLLMENT OF DIVERSE PARTICIPANTS FROM WITHIN AND BEYOND CLINIC SETTINGS USING GOOD PARTICIPATORY PRACTICES; AND 4) CAPITALIZE ON THE RESOURCES AVAILABLE FROM THE DC CFAR AND DC COHORT TO ENGAGE SENIOR INVESTIGATORS, MENTOR INVESTIGATORS IN CLINICAL TRIALS CONDUCT, AND ACCESS A BROAD ARRAY OF SERVICES TO ADDRESS NIH AND NETWORK SCIENTIFIC AND PROGRAMMATIC PRIORITIES. THE DC CTU WILL ENGAGE PARTICIPANTS WHO CAN BENEFIT FROM INNOVATIVE CLINICAL TRIALS WHILE WE CONTRIBUTE TO HIGH-QUALITY PARTICIPATORY RESEARCH THAT WILL EVENTUALLY END THE HIV EPIDEMIC.

THE GEOSCIENCES NODE AT WASHINGTON UNIVERSITY IN ST. LOUIS HAS BEEN AN INTEGRAL PART OF THE PDS ENTERPRISE SINCE NASA FIRST ASSEMBLED A DATA SYSTEM T

NASA PLANETARY DATA SYSTEM GEOSCIENCES NODE

CORE GRANT FOR VISION RESEARCH

NEUROACTIVE STEROIDS AS NOVEL PSYCHIATRIC TREATMENTS: MECHANISTIC STUDIES - CONTE CENTER SUMMARY NEUROACTIVE STEROIDS (NAS) OFFER NOVEL DIRECTIONS FOR PSYCHIATRIC THERAPEUTICS. THE PROTOTYPICAL NAS IS ALLOPREGNANOLONE (ALLOP), WHICH UNDER THE FORMULATION OF BREXANOLONE, HAS RECENTLY BEEN APPROVED BY FDA FOR TREATMENT OF WOMEN WITH POSTPARTUM DEPRESSION; A SECOND, ORALLY-ACTIVE NAS HAS HAD A SUCCESSFUL PHASE 3 STUDY FOR POSTPARTUM DEPRESSION AND A PHASE 2B STUDY FOR MEN AND WOMEN WITH MAJOR DEPRESSION. WHILE ALLOP IS A POTENT AND EFFECTIVE ENHANCER OF GABAA RECEPTORS (GABAARS), IT IS NOT PRESENTLY CLEAR THAT THE ANTIDEPRESSANT EFFECTS OF NAS ARE MEDIATED SOLELY BY GABAERGIC EFFECTS, AND RECENT DATA INDICATE THAT OTHER MECHANISMS INCLUDING EFFECTS ON CELLULAR STRESS AND INFLAMMATORY PATHWAYS COULD ALSO BE INVOLVED. MEMBERS OF OUR CENTER HAVE EXTENSIVE EXPERIENCE STUDYING THE MEDICINAL CHEMISTRY AND MECHANISMS UNDERLYING THE EFFECTS OF ALLOP-LIKE NAS. IN THIS CONTE CENTER PROPOSAL WE WILL LEVERAGE NOVEL NAS COMPOUNDS TO PROBE VARIED MOLECULAR, SYNAPTIC, NETWORK AND BEHAVIORAL EFFECTS OF NAS AS CLUES TO THEIR THERAPEUTIC MECHANISMS AND POTENTIAL. OUR CENTER PROPOSAL IS DRIVEN BY UNIQUE NAS ANALOGUES SYNTHESIZED IN OUR CHEMISTRY CORE AND INVOLVES THREE COMPLEMENTARY AND INTERTWINED PROJECTS THAT WILL PURSUE THREE SPECIFIC GOALS. FIRST, WE WILL TEST THE HYPOTHESIS THAT SELECTIVE ACTIONS OF NAS ON A CLASS OF GABAARS UNDERLIES EFFECTS ON HIPPOCAMPAL ELECTRICAL ACTIVITY, NETWORK FUNCTION AND BEHAVIOR IN NOVEL MOUSE LINES AND MOUSE MODELS OF POSTPARTUM AND MAJOR DEPRESSION. SECOND, WE WILL EXAMINE THE ROLE OF NON-GABAA ION CHANNELS IN MEDIATING HIPPOCAMPAL AND BEHAVIORAL EFFECTS OF NAS FOCUSING ON NOVEL NAS THAT MODULATE NMDA GLUTAMATE RECEPTORS AND LOW VOLTAGE ACTIVATED CALCIUM CHANNELS. THESE STUDIES WILL USE UNIQUE PHOTOAFFINITY LABELING APPROACHES TO ELUCIDATE SITES OF ACTIONS OF NAS ON NMDA RECEPTORS AND OTHER TARGETS. OTHER STUDIES WILL EXAMINE EFFECTS OF NAS ANALOGUES ON CELLULAR FUNCTION, NEURAL NETWORK FUNCTION, AND BEHAVIOR. THIRD, WE WILL TEST THE ROLE OF INTRACELLULAR TARGETS ENGAGED BY NAS ON HIPPOCAMPAL CIRCUITS AND BEHAVIOR, FOCUSING ON THE ROLES OF NEUROINFLAMMATION AND CELLULAR STRESS PATHWAYS. OUR CENTER IS UNIQUELY POSITIONED TO TRAVERSE THE EXPLORATION OF ANTIDEPRESSANT NAS FROM MOLECULES TO SITES OF ACTION AND EFFECTS ON DYSFUNCTIONAL CIRCUITS TO IDENTIFY POTENTIALLY NOVEL AGENTS AND TARGETS FOR PSYCHIATRIC THERAPEUTIC DEVELOPMENT.

A RESOURCE FOR BIOMEDICAL MASS SPECTROMETRY

CANCER PROTEOME CENTER AT WASHINGTON UNIV, UNIV OF NORTH CAROLINA

PREVENTION AT HOME: A MODEL FOR NOVEL USE OF MOBILE TECHNOLOGIES AND INTEGRATED CARE SYSTEMS TO IMPROVE HIV PREVENTION AND CARE WHILE LOWERING COST

CENTER FOR MULTIPLE MYELOMA NANOTHERAPY

HEERF II EMERGENCY STUDENT GRANTS

REGIONAL, SYNPATIC, CELLULAR MODULATION OF ABETA METABOLISM

MULTICENTER CAREER DEVELOPMENT PROGRAM FOR PHYSICAL AND OCCUPATIONAL THERAPY

INNOVATIVE STRATEGIES TO COMBAT ANTIBIOTIC-RESISTANT INFECTIONS - PROJECT SUMMARY/ ABSTRACT: ANTIBIOTIC-RESISTANT BACTERIAL INFECTIONS THAT ARE NO LONGER SENSITIVE TO OUR LIFE SAVING ANTIBIOTIC ARSENAL ARE A LOOMING CATASTROPHE AND LIKE THE RECENT COVID-19 CRISIS, WILL HAVE DIRE CONSEQUENCES FOR HUMAN HEALTH IF WE ARE NOT PREPARED. THIS PROPOSAL LEVERAGES BASIC SCIENCE FINDINGS FOR DEVELOPMENT OF ANTIBIOTIC-SPARING MEDICINES WITH IMPACT ON TREATMENT FOR MOST PATHOGENS DESIGNATED THREATS TO HUMAN HEALTH BY THE CDC. PROJECTS 1 AND 2 TARGET MULTI-DRUG RESISTANT (MDR) GRAM-NEGATIVE PATHOGENS THAT EXPRESS ADHESIVE PILI REQUIRED FOR COLONIZATION AND INFECTION IN THE HOST HABITATS INVOLVED IN ACUTE AND CHRONIC/RECURRENT URINARY TRACT INFECTIONS (UTIS) AND CATHETER-ASSOCIATED UTIS (CAUTIS), INCLUDING MDR ACINETOBACTER, CARBAPENEM-RESISTANT ENTEROBACTERIACEAE (CRE) AND EXTENDED-SPECTRUM BETA-LACTAMASE (ESBL)-PRODUCING ENTEROBACTERIACEAE. PROJECT 2 EXPANDS ON THIS LIST TO INCLUDE OTHER GRAM-NEGATIVE PATHOGENS OF CONCERN. SINCE UTIS ACCOUNT FOR ~10% OF ANTIBIOTIC USE IN HUMANS, THE DEVELOPMENT OF ANTIBIOTIC-SPARING THERAPEUTICS WILL NOT ONLY ALLOW TREATMENT OF ANTIBIOTIC-RESISTANT INFECTIONS, BUT BY REDUCING THE USE OF CURRENT ANTIBIOTICS, WILL DECREASE SELECTIVE PRESSURES FOR RESISTANCE. PROJECT 1 IS FOCUSED ON NEUTRALIZING BACTERIAL PILUS ADHESINS USING GLYCOMIMETICS DESIGNED IN CORE 1 AND MABS DEVELOPED IN CORE 2 THAT WILL BLOCK CRITICAL INTERACTIONS BETWEEN BACTERIAL ADHESINS AND THEIR HOST LIGANDS. GLYCOMIMETICS HAVE SHOWN GREAT PROMISE IN NEUTRALIZING CHAPERONE/USHER PATHWAY (CUP) ADHESINS IN VIVO TO TREAT DISEASE. FOR EXAMPLE, MANNOSIDES, WHICH NEUTRALIZE UROPATHOGENIC E. COLI (UPEC) ADHESIN FIMH, ARE POTENT THERAPEUTICS FOR TREATING AND PREVENTING UTI, SINCE FIMH IS REQUIRED BY UPEC TO COLONIZE THE BLADDER. IN COLLABORATION WITH GLAXOSMITHKLINE A MANNOSIDE HAS BEEN SELECTED TO PROCEED INTO PHASE 1A/1B CLINICAL TRIALS, THUS VALIDATING THE POTENTIAL OF THIS STRATEGY. THERAPEUTIC MABS HAVE NOT YET BEEN FULLY HARNESSED FOR TREATING INFECTIOUS DISEASES. WITH ANTIBIOTIC RESISTANCE ON THE RISE, IT IS TIME TO APPLY THIS STRATEGY. PROJECT 1 WILL ALSO TARGET A SORTASE-ASSEMBLED PILUS ADHESIN OF GRAM-POSITIVE ENTEROCOCCI, WHICH CAUSES CAUTIS AND IS OFTEN MDR. PROJECT 2 WILL USE SIMILAR TOOLS TO FOCUS ON THE CUP MACHINERY THAT ASSEMBLES THE GRAM-NEGATIVE ADHESINS IN PROJECT 1 AT THE TIP OF PILUS FIBERS. PROJECT 3 WILL TARGET ALL GRAM- POSITIVE SPECIES IDENTIFIED BY THE CDC AS SIGNIFICANT THREATS BY FURTHERING THE DEVELOPMENT OF GMPCIDES, A NOVEL FAMILY OF RING-FUSED 2-PYRIDONE COMPOUNDS THAT ARE BACTERICIDAL AGAINST A BROAD SPECTRUM OF GRAM- POSITIVE SPECIES. THE CORES WILL BE FULLY INTEGRATED WITH THE SCIENTIFIC PROJECTS PROVIDING COMPUTATIONAL AND SYNTHETIC MEDICINAL CHEMISTRY IN THE DEVELOPMENT OF SMALL MOLECULE THERAPEUTICS (CORE 1) AND THE APPLICATION OF HIGH THROUGHPUT MAB GENERATION AGAINST BACTERIAL PROTEINS (CORE 2). THE COMBINED KNOWLEDGE, EXPERTISE AND SUCCESSES OF THE LEADERS OF THE PROJECTS AND CORES WILL LEAD TO THE DEVELOPMENT OF ANTIBIOTIC-SPARING THERAPEUTICS FOR TREATMENT OF THE GROWING NUMBER OF ANTIBIOTIC-RESISTANT PATHOGENS TO STAVE OFF THE RETURN TO THE PRE-ANTIBIOTIC ERA WHEN COMMON INFECTIONS WERE ESSENTIALLY UNTREATABLE.

ADVANCED TECHNOLOGY QA CENTER

SILENT CEREBRAL INFARCT MULTI-CENTER CLINICAL TRIAL

BIOMARKERS AND PATHOGENESIS OF MS: FROM MOUSE TO HUMAN

GAINING EARLY AWARENESS AND READINESS FOR UNDERGRADUATE PROGRAMS (GEAR UP PARTNERSHIP)

ALVEOLAR AND AIRWAY MECHANISMS FOR COPD

GRADUATE RESERACH FELLOWSHIP PROGRAM (GRFP)

PRINCIPLES IN PULMONARY RESEARCH

VIRAL TRIGGERS OF ALLOIMMUNITY AND AUTOIMMUNITY IN PEDIATRIC LUNG TRANSPLANTATION

WASHINGTON UNIVERSITY OMICS PRODUCTION CENTER - PROJECT SUMMARY TO IMPROVE OUR UNDERSTANDING OF HUMAN DISEASE IN ANCESTRALLY DIVERSE POPULATIONS, WE PROPOSE TO ESTABLISH THE WASHINGTON UNIVERSITY OMICS PRODUCTION CENTER (WU-OMICS PC). AS PART OF THE MULTI-OMICS OF HEALTH AND DISEASE CONSORTIUM, THE WU-OMICS PC WILL HELP DESIGN A COLLABORATIVE PLAN TO: (I) EXPLORE THE USE OF MULTI- OMICS, ENVIRONMENTAL EXPOSURE DATA, AND PHENOTYPIC INFORMATION TO ASSESS DISEASE STATES; (II) DEVELOP METHODS FOR DATA HARMONIZATION, INTEGRATION, AND INTERPRETATION IN MULTI-OMICS STUDIES; AND (III) CREATE A RICH SET OF ROBUST MULTI-DIMENSIONAL DATA TO SHARE WITH THE RESEARCH COMMUNITY. IN THE FIRST YEAR OF THE AWARD, THE WU- OMICS PC WILL WORK CLOSELY WITH OTHER MEMBERS OF THE CONSORTIUM TO DESIGN A PROJECT ROADMAP THAT DETAILS STRATEGIES FOR SUBJECT RECRUITMENT, THE TYPES OF BIOSPECIMENS TO BE COLLECTED, SAMPLE HANDLING AND SHIPPING PROCEDURES, OMICS TECHNIQUES TO BE PERFORMED, AND BEST PRACTICES FOR TRANSFERRING AND INTEGRATING HARMONIZED DATA. AFTER YEAR 1, WE PROPOSE FOR THE WU-OMICS PC TO COLLECT WHOLE GENOME SEQUENCING, WHOLE GENOME BISULFITE SEQUENCING, ATAC-SEQ, RNA-SEQ, PROTEOMICS, AND METABOLOMICS DATA BY USING THE AGREED UPON METHODS. THE WU-OMICS PC WILL COLLECT OMICS DATA BY USING WELL-ESTABLISHED WORKFLOWS THAT THE SAME INVESTIGATIVE TEAM HAS ALREADY SUCCESSFULLY APPLIED TO OTHER MULTI-OMICS STUDIES OF SIMILAR SCOPE AND SCALE. OUR OMICS WORKFLOWS HAVE BEEN EXTENSIVELY BENCHMARKED AND WE HAVE DETAILED PROTOCOLS FOR QUALITY ASSURANCE, QUALITY CONTROL, AND CORRECTION OF BATCH EFFECTS. THE WU-OMICS PC IS UNIQUELY POSITIONED TO ACCOMPLISH ITS GOALS BECAUSE THE INFRASTRUCTURE TO PERFORM LARGE-SCALE, HIGH-THROUGHPUT OMICS ASSAYS IS ALREADY IN PLACE. MOREOVER, THE LEADERSHIP OF THE WU-OMICS PC HAS A SUCCESSFUL TRACK RECORD OF PARTICIPATING IN OMICS CONSORTIA AND PROVIDES COMPLEMENTARY AND SYNERGISTIC RESEARCH EXPERTISE IN GENETICS, BIOCHEMISTRY, ANALYTICAL INSTRUMENTATION, COMPUTATIONAL DATA PROCESSING, AND MULTI-DIMENSIONAL DATA INTEGRATION.

COMMUNICATION-BASED STRATEGIES TO ELIMINATE CANCER DISPARITIES

WASHINGTON UNIVERSITY SPORE IN PANCREATIC CANCER

ORWH: SCORE ON SEX AND GENDER FACTORS AFFECTING WOMEN'S HEALTH

WASHINGTON UNIVERSITY PAUL CALABRESI CAREER DEVELOPMENT AWARD FOR CLINICAL ONCOLO

ANTIBODY-BASED PROTECTION AGAINST DENGUE VIRUS

HEAD START

MEMBRANE-MEDIATED ALTERATIONS IN DIABETES

EARLY HEAD START

THE DEVELOPMENT AND EVALUATION OF PAN-CORONAVIRUS VACCINES - OVERALL SUMMARY GIVEN THE HISTORICAL OUTBREAKS OF CORONAVIRUSES, COUPLED WITH THE RECENT EMERGENCE OF SARS- COV-2 AND THE DESTABILIZING CONSEQUENCE OF COVID-19 ON GLOBAL HEALTH AND ECONOMY, THERE IS AN URGENT AND CRITICAL NEED TO DEVELOP NEW VACCINES CAPABLE OF BROAD PROTECTION AGAINST EXISTING AND FUTURE SARBECOVIRUSES AND MERBECOVIRUSES. THIS P01 PROGRAM PROJECT (PPG) ADDRESSES THE HYPOTHESIS THAT A COMBINATION OF EVOLUTIONARILY-DESIGNED AND OPTIMIZED B AND T CELL ANTIGENS CAN CONFER BROAD AND PROTECTIVE IMMUNITY AGAINST SARBECOVIRUSES AND MERBECOVIRUSES THAT CURRENTLY EXIST OR COULD EMERGE FROM ZOONOTIC RESERVOIRS. THE PPG INTEGRATES THE WORK OF ELEVEN LEADING LABORATORIES WITH RECORDS OF COLLABORATION THAT HAVE EXPERTISE IN CORONAVIRUS BIOLOGY, VIRAL PATHOGENESIS, B AND T CELL IMMUNITY, VACCINE DEVELOPMENT, ANIMAL CHALLENGE STUDIES, STRUCTURAL BIOLOGY, ANTIBODY STRUCTURE AND FUNCTION, ANTIGEN DESIGN, AND EVOLUTIONARY ANALYSIS OF VIRUSES. ALL PROJECTS AND CORES PLAN INTERACTIVE STUDIES WITH THE FOCUSED GOAL OF DESIGNING OPTIMIZED B AND T CELL ANTIGENS FOR INCORPORATION IN ADENOVIRAL (CHAD) AND VESICULAR STOMATITIS VIRUS (VSV) VECTORS TO CREATE MUCOSAL AND SYSTEMIC VACCINES THAT PROTECT AGAINST INFECTION AND DISEASE CAUSED BY A RANGE OF CORONAVIRUSES OF POTENTIAL CONCERN. THE PPG IS SERVED BY A CENTRAL ANIMAL CHALLENGE CORE THAT PERFORMS VACCINATION AND INFECTION EXPERIMENTS IN MICE AND HAMSTERS AND A CENTRAL ADMINISTRATIVE CORE THAT STREAMLINES DATA MANAGEMENT AND SHARING, PROVIDES COMPUTATIONAL ANALYSIS FOR DOWN-SELECTION AND SCIENTIFIC DECISION-MAKING, AND FACILITATES COMMUNICATION. OUR PROPOSAL AND ANTIGEN DESIGN PROGRAM SERVES AS A BLUEPRINT FOR POSSIBLE PRODUCT DEVELOPMENT WITH CHAD VACCINES, VSV-BASED VACCINES, OR EVEN WITH OTHER PLATFORMS (E.G., MRNA VACCINES, NANOPARTICLES, ETC.) NOT DIRECTLY EVALUATED HERE. BY THE CONCLUSION OF OUR PPG, WE ENVISION GENERATING AT LEAST ONE AND LIKELY MULTIPLE VIRAL- VECTORED VACCINE PLATFORMS THAT INDUCE BROAD SPECTRUM IMMUNITY TO MULTIPLE CORONAVIRUSES OF CONCERN INCLUDING HUMAN AND ZOONOTIC SARBECOVIRUSES AND MERBECOVIRUSES THAT COULD EMERGE IN THE FUTURE.

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP)

NEUROIMAGING IN EARLY ONSET DEPRESSION: LONGITUDINAL ASSESSMENT OF BRAIN CHANGES

ADJUNCTIVE AZITHROMYCIN PROPHYLAXIS FOR SCHEDULED/PRELABOR CESAREAN DELIVERY - ABSTRACT WE PROPOSE A LARGE RANDOMIZED CLINICAL TRIAL WITHIN THE MFMU NETWORK DESIGNED TO EVALUATE THE BENEFITS AND SAFETY OF AZITHROMYCIN-BASED PROPHYLAXIS (AZITHROMYCIN PLUS STANDARD CEPHALOSPORIN) RELATIVE TO STANDARD CEPHALOSPORIN ALONE PRIOR TO SURGICAL INCISION TO PREVENT POST-CESAREAN (CD) INFECTION. IN CONTRAST TO CEPHALOSPORIN, AZITHROMYCIN IS EFFECTIVE AGAINST ADDITIONAL PATHOGENS ENCOUNTERED IN POLYMICROBIAL POST-CD INFECTIONS. WE DEMONSTRATED ADJUNCTIVE AZITHROMYCIN, COMPARED TO STANDARD PROPHYLAXIS, REDUCED MATERNAL INFECTIONS BY 50% WITH REMARKABLE COST-SAVINGS IN UNSCHEDULED CDS. THE AMERICAN COLLEGE OF OBSTETRICIANS AND GYNECOLOGISTS (ACOG) NOW RECOMMENDS ROUTINE USE IN UNSCHEDULED CDS. OUR PRELIMINARY STUDIES SUGGEST AZITHROMYCIN MAY ALSO LOWER INFECTION RISK IN THE 40-50% THAT ARE SCHEDULED/PRE-LABOR CDS, BUT THERE ARE SAFETY CONCERNS REGARDING THE ADVERSE NEONATAL AND LONG-TERM MICROBIOME-MEDIATED EFFECTS OF PERINATAL EXPOSURE. DURING THE PROJECT PERIOD OF 5 YEARS, WE WILL RANDOMIZE UP TO 8000 WOMEN UNDERGOING SCHEDULED/PRE-LABOR CD TO EITHER 500MG OF INTRAVENOUS AZITHROMYCIN OR IDENTICAL PLACEBO INITIATED PRIOR TO SURGERY. BOTH GROUPS WILL ALSO RECEIVE STANDARD SINGLE-DOSE CEFAZOLIN PROPHYLAXIS (OR ALTERNATIVE IN THE 5% ALLERGIC TO CEPHALOSPORIN). WOMEN WILL BE FOLLOWED FOR 6 WEEKS ACCORDING TO ADAPTED CENTERS FOR DISEASE CONTROL AND PREVENTION (CDC) RECOMMENDATIONS FOR ASCERTAINING SURGICAL SITE INFECTIONS. THE FOLLOWING SPECIFIC AIMS WILL BE ADDRESSED: PRIMARY AIM (EFFICACY): TEST IN PATIENTS UNDERGOING SCHEDULED/PRELABOR CD IF PRE-INCISION ADJUNCTIVE AZITHROMYCIN PROPHYLAXIS REDUCES THE RISK OF POST-CD INFECTIONS COMPARED TO PLACEBO. PRIMARY HYPOTHESIS: COMPARED TO STANDARD PROPHYLAXIS (I.E. PLACEBO + CEFAZOLIN ALONE), AZITHROMYCIN (+ CEFAZOLIN) REDUCES THE INCIDENCE OF POST-CD INFECTIONS (PRIMARY COMPOSITE OUTCOME OF ENDOMETRITIS, WOUND AND OTHER SEVERE INFECTIONS). SECONDARY AIM 1 (SAFETY): ASSESS THE PERINATAL AND MATERNAL SAFETY OF PRE-INCISION ADJUNCTIVE AZITHROMYCIN. HYPOTHESIS: COMPARED TO STANDARD PROPHYLAXIS (CEFAZOLIN ALONE), THE USE OF AZITHROMYCIN FOR SCHEDULED CD DOES NOT INCREASE ADVERSE PERINATAL OUTCOMES INCLUDING A PERINATAL COMPOSITE OF DEATH, NEONATAL MORBIDITIES, CARDIAC RESUSCITATION, AND HYPERTROPHIC PYLORIC STENOSIS. WE WILL ALSO EXAMINE MATERNAL AND NEONATAL ADVERSE EVENTS. SECONDARY AIM 2 (RESOURCE USE): TEST THE HYPOTHESIS THAT COMPARED TO STANDARD CEFAZOLIN PROPHYLAXIS ALONE, ADJUNCTIVE AZITHROMYCIN REDUCES A SECONDARY MATERNAL COMPOSITE OUTCOME (POSTPARTUM READMISSION OR ER OR UNSCHEDULED CLINIC VISITS), MATERNAL HOSPITAL STAY, NEONATAL ICU ADMISSION AND NEONATAL HOSPITAL STAY. WE WILL COLLECT AND STORE BIOLOGICAL SPECIMENS INCLUDING MATERNAL AND UMBILICAL CORD BLOOD FOR FUTURE MECHANISTIC AND BIOMARKER STUDIES. WE ALSO PLAN A SEPARATE MICROBIOME SUB-STUDY PROPOSAL. COMPLETION OF THIS TRIAL, RANKED #1/28 BY MFMU, WILL LIKELY CHANGE POLICY, EXTENDING THE BENEFITS OF AZITHROMYCIN PROPHYLAXIS TO SCHEDULED CDS FASTER THAN THE 20 YEARS IT TOOK TO FOR STANDARD PROPHYLAXIS.

WASHINGTON UNIVERSITY SPOTRIAS CENTER

THE PET RADIOTRACER TRANSLATION AND RESOURCE CENTER (PET-RTRC)

SURGICAL ONCOLOGY TRAINING GRANT

WASHINGTON UNIVERSITY CENTER FOR DIABETES TRANSLATION RESEARCH

MOLECULAR PATHOGENESIS OF ACUTE MYELOID LEUKEMIA

DIABETES RESEARCH & TRAINING CENTER

RECONSTRUCTIONS AND REPRESENTATIONS OF CEREBRAL CORTEX

THE PDS GEOSCIENCES NODE LED BY WASHINGTON UNIVERSITY IN SAINT LOUIS HAS BEEN AN INTEGRAL PART OF

INFECTIOUS DISEASE/BASIC MICROBIAL PATHOGENIC MECHANISMS

EASTERN WASHINGTON UNIVERSITY EARLY HEAD START RURAL HOME-VISITING PROGRAM FOR PREGNANT WOMEN, INFANTS AND TODDLERS

MOLECULAR ASPECTS OF CORNEAL EPITHELIAL MIGRATION

IMPLEMENTATION RESEARCH STRATEGIES FOR HEART, LUNG, AND BLOOD CO-MORBIDITIES IN PEOPLE LIVING WITH HIV - RESEARCH COORDINATING CENTER

PRE-AND POSTGRADUATE TRAINING IN MOLECULAR HEMATOLOGY

WASHINGTON UNIVERSITY PDX DEVELOPMENT AND TRIAL CENTER

WASHINGTON UNIVERSITY/SITEMAN CANCER CENTER LEAD ACADEMIC SITE

MUCOSAL IMMUNE DEFENSE MECHANISMS OF THE URINARY BLADDER

INTERCEPT: INTEGRATED RESEARCH CENTER FOR HUMAN PAIN TISSUES - ABSTRACT: TENS OF MILLIONS OF AMERICANS SUFFER FROM CHRONIC PAIN. OPIOIDS REPRESENT THE MAIN TOOL FOR TREATING PAIN, BUT THEIR USE IN CHRONIC PAIN CONDITIONS SUFFERS FROM A POOR EVIDENCE BASE AND THE INHERENT RISK OF ADDICTION. THE CURRENT CRISIS OF OPIOID-RELATED DEATHS HIGHLIGHTS THE RISK ASSOCIATED WITH WIDESPREAD OPIOID USE. THE PRECISION HUMAN PAIN NETWORK, PART OF THE NIH HEAL INITIATIVE, SEEKS TO PROVIDE FOUNDATIONAL DATA ON THE DIVERSITY AMONG CELL TYPES THAT COMPRISE THE PAIN NEURAXIS. HERE, WE PROPOSE A U19 PROGRAM ENTITLED “INTEGRATED RESEARCH CENTER FOR HUMAN PAIN TISSUES” (INTERCEPT PAIN). WE WILL BUILD ON PRIOR SUCCESSES IN OUR HUMAN TISSUE RESEARCH PROGRAM, AND EXPAND THE SCOPE OF WORK TO DIRECTLY ADDRESS THE GOALS OF THE PRECISION HUMAN PAIN NETWORK. OUR PROGRAM LEVERAGES THE WORLD-CLASS GENOMICS AND COMPUTATIONAL ASSETS OF THE MCDONNELL GENOME INSTITUTE HERE AT WASHINGTON UNIVERSITY AND SUBSTANTIAL INSTITUTIONAL STRENGTHS IN NEUROBIOLOGY OF PAIN, AXON DEGENERATION AND REGENERATION, AND GENETICS IN A COORDINATED PROGRAM TO DEVELOP FOUNDATIONAL NEW KNOWLEDGE REGARDING THE TRANSCRIPTIONAL AND FUNCTIONAL PROPERTIES OF TISSUES AND CELLS INVOLVED IN PAIN TRANSDUCTION, TRANSMISSION AND MODULATION IN HUMANS. WE WILL PROVIDE A COMPREHENSIVE ATLAS OF CELLULAR GENE EXPRESSION IN HUMAN PERIPHERAL NERVE USING SINGLE NUCLEI RNASEQ, SPATIAL TRANSCRIPTOMICS AND MULTIPLEX PROTEOMICS, AND LEVERAGE THIS TO UNDERSTAND THE DISTRIBUTION OF GENES INVOLVED IN TRAUMATIC (NEUROMAS) AND IDIOPATHIC (HEREDITARY) PAINFUL NEUROPATHIES. WE WILL ALSO PROVIDE EXPANDED SINGLE-NUCLEUS SEQUENCING ATLASES OF DORSAL ROOT GANGLIA, INCLUDING DRG FROM DONORS WITHOUT AND WITH A RECENT HISTORY OF PAIN. WE WILL GENERATE A SPATIAL ATLAS OF HDRG USING IMAGING MASS CYTOMETRY, AND OPTIMIZE COMPUTATIONAL APPROACHES FOR INTEGRATED IMC AND SINGLE CELL TRANSCRIPTOMIC ANALYSIS OF HDRG. FINALLY, WE WILL COMBINE ANALYSIS OF ELECTROPHYSIOLOGICAL, TRANSCRIPTIONAL, AND MORPHOLOGICAL DATA FROM HDRG AND HUMAN SPINAL CORD DORSAL HORN NEURONS. WE WILL WORK WITH OTHER CENTERS TO OPTIMIZE PROTOCOLS AND DATA COLLECTION TO ALLOW INTEGRATED ANALYSIS ACROSS MULTIPLE CENTERS, IN COLLABORATION WITH THE U24 DCIC AND HEAL DATA ECOSYSTEM. THESE GOALS WILL BE ACCOMPLISHED THROUGH THE COORDINATED ACTIVITY OF 3 SCIENTIFIC PROJECTS, LED BY INTERNATIONAL LEADERS IN THE FIELDS OF PAIN NEUROBIOLOGY, GENETICS, AND MECHANISMS OF AXON DEGENERATION AND REGENERATION. THE PROJECT TITLES ARE AS FOLLOWS: PROJECT 1: MULTI-OMICS PERIPHERAL NERVE ATLAS ENABLES FINE-MAPPING OF PAIN MOLECULAR PHENOTYPES. PROJECT 2: CHARACTERIZATION OF THE HUMAN DORSAL ROOT GANGLIA AT THE SINGLE CELL LEVEL VIA INTEGRATED TRANSCRIPTOMICS AND SPATIAL PROTEOMICS PROJECT 3: FUNCTIONAL AND GENETIC CHARACTERIZATION OF HUMAN DRG AND SPINAL CORD AT SINGLE CELL RESOLUTION THE PROJECTS ARE SUPPORTED BY AN EXPERIENCED PROGRAM LEADERSHIP TEAM AND AN ADMINISTRATION CORE, A HUMAN TISSUE PROCUREMENT AND PROCESSING CORE, AND A DATA CORE.

RARE DISEASE NETWORK FOR MYASTHENIA GRAVIS

DOMINANTLY INHERITED ALZHEIMER NETWORK

IBMPFD MUTATIONS IMPAIR UPS FUNCTION

THE XNAT IMAGING INFORMATICS PLATFORM

RESILIENCE AND BRAIN HEALTH OF OLDER ADULTS DURING THE COVID-19 PANDEMIC - ABSTRACT: EXERCISE AND MINDFULNESS ARE BELIEVED TO BE EFFECTIVE STRESS REDUCTION INTERVENTIONS, BUT RESEARCH TO DATE HAS NOT BEEN ABLE TO ASSESS THEIR BENEFITS WHILE INDIVIDUALS ARE COPING WITH A MAJOR STRESSOR IN REAL TIME. THE COVID-19 PANDEMIC IS AN UNWANTED NATURAL EXPERIMENT IN THE DELETERIOUS EFFECTS OF STRESS – ESPECIALLY SOCIAL ISOLATION (SOCIAL DISCONNECTEDNESS AND LONELINESS), A STRESSOR PARTICULARLY STRONGLY ASSOCIATED WITH THE PANDEMIC - ON OLDER AMERICANS’ COGNITIVE AND EMOTIONAL HEALTH AND RISK FOR ALZHEIMER’S DISEASE (AD). THIS PROJECT WILL ELUCIDATE WHETHER EXERCISE AND MINDFULNESS CAN MITIGATE THE EFFECTS OF PANDEMIC STRESS ON COGNITIVE FUNCTION AND EMOTIONAL HEALTH IN LATER LIFE, INCLUDING NEUROBIOLOGICAL MEASURES OF RISK FOR AD. WE WILL LEVERAGE A UNIQUE RESOURCE: THE NIH-FUNDED TRIAL, “MINDFULNESS-BASED STRESS REDUCTION AND EXERCISE FOR AGE-RELATED COGNITIVE DECLINE” (MEDEX). BY LEVERAGING MEDEX AND FOLLOWING THESE PARTICIPANTS, WHO CONTINUE TO ATTEND MONTHLY BOOSTER SESSIONS OF THEIR RANDOMIZED CONDITION REMOTELY DURING THE PANDEMIC, WE WILL HAVE REPEATED SETS OF CLINICAL, COGNITIVE, MOLECULAR, AND NEUROIMAGING MEASURES COVERING 7.5 YEARS DURING THE PRE-, DURING-, AND POST-PANDEMIC PERIOD. WE CAN EXAMINE INTERVENTION EFFECTS, AS WELL AS INDIVIDUAL FACTORS SUCH AS RESILIENCE, ON LONG-TERM OUTCOMES. AMONG OTHER INNOVATIVE ASPECTS OF THE PROJECT, WE WILL ANALYZE EFFECTS ON TWO NOVEL PERIPHERAL BIOMARKERS: SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP), WHICH MEASURES MECHANISMS OF BIOLOGICAL AGING, AND PLASMA AMYLOID ASS42 AND ASS40, WHICH MEASURE AD RISK. IN THE PROPOSED PROJECT, (1) DURING THE PANDEMIC, WE WILL USE NOVEL METHODS SUCH AS ECOLOGICAL MOMENTARY ASSESSMENT (EMA) TO CHARACTERIZE SOCIAL ISOLATION BOTH OBJECTIVELY (E.G., NUMBER OF SOCIAL CONTACTS) AND SUBJECTIVELY (E.G., LONELINESS), AND ITS BIOLOGICAL MECHANISMS ON AGING (SUCH AS ELEVATIONS IN SASP AND PLASMA AMYLOID); (2) POST-PANDEMIC, WE WILL ASSESS DOWNSTREAM EFFECTS ON COGNITIVE FUNCTION, EMOTIONAL WELL-BEING, AND BRAIN HEALTH, INCLUDING AD RISK, USING NEUROPSYCHOLOGICAL ASSESSMENTS, EMA, AND NEUROIMAGING. OUTCOMES INCLUDE (AIM 1) CHANGES IN COGNITIVE PERFORMANCE AND EMOTIONAL WELL-BEING, AND DECLINE IN EMOTIONAL WELL-BEING MEASURED BY POSITIVE AND NEGATIVE AFFECT AND SLEEP QUALITY; INCREASES IN BIOLOGICAL AGING AND DECREASING A42/40 RATIO IN THE POST-PANDEMIC PHASE, INDICATING HIGHER RISK OF AD; ATROPHY IN HIPPOCAMPAL AND PREFRONTAL VOLUME (STRUCTURAL MRI) AND REDUCED GLOBAL FUNCTIONAL CONNECTIVITY (RESTING-STATE FMRI). MODIFIERS OF THESE EFFECTS (AIM 2) INCLUDE EXERCISE AND MINDFULNESS; PSYCHOLOGICAL RESILIENCE; COVID-19 EXPOSURE; MEDICAL MORBIDITIES; AND APOE GENOTYPE. MECHANISMS OF COGNITIVE, EMOTIONAL, AND BRAIN HEALTH CHANGES (AIM 3) INCLUDE AMYLOID (ASS40 AND ASS42), SASP, DNA METHYLATION, AND CORTISOL DURING THE PANDEMIC. THIS PROJECT WILL ADVANCE OUR KNOWLEDGE OF THE IMPACT OF SOCIAL ISOLATION AND OTHER STRESSORS ON OLDER ADULTS, INCLUDING MECHANISMS BY WHICH THESE STRESSORS PRODUCE DELETERIOUS COGNITIVE, EMOTIONAL, AND BRAIN HEALTH CHANGES OVER TIME, AND WHETHER EXERCISE AND MINDFULNESS HAVE DURABLE PROTECTIVE EFFECTS.

RYAN WHITE TITLE IV WOMEN, INFANTS, CHILDREN, YOUTH AND AFFECTED FAMILY MEMBERS AIDS HEALTHCARE

CRX AND ITS REGULATORY NETWORK IN RETINAL DEGENERATIONS

RYAN WHITE TITLE IV WOMEN, INFANTS, CHILDREN, YOUTH AND AFFECTED FAMILY MEMBERS AIDS HEALTHCARE

A MULTILEVEL APPROACH TO ENERGY BALANCE AND CANCER ACROSS THE LIFECOURSE

COMPUTATIONAL AND EXPERIMENTAL RESOURCES FOR VIROME ANALYSIS IN INFLAMMATORY BOWEL DISEASE (CERVAID)

THE NORTHWEST EARTH AND SPACE SCIENCE PATHWAYS (FORMERLY PIPELINE) BRINGS AUTHENTIC HANDS-ON OPPORTUNITIES TO UNDERSERVED AND UNDERREPRESENTED COMMUNITIES IN WA OR ID AND MT. WE DO THIS BY OFFERING NASA-FOCUSED OUTREACH PROFESSIONAL DEVELOPMENT

TRAINING PROGRAM IN IMMUNOLOGY AND IMMUNOGENETICS

DOMINANTLY INHERITED ALZHEIMER NETWORK TRIAL: AN OPPORTUNITY TO PREVENT DEMENTIA

23/24 HEALTHY BRAIN AND CHILD DEVELOPMENT NATIONAL CONSORTIUM - PROJECT SUMMARY/ABSTRACT NEURODEVELOPMENTAL PROCESSES ARE SHAPED BY DYNAMIC INTERACTIONS BETWEEN GENES AND ENVIRONMENTS. MALADAPTIVE EXPERIENCES EARLY IN LIFE CAN ALTER DEVELOPMENTAL TRAJECTORIES, LEADING TO HARMFUL AND ENDURING DEVELOPMENTAL SEQUELAE. PRE- AND POSTNATAL HAZARDS INCLUDE MATERNAL SUBSTANCE EXPOSURE, TOXICANT EXPOSURES IN PREGNANCY AND EARLY LIFE, MATERNAL HEALTH CONDITIONS, PARENTAL PSYCHOPATHOLOGY, MALTREATMENT, STRUCTURAL RACISM, AND EXCESSIVE STRESS. TO ELUCIDATE HOW VARIOUS ENVIRONMENTAL HAZARDS IMPACT CHILD DEVELOPMENT, IT IS IMPERATIVE THAT A NORMATIVE TEMPLATE OF DEVELOPMENTAL TRAJECTORIES OVER THE FIRST 10 YEARS OF LIFE BE ESTABLISHED BASED ON A SUFFICIENTLY LARGE AND DEMOGRAPHICALLY DIVERSE SAMPLE OF THE US POPULATION. TO ACCOMPLISH THIS, THE HEALTHY BRAIN AND CHILD DEVELOPMENT NATIONAL CONSORTIUM (HBCD-NC) HAS BEEN FORMED TO DEPLOY A HARMONIZED, OPTIMIZED, AND INNOVATIVE SET OF NEUROIMAGING (MRI, EEG) MEASURES COMPLEMENTED BY AN EXTENSIVE BATTERY OF BEHAVIORAL, PHYSIOLOGICAL, AND PSYCHOLOGICAL TOOLS, AND BIOSPECIMENS TO UNDERSTAND NEURODEVELOPMENTAL TRAJECTORIES IN A SAMPLE OF 7,500 MOTHERS AND INFANTS ENROLLED AT 24 SITES ACROSS THE UNITED STATES (US). THE HBCD-NC WILL CARRY OUT A COMMON RESEARCH PROTOCOL UNDER DIRECTION OF THE HBCD-NC ADMINISTRATIVE CORE (HCAC) AND WILL ASSEMBLE AND DISTRIBUTE A COMPREHENSIVE AND WELL-CURATED RESEARCH DATASET TO THE SCIENTIFIC COMMUNITY AT LARGE UNDER THE DIRECTION OF THE HBCD-NC DATA COORDINATING CENTER (HDCC). THE OVERARCHING GOAL OF THE HBCD-NC IS TO CREATE A COMPREHENSIVE, HARMONIZED, AND HIGH- DIMENSIONAL DATASET THAT WILL CHARACTERIZE TYPICAL NEURODEVELOPMENTAL TRAJECTORIES IN US CHILDREN AND THAT WILL ASSESS HOW BIOLOGICAL AND ENVIRONMENTAL EXPOSURES AFFECT THOSE TRAJECTORIES. A SPECIAL EMPHASIS WILL BE PLACED ON UNDERSTANDING THE IMPACT OF PRE- AND POSTNATAL EXPOSURE TO OPIOIDS, MARIJUANA, ALCOHOL, TOBACCO AND/OR OTHER SUBSTANCES. TO ADDRESS THESE BROAD OBJECTIVES, THE SAMPLE OF WOMEN ENROLLED WILL INCLUDE: 1) A RACIALLY, ETHNICALLY, AND SOCIOECONOMICALLY DIVERSE COHORT THAT IS REPRESENTATIVE OF THE US POPULATION; 2) PREGNANT WOMAN WITH USE OF TARGETED SUBSTANCES (OPIOIDS, MARIJUANA, ALCOHOL, TOBACCO); AND 3) DEMOGRAPHICALLY AND BEHAVIORALLY SIMILAR WOMEN WITHOUT SUBSTANCE USE IN PREGNANCY TO ENABLE VALID CAUSAL INFERENCES. IN ADDITION, THE HBCD-NC WILL IDENTIFY KEY DEVELOPMENTAL WINDOWS DURING WHICH BOTH HARMFUL AND PROTECTIVE ENVIRONMENTS HAVE THE MOST INFLUENCE ON LATER NEURODEVELOPMENTAL OUTCOMES. THE LARGE, MULTI-MODAL, LONGITUDINAL, AND GENERALIZABLE DATASET THAT WILL BE PRODUCED FOR THE FIRST TIME BY THIS STUDY WILL PROVIDE NOVEL INSIGHTS INTO CHILD DEVELOPMENT USING STATE- OF-THE-ART METHODS. THE HBCD-NC STUDY WILL INFORM PUBLIC POLICY TO IMPROVE THE HEALTH AND DEVELOPMENT OF CHILDREN ACROSS THE NATION.

MULTI-DISCIPLINARY EVALUATION OF CHRONIC PELVIC PAIN SYNDROME

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP)

A MULTI-ANCESTRY STUDY OF GENE-LIFESTYLE INTERACTIONS AND MULTI-OMICS IN CARDIOMETABOLIC TRAITS - PROJECT SUMMAR/ABSTRACT CARDIOMETABOLIC DISEASES AND RISK FACTORS, INCLUDING HYPERTENSION, DYSLIPIDEMIA, ADIPOSITY, AND TYPE 2 DIABETES, REPRESENT A MAJOR PUBLIC HEALTH BURDEN THAT DISPROPORTIONATELY AFFECTS DIVERSE (NON-EUROPEAN ANCESTRY) POPULATIONS. CARDIOMETABOLIC TRAITS ARE INFLUENCED BY BOTH GENETIC AND ENVIRONMENTAL (LIFESTYLE) FACTORS. THEREFORE, UNDERSTANDING INTERACTIONS (GXE) BETWEEN THESE FACTORS COULD PROVIDE INSIGHTS INTO INTERVENTION, PREVENTION AND THERAPEUTIC STRATEGIES TO REDUCE THE BURDEN OF DISEASE. MANY GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE MADE IMPORTANT GENETIC DISCOVERIES FOR MANY COMPLEX TRAITS THROUGH APPROACHES BASED ON “GENETIC MAIN EFFECTS”. HOWEVER, GENOME-WIDE INTERACTION STUDIES (GWIS) ARE STILL LIMITED. THE OBJECTIVE OF THIS STUDY IS THEREFORE TO IDENTIFY NOVEL GENETIC LOCI ASSOCIATED WITH CARDIOMETABOLIC TRAITS THROUGH GWIS IN LARGE SAMPLES, TO INVESTIGATE GENE-LIFESTYLE INTERACTIONS IN THE CARDIOMETABOLIC TRAIT LOCI, AND TO CHARACTERIZE THE MOLECULAR EFFECTS UNDERLYING THE INTERACTIONS BY LEVERAGING EXISTING “OMICS” DATA SUCH AS DNA METHYLATION, GENE EXPRESSION, AND METABOLITES. BY INVESTIGATING GENOMIC AND LIFESTYLE CONTRIBUTORS TO HEALTH OUTCOMES THROUGH THEIR INTERACTIONS ACROSS DIVERSE POPULATIONS AND BETWEEN SEXES, OUR PROPOSAL REFLECTS THE PRIORITIES OF THE PRECISION MEDICINE INITIATIVE (PMI) WHOSE FOCUS IS THE INTERPLAY BETWEEN LIFESTYLE/ENVIRONMENT AND GENETICS, WITH AN EMPHASIS ON DIVERSE POPULATIONS. WE PROPOSE TO EVALUATE GENE-LIFESTYLE INTERACTIONS ACROSS DIVERSE POPULATIONS (EUROPEAN, AFRICAN, HISPANIC, AND ASIAN). OUR RECENT PROGRESS WITH BLOOD PRESSURE, LIPIDS, AND DICHOTOMIZED LIFESTYLE FACTORS (SMOKING, ALCOHOL CONSUMPTION, PHYSICAL ACTIVITY, EDUCATIONAL ATTAINMENT, PSYCHOSOCIAL FACTORS, AND SLEEP) ENCOUNTERED LIMITED STATISTICAL POWER. THEREFORE, WE PROPOSE TO VASTLY INCREASE THE POWER FOR GWIS WITH AN ~10-FOLD LARGER SAMPLE SIZE AND EXPAND OUR FOCUS TO INCLUDE OTHER CARDIOMETABOLIC TRAITS (ADIPOSITY AND DIABETES TRAITS), QUANTITATIVE LIFESTYLE EXPOSURES (E.G., CIGARETTES PER DAY), AND AGGREGATE LIFESTYLE RISK SCORES AS AN OVERALL LIFESTYLE RISK FACTOR FOR CARDIOMETABOLIC HEALTH; EVALUATE THE IMPACT OF IDENTIFIED INTERACTIONS ON CLINICAL ENDPOINTS (LIKE CORONARY HEART DISEASE); ASSESS THE DRUGGABILITY OF IDENTIFIED INTERACTIONS; AND CHARACTERIZE INTERACTIONS USING MULTIPLE OMICS DATA. OUR PROPOSAL INCLUDES OUR RECENT DISCOVERY STUDIES (N~130,000), OUR RECENT REPLICATION STUDIES (N~252,000), AND THE ADDITION OF SEVERAL NEW, SUBSTANTIALLY LARGER STUDIES INCLUDING THE MILLION VETERAN PROGRAM (N~234,000), THE UK BIOBANK (N~478,000), THE BIOBANK JAPAN (N~160,000), AND THE STUDY OF LATINOS (N~13,000), AMONG OTHERS. THE OVERALL SAMPLE, INCLUDING 912,000 EUROPEAN, 91,000 AFRICAN, 33,000 HISPANIC, AND 231,000 ASIAN ANCESTRY INDIVIDUALS, REPRESENTS THE MOST SIGNIFICANT EFFORT TO DATE TO INVESTIGATE INTERACTIONS WITH AN AGGREGATE SAMPLE SIZE OF ABOUT 1.267 MILLION. FINDINGS CAN LEAD TO NEW DIAGNOSTIC AND THERAPEUTIC TOOLS, CONTRIBUTE TO PRECISION CARE IN THE MANAGEMENT OF CARDIOMETABOLIC DISORDERS, AND PROVIDE INSIGHTS FOR THE PMI WITH THE ULTIMATE GOAL OF ENHANCING CLINICAL PRACTICE.

MARC: RISK MECHANISMS IN ALCOHOLISM AND COMORBIDITY

PROTEASES IN THE PATHOGENESIS AND TREATMENT OF THROMBOSIS

REGULATION OF MYOCARDIAL PHOSPHOLIPASES AND LIPASES IN DIABETIC MYOCARDIUM

MECHANISMS IN THE REMODELING OF LUNG STRUCTURE

WASHINGTON UNIVERSITY INSTITUTE OF CLINICAL AND TRANSLATIONAL SCIENCES (TL1)

PULMONARY COMPLICATIONS IN A BIRTH COHORT AFTER A RANDOMIZED TRIAL OF ANTENATAL CORTICOSTEROIDS: THE ALPS FOLLOW-UP STUDY - DATA COORDINATING CENTER

1/2 CATHETER-DIRECTED THERAPY FOR CHRONIC DVT (C-TRACT TRIAL)

THE DISTRICT OF COLUMBIA DEVELOPMENTAL CENTER FOR AIDS RESEARCH (DC D-CFAR)

THE COLLABORATIVE GENETIC STUDY OF NICOTINE DEPENDENCE

A MULTI-ETHNIC STUDY OF GENE-LIFESTYLE INTERACTIONS IN CARDIOVASCULAR TRAITS

WASHU-NORTHWESTERN GENOMIC VARIATION AND FUNCTION DATA AND ADMINISTRATIVE COORDINATING CENTER - PROJECT SUMMARY THE GOALS OF THE WASHU-NORTHWESTERN GENOMIC VARIATION AND FUNCTION DATA AND ADMINISTRATIVE COORDINATING CENTER (IGVF-DACC) COMPONENT OF THE IGVF CONSORTIUM ARE TO COLLECT, STORE, CURATE, AND DISPLAY ALL DATA, METADATA, AND ANALYSIS TOOLS GENERATED BY THE IGVF CONSORTIUM. THE DACC WILL ASSIST IN DEVELOPING AND DISSEMINATING METADATA AND STANDARDS TO BE ADOPTED BY THE COMMUNITY AT LARGE, APPROACHES FOR INTEGRATIVE ANALYSIS OF A WIDE RANGE OF DATA TYPES, AND VISUALIZATION AND ANALYSIS TOOLS TO FACILITATE ACCESS AND UNDERSTANDING OF COMPLEX DATASETS TO NON-EXPERT USERS. ULTIMATELY, THE IGVF CONSORTIUM WILL PRODUCE TOOLS, ANALYSES, MODELS, AND DATA THAT FORM THE CATALOG OF VARIANTS AND THEIR FUNCTIONAL IMPACT. WE WILL DEVELOP THE DACC INTO A SUBSTANTIAL SERVICE ORGANIZATION ALLOWING SCIENTIFIC RESEARCH TO TAKE FULL ADVANTAGE OF THE IGVF REFERENCE CATALOG OR MAP. TO SUPPORT THE IGVF CONSORTIUM, WE WILL ESTABLISH DATABASES WITH AN APPLICATION FRAMEWORK TO FACILITATE COMPLEX DATA LOADING. WE WILL INCLUDE DETAILED EXPERIMENTAL DESCRIPTIONS AND METADATA. WE WILL DEFINE AND DEVELOP PIPELINES THAT CONNECT ALL CONSORTIUM MEMBERS TO THE DATA AND CREATE AVENUES OF ACCESS THAT DISTRIBUTE THE DATA TO THE GREATER BIOLOGICAL RESEARCH COMMUNITY. WE WILL ESTABLISH METADATA REQUIREMENTS, CONTROLLED VOCABULARIES, STANDARDIZED DATA FORMATS, AND QUALITY CONTROL METRICS FOR ALL IGVF DATA. WE WILL BRING TOGETHER LABORATORIES THAT GENERATE COMPLEX DATA TYPES VIA EXPERIMENTAL ASSAYS WITH LABORATORIES THAT INTEGRATE THESE DATA USING COMPUTATIONAL TOOLS TO DEFINE THE EFFECTS OF GENOMIC VARIATION ON GENOME FUNCTION AND HOW THESE EFFECTS SHAPE PHENOTYPES. BY CREATING STRUCTURES AND DATA FLOW PIPELINES FOR THE VERIFICATION AND VALIDATION OF ALL DATA AND PROVIDING PROCESSES FOR THE DOCUMENTATION OF METADATA, THE DACC WILL ENHANCE THE IGVF DATA PRODUCTION. THE DACC WILL ALSO COORDINATE INTEGRATIVE DATA ANALYSIS BY CREATING AND ADAPTING ANALYSIS PIPELINES AND DEVELOPING ADVANCED GENOME BROWSER FUNCTIONS FOR THE VISUAL INTEGRATION OF IGVF DATA. ALSO, WE WILL MAKE THE IGVF WEB PORTAL THAT WILL BE THE PRIMARY ENTRY POINT TO THE WEALTH OF EXPERIMENTAL DATA AND COMPUTATIONAL ANALYSES. THE PORTAL WILL INTEGRATE THESE DATA RESOURCES AND MAKE THEM AVAILABLE VIA ENHANCED SEARCH AND BROWSING CAPABILITIES. FINALLY, THE DACC WILL PROVIDE DOCUMENTATION, TRAINING, AND OUTREACH VIA MANY MEDIA, INCLUDING WRITTEN DOCUMENTATION, VIDEO TUTORIALS, ONLINE BOOKS, WEBINARS, AND MEETING WORKSHOPS AND PRESENTATIONS.

ROUTE 66 ENDOMETRIAL CANCER SPORE - PROJECT SUMMARY THE ROUTE 66 ENDOMETRIAL CANCER SPORE BRINGS TOGETHER INTERACTIVE RESEARCH TEAMS FROM THREE INSTITUTIONS TO CREATE A DYNAMIC TRANSLATIONAL RESEARCH PROGRAM AIMED AT DEVELOPING AND TESTING NEW STRATEGIES TO PREVENT AND TREAT ENDOMETRIAL CANCER. THIS SPORE INCLUDES THREE RESEARCH PROJECTS; AN ADMINISTRATIVE CORE; A BIOSTATISTICS AND BIOINFORMATICS CORE; A BIOSPECIMENS, METABOLOMICS, AND PATHOLOGY CORE; AND DEVELOPMENTAL RESEARCH AND CAREER ENHANCEMENT PROGRAMS. THE THREE PROJECTS, CHOSEN AND REFINED WITH EXTENSIVE INPUT FROM OUR INTERNAL AND EXTERNAL ADVISORY BOARDS, ARE DESIGNED TO HAVE SIGNIFICANT POTENTIAL TO CHANGE CLINICAL PRACTICE WITHIN FIVE YEARS. PROJECT 1: HSPA PROTEINS IN ADVANCED AND RECURRENT ENDOMETRIAL CANCER THERAPY. PROJECT 2: INHIBITING AXL TO IMPROVE TREATMENT RESPONSE IN ENDOMETRIAL CANCER. PROJECT 3: IMPROVING PRIMARY PREVENTION AND UTERINE PRESERVATION IN PREMENOPAUSAL WOMEN WITH OBESITY AND ENDOMETRIAL HYPERPLASIA. PROJECTS 1 AND 2 ARE CLINICAL/TRANSLATIONAL PROJECTS, WHEREAS PROJECT 3 IS AN EARLY DETECTION, PREVENTION, OR POPULATION SCIENCE PROJECT. ALL THREE PROJECTS INCLUDE CLINICAL TRIALS AND REPRESENT CAREFULLY CHOSEN MARRIAGES BETWEEN SELECTED ENDOMETRIAL CANCER RESEARCH PRIORITIES AND THE STRENGTHS OF WASHINGTON UNIVERSITY IN ST. LOUIS AND OUR COLLABORATORS AT THE UNIVERSITY OF NEW MEXICO AND THE UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER. THE OVERALL AIMS OF OUR SPORE ARE TO 1) TEST PROMISING NEW THERAPIES TO TREAT OR PREVENT ENDOMETRIAL CANCER; 2) ELUCIDATE THE KEY BIOLOGIC PROCESSES THAT DRIVE ENDOMETRIAL CANCER AND DEVELOP NOVEL BIOMARKERS TO PREDICT DEVELOPMENT OF ENDOMETRIAL CANCER AND RESPONSE TO THERAPIES; 3) LEVERAGE AND ENHANCE CAPACITIES OF SHARED RESEARCH RESOURCES; 4) RECRUIT AND MENTOR NEW INVESTIGATORS AND SUPPORT INNOVATIVE IDEAS IN TRANSLATIONAL ENDOMETRIAL CANCER RESEARCH; 5) FACILITATE COLLABORATION OF THOSE INTERESTED IN ENDOMETRIAL CANCER RESEARCH; AND 6) ENSURE EQUITABLE ENROLLMENT IN CLINICAL TRIALS AND INVOLVEMENT OF DIVERSE COMMUNITY MEMBERS AND INVESTIGATORS IN RESEARCH. IN COMPLETING THE WORK PROPOSED HERE, WE WILL TEST THREE NEW STRATEGIES TO PREVENT OR TREAT ENDOMETRIAL CANCER. FUTURE WORK CAN BE DIRECTED AT MOVING THE MOST PROMISING TREATMENT APPROACHES INTO LARGER TRIALS. ADDITIONALLY, WE WILL OBTAIN AN UNPRECEDENTED LEVEL OF MOLECULAR, CELLULAR, IMMUNOLOGIC, AND METABOLOMIC DETAIL REGARDING ENDOMETRIAL CANCER AND RESPONSE TO TREATMENT, WHICH WILL LIKELY LEAD TO DEVELOPMENT OF ADDITIONAL NOVEL CLINICAL TRIALS. FINALLY, BY DEVELOPING NEW IDEAS, INVESTIGATORS, AND COLLABORATIONS, WE WILL EXPAND THE BREADTH AND DEPTH OF RESEARCH AIMED AT TREATING OR PREVENTING ENDOMETRIAL CANCER.

TRAINING IN CANCER BIOLOGY

EMERGING INFECTIONS: SURVEILLANCE, EPIDEMIOLOGY AND PATHOGENESIS

AGE OF BLOOD IN CHILDREN IN PEDIATRIC INTENSIVE CARE UNITS

PRINCIPLES IN CARDIOVASCULAR RESEARCH TRAINING PROGRAM

A WASHINGTON UNIVERSITY GNOTOBIOTIC RESEARCH, EDUCATION AND TRANSGENIC (WU-GREAT) CENTER FOR MODELING GENETIC AND ENVIRONMENTAL EFFECTORS OF DISEASE PATHOGENESIS

INVESTIGATIONS OF DEMENTIA IN PARKINSON DISEASE

RFA-IP-22-004, MULTIDISCIPLINARY APPROACH TO UNDERSTANDING VACCINE EFFICACY AND TRANSMISSION OF VIRAL RESPIRATORY TRACT INFECTIONS IN THE REAL WORLD

A DOSE ESCALATION STUDY OF LOW DOSE ASPIRIN FOR THE PREVENTION OF RECURRENT PRETERM BIRTH - PROJECT SUMMARY/ABSTRACT PRETERM BIRTH IS WELL ESTABLISHED AS THE LEADING CAUSE OF PERINATAL MORTALITY AND A SIGNIFICANT CONTRIBUTOR TO BOTH CHRONIC MEDICAL CONDITIONS AND LEARNING/SOCIETAL CHALLENGES AMONGST THOSE BORN TOO SOON. THOUGH COMPLEX IN ITS ORIGINS, PRETERM BIRTH IS PREDOMINANTLY THE RESULT OF SPONTANEOUS PRETERM BIRTH AND ISCHEMIC PLACENTAL DISEASES (PREECLAMPSIA, FETAL GROWTH RESTRICTION AND ABRUPTION). BEGINNING IN THE 1980'S LOW DOSE ASPIRIN (LDA) WAS TRIALED AS A THERAPY FOR THE PREVENTION OF PREECLAMPSIA. SUBSEQUENT META-ANALYSES OF RANDOMIZED CONTROLLED TRIALS OF LDA HAVE DEMONSTRATED ITS EFFICACY IN PREVENTING BOTH PRETERM BIRTH AND OTHER COMPONENTS OF ISCHEMIC PLACENTAL DISEASES. LIMITED DATA SUGGEST THAT THE EFFECT OF LDA IN PREVENTING BOTH PRETERM BIRTH AND PREECLAMPSIA MAY BE GREATER IF THERAPY IS BEGUN BEFORE 16 WEEKS AND UTILIZING DOSES >100 MG. RECENTLY THE ASPIRIN TRIAL RANDOMIZED 11,976 NULLIPAROUS WOMEN WITH A SINGLETON GESTATION IN LOW-MIDDLE INCOME COUNTRIES TO EITHER ASPIRIN 81 MG ORALLY OR AN IDENTICAL APPEARING PLACEBO BETWEEN 60/7 WEEKS AND 136/7 WEEKS. THIS TRIAL DEMONSTRATED A 11% DECREASE IN PRETERM BIRTH, 25% DECREASE IN EARLY PRETERM BIRTH <34 WEEKS, 11% DECREASE IN HYPERTENSIVE DISORDERS OF PREGNANCY AND 62% DECREASE IN PRETERM DELIVERY AT <34 WEEKS WITH HYPERTENSION. THOUGH PROMISING, ASPIRIN HAS YET TO BE FULLY ACCEPTED AS A PREVENTIVE STRATEGY FOR PRETERM BIRTH, WHETHER ASPIRIN PORTENDS EFFICACY IN A DOSE-RESPONSE FASHION REMAINS UNEXPLORED, AND MECHANISTIC STUDIES OF THE PATHWAYS BY WHICH LDA PREVENTS BOTH PRETERM BIRTH AND ISCHEMIC PLACENTAL DISEASE ARE LACKING. THE PROPOSED PROJECT IS DESIGNED TO OVERCOME THESE LIMITATIONS. THE GOAL IS TO ENROLL 1,300 WOMEN WITH A PRIOR PRETERM BIRTH DUE TO EITHER SPONTANEOUS BIRTH OR INDICATED PRETERM BIRTH AND A CURRENT SINGLETON PREGNANCY BETWEEN 100/7 WEEKS TO 166/7 TO A RANDOMIZED CLINICAL TRIAL OF ASPIRIN 81 MG ORALLY DAILY AND A SHAM (N = 650) OR 162 MG ORALLY DAILY (N = 650). WE WILL TEST THREE OVERARCHING HYPOTHESES: (I) WOMEN WITH A PRIOR PRETERM BIRTH RANDOMIZED TO 162 MG OF ASPIRIN DAILY COMPARED TO 81 MG OF ASPIRIN DAILY WILL HAVE LOWER RATES OF PRETERM BIRTH; (II) WOMEN WITH A PRIOR PRETERM BIRTH RANDOMIZED TO 162 MG OF ASPIRIN DAILY COMPARED TO 81 MG OF ASPIRIN DAILY WILL HAVE LOWER RATES OF ISCHEMIC PLACENTAL DISEASES; AND (III) BIOCHEMICAL MARKERS (THROMBOXANE B2, SPECIALIZED PRO-RESOLVING MEDIATORS, ETC.) WILL CORRELATE WITH CLINICAL OUTCOMES. OUR RESEARCH GROUP WILL DRAW UPON THE COLLECTIVE EXPERIENCE AND LEADERSHIP OF THE PERINATAL RESEARCH CONSORTIUM (10 ACADEMIC CENTERS), AN EXPERIENCED DATA MANAGEMENT AND STATISTICAL ANALYSIS CORE AND A STRONG BIOSPECIMEN ANALYTIC CORE. THIS INNOVATIVE PROJECT BY COMBINING A RIGOROUSLY CONDUCTED RCT WITH APPROPRIATE BIOSPECIMEN ANALYSIS WILL BOTH ADDRESS A PRESSING QUESTION ABOUT ONE OF THE FEW THERAPIES SHOWN TO IMPROVE THE OBSTETRICAL OUTCOMES OF PRETERM BIRTH AND ISCHEMIC PLACENTAL DISEASES AND PROVIDE INSIGHT TO THE MECHANISMS OF HOW ASPIRIN IMPROVES OUTCOMES.

CONSORTIUM ON NAVAL ENTERPRISE PATHWAYS (CONEP)

WASHINGTON UNIVERSITY HUMAN TUMOR ATLAS RESEARCH CENTER

KIDNEY SINGLE CELL AND SPATIAL MOLECULAR ATLAS PROJECT - KIDSSMAP - $EVWUDFW 2YHUDOO THE GOAL OF THE KIDNEY SINGLE CELL AND SPATIAL MOLECULAR ATLAS PROJECT (KIDSSMAP) IS TO CREATE AN ANATOMICAL AND MOLECULAR “METAVERSE” OF THE HUMAN KIDNEY. KIDSSMAP WILL ACCOMPLISH THIS BY GENERATING MULTISCALAR, MULTIDIMENSIONAL AND MULTIMODAL MAPS OF THE ADULT NON-DISEASED HUMAN KIDNEY AT A SINGLE CELL RESOLUTION. THIS WORK WILL BUILD ON AND EXTEND THE EXISTING EFFORTS OF THE INVESTIGATIVE TEAM THROUGH THE FIRST PHASE OF HUBMAP. WE WILL SPECIFICALLY FOCUS ON MICRO FUNCTIONAL TISSUE UNITS (FTUS) AND STRUCTURES THAT ARE ALONG THE CORTICO- MEDULLARY AXIS OF THE KIDNEY. THE TECHNOLOGIES GENERATING DATA INCLUDE PAIRED SINGLE NUCLEUS CHROMATIN ACCESSIBILITY AND RNA EXPRESSION (SNRNA/ATAC-SEQ -CELL TYPE AND STATE DIVERSITY), SMFISH AND DART-FISH (TARGETED HIGH RESOLUTION SPATIAL INTERROGATION OF 30-1000 TRANSCRIPTS), SPATIAL TRANSCRIPTOMICS (UNTARGETED GENOME WIDE SPATIAL MAPPING OF DISSOCIATIVE TECHNOLOGIES), CODEX (MULTIPLEXED SPATIAL PROTEIN INTERROGATION TO BRIDGE WITH RNA TECHNOLOGIES AND 3D IF TECHNOLOGIES), 3D MULTIPLEXED IMMUNOFLUORESCENCE (3D IF- SUBCELLULAR RESOLUTION TO DEFINE NEIGHBORHOODS IN MICROFTUS), LIGHTSHEET FLUORESCENCE MICROSCOPY (LSFM- ANATOMICAL MAPS AT MESOSCALE OF KEY AND 3D MAPS OF NEUROVASCULAR ASSOCIATIONS WITH FTUS) AND SCATTERING RAMAN SPECTROSCOPY (SRS-2D, 3D LABEL FREE VOLUMETRIC MAPPING AT SUBCELLULAR SCALE). THE MAPS GENERATED WILL DEFINE QUANTITATIVE METRICS OF CELL DIVERSITY, SPATIAL DEFINED NEIGHBORHOODS ACROSS WIDE SCALES FOR DIFFERENT TYPES OF ANALYTES INTERROGATED BY A DIVERSE SET OF SINGLE CALL BASED AND SPATIAL TECHNOLOGIES ENCOMPASSING CHROMATIN STATES, GENE EXPRESSION, PROTEIN, EXTRACELLULAR MATRIX, METABOLITES AND LIPIDS RANGING FROM SUBCELLULAR TO VOLUMETRIC MESO AND ANATOMIC SCALE. THESE WILL BE FURTHER AUGMENTED BY CHARACTERIZING BIOLOGICALLY DIVERSE (SEX, AGE, RACE) SAMPLES. THESE TASKS WILL BE ACCOMPLISHED THROUGH A KIDNEY ORGAN SPECIFIC PROJECT (KIDOSP) AND A KIDNEY DATA ANALYSIS CENTER (KIDDAC), WITH THEIR OUTPUTS, MILESTONES AND DELIVERY TO THE HIVE CENTRALLY MANAGED. KIDSSMAP IS FORMED BY THE ALLIANCE OF INVESTIGATORS WHO HAVE EXTENSIVE EXPERTISE IN KIDNEY TISSUE INTERROGATION, SPATIAL MAPPING AND DATA INTEGRATION. THE INVESTIGATORS HAVE A TRACK RECORD OF CONTRIBUTING TO LARGE CONSORTIA SUCH AS HUBMAP AND KPMP THROUGH FRUITFUL AND COLLABORATIVE INTERACTIONS. BY MAPPING THE HUMAN KIDNEY WITH ITS DIVERSE FUNCTIONAL UNITS AT HIGH RESOLUTION AND LARGE SCALE, KDSSMAP WILL GENERATE A VALUABLE RESOURCE FOR THE COMMUNITY TO UNDERSTAND KIDNEY HEALTH AND DISEASE.

STRUCTURE, BIOSYNTHESIS AND FUNCTION OF GLYCOPROTEINS

WASHINGTON UNIVERSITY INSTITUTE OF CLINICAL AND TRANSLATIONAL SCIENCES

SURGICAL TREATMENT OF CARDIAC ARRHYTHMIAS

WASHINGTON UNIVERSITY/ SITEMAN CANCER CENTER LEAD ACADEMIC SITE

WASHINGTON UNIVERSITY SENESCENCE TISSUE MAPPING CENTER (WU-SN-TMC) - OVERALL PROJECT SUMMARY/ABSTRACT CELLULAR SENESCENCE HAS BEEN CHARACTERIZED AS A STATE OF IRREVERSIBLE CELL-CYCLE ARREST COUPLED WITH A SECRETORY PROGRAM THAT CAN PROFOUNDLY IMPACT THE TISSUE MICROENVIRONMENT. OUR CURRENT UNDERSTANDING OF SENESCENCE IS LARGELY BASED ON CELL CULTURE AND MODEL-BASED STUDIES. RESEARCH ON THE RELEVANT SIGNALING PATHWAYS AND MECHANISMS UNDERLYING CELLULAR SENESCENCE ACROSS HUMAN TISSUES OVER TIME IS LACKING. OUR ABILITY TO LEVERAGE RECENT ADVANCES IN OMICS AND MOLECULAR IMAGING TECHNOLOGIES ENABLES US TO INVESTIGATE THE TRANSCRIPTIONAL CHANGES AND SECRETORY FEATURES DRIVING AND/OR ASSOCIATED WITH SENESCENCE AT HIGHER DEPTHS AND RESOLUTION THAN EVER BEFORE. HERE, WE PROPOSE TO DEVELOP THE WASHINGTON UNIVERSITY SENESCENCE TISSUE MAPPING CENTER (WU-SN-TMC) WITHIN THE NIH SENESCENCE NETWORK (SENNET). OUR WU-SN-TMC WILL DEVELOP CELLULAR SENESCENCE ATLASES USING 500 HUMAN SAMPLES FROM FOUR ESSENTIAL TISSUE TYPES: BONE MARROW, BREAST, COLON, AND LIVER. WE WILL FIRST OPTIMIZE OUR OMICS AND IMAGING TECHNOLOGIES AND PLATFORMS FOR CAPTURING, DETECTING, CHARACTERIZING, AND VISUALIZING SENESCENT CELLS; DEVELOP COMPUTATIONAL TOOLS AND MODELS FOR ACCURATE IDENTIFICATION OF SENESCENT CELLS AND MARKERS; CONSTRUCT BREAST, BONE MARROW, COLON, AND LIVER SENESCENCE ATLASES IN SPATIAL AND TEMPORAL CONTEXTS; AND ASSESS THE LANDSCAPE AND HETEROGENEITY OF SENESCENCE. WITH THESE INITIAL ATLASES, WE WILL FURTHER CHARACTERIZE, VALIDATE, AND DEFINE CELLULAR SENESCENCE PHENOTYPES AND BIOMARKERS USING PERTURBATION METHODS AND INVESTIGATE THE INTERACTIONS BETWEEN SENESCENT CELLS AND THE SENESCENCE-ASSOCIATED MICROENVIRONMENT. FINALLY, WE WILL WORK WITH OTHER SENNET CENTERS TO BUILD COMPREHENSIVE, MAJOR ORGAN/TISSUE SENESCENCE ATLASES BY INTEGRATED AND COMPARATIVE STUDIES OF ALL SENNET DATA ACROSS TISSUE TYPES, TIME, SEX, AGE, AND ANCESTRY GROUPS. AS A MEMBER OF THE SENNET PROGRAM, WU-SN- TMC WILL EMPLOY STATE-OF-THE-ART OMICS AND IMAGING TECHNOLOGIES, INCLUDING BULK PROTEOGENOMICS, SINGLE CELL SEQUENCING, SPATIAL TRANSCRIPTOMICS, CODEX MOLECULAR IMAGING, 3D LIGHT SHEET MICROSCOPY PLUS EXPANSION TECHNOLOGIES THAT ARE LIKELY TO MATURE OVER THE FUNDING PERIOD, SUCH AS SINGLE MOLECULE SEQUENCING, TO GENERATE HIGH-RESOLUTION, MULTI-PARAMETER BIOMARKERS AND MAPS OF CELLULAR SENESCENCE IN THE FOUR TISSUE TYPES SELECTED. WE HAVE THE ESTABLISHED INFRASTRUCTURE AND EXPERTISE TO SUCCESSFULLY CONDUCT THIS WORK, INCLUDING HIGH QUALITY BIOSPECIMEN COLLECTION, OMICS AND IMAGING DATA PRODUCTION, EXPERIMENTAL CONFIRMATION AND VALIDATION, AND HIGH THROUGHPUT, STANDARDIZED, AND REPRODUCIBLE DATA ANALYSIS. IN CONCLUSION, WE WILL WORK CLOSELY WITH OTHER SENNET CENTERS AND THE CONSORTIUM ORGANIZATION AND DATA COORDINATION CENTER (CODCC), TO GENERATE COMPREHENSIVE ATLASES ACROSS MAJOR HUMAN TISSUE TYPES UNDER VARIOUS PHYSIOLOGICAL CONDITIONS, INCLUDING CHANGES ACROSS THE HUMAN LIFESPAN.

INDUCTIVE AND MORPHOGENETIC PROCESSES SHAPING THE ZEBRAFISH EMBRYONIC AXES

GWB MENTAL HEALTH SERVICE RESEARCH TRAINING

EARLY HEAD START

HEMANGIOGLAST DEVELOPMENT AND REGULATION

THE NEONATAL MICROBIOME AND NECROTIZING ENTEROCOLITIS

IDENTIFICATION AND CHARACTERIZATION OF CELL-SPECIFIC TRANSPOSABLE ELEMENTS IMPLICATED ON ALZHEIMER DISEASE AND HEALTHY AGING - ABSTRACT ALZHEIMER DISEASE (AD) IS THE MOST COMMON FORM OF DEMENTIA AND NEURODEGENERATION AFFECTING MORE THAN 5 MILLION AMERICANS WITH NO CURRENT EFFECTIVE TREATMENT. SEVERAL MENDELIAN MUTATIONS AND RISK VARIANTS HAVE BEEN IDENTIFIED. WE AND OTHERS HAVE SHOWN THAT AD IS ASSOCIATED WITH CHANGES IN BRAIN CELL PROPORTION AND TRANSCRIPTOMIC CHANGES, SOME OF THEM ARE ALSO CELL SPECIFIC. ADDITIONALLY, THE LATEST GENETIC STUDIES IMPLICATE CELL-SPECIFIC PATHOGENIC EVENTS THAT LEAD TO DISEASE. PATHOGENIC VARIANTS IN APP, PSEN1 AND PSEN2 AFFECTS APP PROCESSING LEADING TO ASS AGGREGATES AND NEURONAL DEATH. GENETIC VARIANTS IN TREM2 AND MS4A MODIFY AD RISK BY AFFECTING MICROGLIA ACTIVITY. TO FULLY UNDERSTAND AND CHARACTERIZE THE ROLE OF TRANSPOSABLE ELEMENTS (TE) IN AD PATHOGENESIS THERE IS A NEED TO NOVEL AND MULTIDISCIPLINARY APPROACHES. HERE WE WILL COMBINE NOVEL GENOMIC APPROACHES IN HUMAN BRAIN TISSUES, DIRECT CONVERTED NEURONS AND IPSC-DERIVED MICROGLIA (IMGL) TO IDENTIFY CELL-SPECIFIC TE AND DOWNSTREAM (CHROMATIN ACCESSIBILITY, TRANSCRIPTION) CHANGES IMPLICATED IN AD. WE WILL LEVERAGE A LARGE AND UNIQUE RESOURCES OF HUMAN BRAIN SAMPLES AND FIBROBLAST FROM INDIVIDUALS WITH MUTATIONS IN APP, PSEN1, PSEN2, AS WELL AS RISK VARIANTS IN TREM2, MS4A OR APOE. WE WILL ALSO USE THE DIRECT CONVERTED NEURONS AND IMGL, TOGETHER WITH NEW GENOMIC EDITING APPROACHES TO TARGET AND CHARACTERIZE THE MECHANISM BY WHICH TE CONTRIBUTE TO DISEASE.

DUAL MECHANISMS OF COGNITIVE CONTROL

CK20-004, WASHINGTON UNIVERSITY & BJC EPICENTER TO PREVENT HEALTHCARE ASSOCIATED INFECTIONS & ANTIBIOTIC RESISTANCE

PHARMACOMECHANICAL CATHETER-DIRECTED THROMBOLYSIS FOR ACUTE DVT - ATTRACT TRIAL

WASHINGTON UNIVERSITY & BJC EPICENTER FOR PREVENTION OF HEALTHCARE ASSOCIATED INFECTIONS

PHYSIOLOGY AND GENETICS OF GDNF FAMILY OF LIGANDS (GFLS)