Emory University

SUPPORT OF YERKES NATIONAL PRIMATE RESEARCH CENTER

NATIONAL EBOLA TRAINING AND EDUCATION CENTER

ATLANTA CENTER FOR MICROSYSTEMS ENGINEERED POINT-OF-CARE TECHNOLOGIES (ACME POCT)

GEORGIA CLINICAL & TRANSLATIONAL SCIENCE ALLIANCE (GACTSA)

LEADERSHIP GROUP FOR THE INFECTIOUS DISEASES CLINICAL RESEARCH CONSORTIUM (IDCRCLG)

B CELL AUTOIMMUNITY IN HUMAN SLE

VACCINE INDUCED IMMUNITY IN THE YOUNG AND AGED

EMORY/ATLANTA CENTER FOR AIDS RESEARCH

OPEN DRUG DISCOVERY CENTER FOR ALZHEIMER'S DISEASE

ANTIVIRAL COUNTERMEASURES DEVELOPMENT CENTER (AC/DC) - THE ANTIVIRAL COUNTERMEASURES DEVELOPMENT CENTER (AC/DC) WILL TARGET PATHOGENS IN FIVE FAMILIES OF RNA VIRUSES WITH SIGNIFICANT PANDEMIC POTENTIAL, WITH THE OVERARCHING GOAL TO IDENTIFY AND DEVELOP ORALLY BIOAVAILABLE, DIRECT ACTING ANTIVIRAL DRUGS (DAAS). SPECIFIC VIRAL TARGETS INCLUDE ZOONOTIC AND HUMAN VIRUSES IN THE CORONAVIRUS, PARAMYXOVIRUS, FLAVIVIRUS, PICORNAVIRUS, AND TOGAVIRUS FAMILIES. THE AC/DC MPIS DRS. PAINTER AND PLEMPER, WHO WILL LEAD THIS EFFORT, HAVE DEMONSTRATED THE POWER OF THEIR COMBINED EXPERTISE IN IDENTIFYING NOVEL ANTIVIRAL CHEMOTYPES AND ADVANCING THEM FROM HIT STAGE TO CLINICAL CANDIDATE, BEST EXEMPLIFIED BY THEIR SUCCESSFUL JOINT WORK ON MOLNUPIRAVIR, CONSIDERED FOR EMERGENCY APPROVAL AS THE FIRST ORAL THERAPEUTIC FOR THE TREATMENT OF COVID- 19. THE MPIS HAVE ASSEMBLED A TEAM OF RECOGNIZED EXPERTS IN THE BIOLOGY OF THE VIRAL PATHOGENS BEING TARGETED. THEIR EFFORTS ARE ORGANIZED INTO FIVE SYNERGISTIC PROJECTS SUPPORTED BY CUTTING-EDGE TECHNICAL EXPERTISE IN FIVE AC/DC SCIENTIFIC CORES, COVERING KEY AREAS OF PRECLINICAL DRUG DISCOVERY AND DEVELOPMENT. A NUMBER OF THE CORE LEADERS HAVE SIGNIFICANT EXPERIENCE IN THE DEVELOPMENT OF ANTIVIRALS IN THE PHARMA AND BIOTECHNOLOGY SECTORS. THE AC/DC WILL ACHIEVE ITS OVERARCHING GOAL IN TWO MAJOR OBJECTIVES. PILOT STUDIES IDENTIFIED TWO CHEMICALLY DISTINCT BROAD-SPECTRUM RIBONUCLEOSIDE ANALOGS AND TWO NON-NUCLEOSIDE VIRAL POLYMERASE INHIBITORS WITH CONFIRMED ORAL EFFICACY AGAINST ONE OR SEVERAL OF THE FIVE VIRAL FAMILIES TARGETED, INCLUDING A NOVEL CHEMOTYPE THAT IS ORALLY EFFICACIOUS AGAINST SARS-COV-2 IN RELEVANT ANIMAL MODELS. OBJECTIVE 1 WILL ADVANCE THIS SET OF FOUR NOVEL DAA LEADS THROUGH FINAL SYNTHETIC OPTIMIZATION AND DE-RISKING IN ANIMAL MODELS AND PRIMARY HUMAN ORGANOIDS AS IMMEDIATE DELIVERABLES TO MITIGATE THE URGENT THREAT TO PUBLIC HEALTH. SIMULTANEOUSLY, OBJECTIVE 2 WILL IDENTIFY ADDITIONAL VIABLE HIT CHEMOTYPES TO EXPAND THE AC/DC'S ANTIVIRAL PORTFOLIO BY LEVERAGING CENTER EXPERTISE IN REVERSE GENETICS OF ALL VIRAL TARGET FAMILIES, EXISTING GROUNDBREAKING REPORTER VIRUS TECHNOLOGIES, AND HIGH-THROUGHPUT SCREENING UNDER STANDARD AND HIGH BIOCONTAINMENT CONDITIONS. HITS WILL BE COUNTERSCREENED AGAINST ALL CENTER TARGET FAMILIES, MOLECULAR VIRAL TARGETS AND MECHANISM OF ACTION CHARACTERIZED, AND A POTENCY, PHARMACOKINETICS, AND PHARMACOPHORE-DRIVEN SYNTHETIC DEVELOPMENT PROGRAM LAUNCHED TO IDENTIFY OPTIMIZED LEADS. ALL DATA GENERATED BY THE PROJECTS AND CORES WILL BE EVALUATED CENTER-WIDE UTILIZING QUANTITATIVE PERFORMANCE MILESTONES OF A DEFINED AC/DC LEAD ADVANCEMENT CASCADE THAT GOVERNS THE PROGRESSION OF A CHEMOTYPE FROM HIT TO CLINICAL DEVELOPMENT CANDIDATE.

TOGETHER TAKEMEHOME: ACHIEVING SCALE AND IMPROVING ACCESS TO MAILED HIV SELF-TESTING FOR KEY US POPULATIONS - EMORY UNIVERSITY, COLLABORATION WITH BUILDING HEALTHY ONLINE COMMUNITIES, SIGNAL GROUP, ORASURE TECHNOLOGIES, AND NASTAD PROPOSE A PROGRAM THAT WILL USE AN ITERATIVE IMPROVEMENT PROCESS TO OPTIMIZE OUR EXISTING WEB-BASED ORDERING AND FULFILLMENT SYSTEMS AND INTEGRATE WITH CDC'S LET'S END HIV TOGETHER MARKETING CAMPAIGNS TO PROVIDE AT LEAST 875,000 AND UP TO 1 MILLION MAILED HIV SELF-TESTS OVER THE 5 YEAR PROGRAM WITH A FOCUS ON KEY US POPULATIONS, INCLUDING MSM, TRANSGENDER WOMEN, BLACK OR AFRICAN AMERICAN CISGENDER WOMEN, AND OTHER RESIDENTS OF PHASE 1 EHE AREAS. THE OVERARCHING PUBLIC HEALTH GOAL OF THE PROGRAM IS TO INCREASE AWARENESS OF HIV STATUS AND IMPROVE UTILIZATION OF OTHER HIV PREVENTION AND CARE SERVICES LEADING TO IMPROVED HEALTH AND REDUCTION IN HIV TRANSMISSION AMONG US POPULATIONS DISPROPORTIONATELY AFFECTED BY HIV. THE SPECIFIC SHORT TERM OUTCOMES FROM THE PROGRAM ARE: 1) CULTURALLY APPROPRIATE IMAGERY AND INFORMATION DEVELOPED BY CDC AVAILABLE ON THE SELF-TEST ORDERING PORTAL; 2) FULLY FUNCTIONAL COMPREHENSIVE HIVST DISTRIBUTION PROGRAM FOR PROCUREMENT, STORAGE, PROCESSING OF ORDERS AND PROGRAM MONITORING; 3) INCREASED ACCESS TO HIV SELF-TESTS AND PREVENTION SERVICES INCLUDING PREP AND STI TESTING AMONG PERSONS DISPROPORTIONATELY AFFECTED BY HIV; 4) INCREASED UNDERSTANDING OF STRATEGIES TO SUCCESSFULLY DELIVER HIV SELF-TESTS TO POPULATIONS DISPROPORTIONATELY AFFECTED BY HIV; AND 5) INCREASED UNDERSTANDING OF USER EXPERIENCE FOR HIV SELF-TESTING AMONG POPULATIONS DISPROPORTIONATELY AFFECTED BY HIV. THERE ARE ALSO INTERMEDIATE TERM OUTCOMES FROM THE PROGRAM: 1) INCREASED HIV TESTING AMONG POPULATIONS DISPROPORTIONATELY AFFECTED BY HIV AND 2) INCREASED NEW HIV DIAGNOSES AMONG POPULATIONS DISPROPORTIONATELY AFFECTED BY HIV. THE TOGETHER TAKEMEHOME (TTMH) PROGRAM IS THE NATIONAL SCALE-UP OF OUR EXISTING TAKEMEHOME PROGRAM THAT FOCUSES ON PROVIDING INFRASTRUCTURE FOR STATE/LOCAL HEALTH DEPARTMENTS TO ENGAGE IN MAILED HIVST DISTRIBUTION FOR THEIR RESIDENTS. THIS STATE/LOCAL PROGRAM WAS THE BASIS FOR THE NATIONWIDE TTMH DEMONSTRATION PROJECT, WHICH WILL BE REFINED AND RELAUNCHED FOR THE SCALE-UP PROGRAM. THE PROGRAM IMPLEMENTATION MODEL INVOLVES COLLABORATING WITH CDC TO IMPLEMENT REFINEMENTS TO OUR SYSTEMS AND MATERIALS AND IMPLEMENT MARKETING EFFORTS TO REFER KEY POPULATIONS TO THE TTMH WEB-PORTAL FOR ORDERING. THESE ORDERS ARE AUTOMATICALLY PROCESSED AND SENT TO AMAZON FULFILLMENT SERVICES. WE WILL CONSISTENTLY COMMUNICATE WITH PARTICIPANTS ON ORDER STATUS AND SEND REMINDERS FOR REPEAT ORDERING. IN ADDITION TO SELF-SERVICE WEB-PORTAL RESOURCES, TRAINED STAFF WILL BE AVAILABLE TO PROVIDE REFERRALS TO HIV/STI CARE AND PREVENTION SERVICES, INCLUDING PROVISION OF PREP NAVIGATION. THE PROGRAM WILL BE MONITORED AND EVALUATED WITH DATA FROM MULTIPLE SOURCES, INCLUDING ORDER INFORMATION, WEB-TRAFFIC/REFERRAL TRACKING, SURVEYS, AND QUALITATIVE INTERVIEWS. TO OPTIMIZE PROGRAM OUTCOMES, ITERATIVE IMPROVEMENTS WILL BE MADE TO THE TTMH SYSTEMS AND MATERIALS AND PROVIDE TIMELY INFORMATION TO CDC FOR REFINEMENT OF THEIR MARKETING EFFORTS.

SUPPORT OF YERKES NATIONAL PRIMATE RESEARCH CENTER

EMORY HIV/AIDS CLINICAL TRIALS UNIT

SYSTEMS BIOLOGICAL ANALYSIS OF INNATE AND ADAPTIVE RESPONSES TO VACCINATION

EMORY WINSHIP CANCER INSTITUTE CANCER CENTER SUPPORT GRANT

B AND T CELL BIOLOGY OF PROTECTION FROM AND ERADICATION OF SIV/SHIV INFECTION

TRANSPLANT TOLERANCE IN NON-HUMAN PRIMATES

VACCINE AND TREATMENT EVALUATION UNITS

THE EMORY HEALTHY BRAIN STUDY: DISCOVERING PREDICTIVE BIOMARKERS FOR ALZHEIMER'S DISEASE - ABSTRACT/SUMMARY PROGRESS IN UNDERSTANDING ALZHEIMER’S DISEASE AND RELATED DISORDERS (ADRD) IS CLOSE TO PRODUCING MORE EFFECTIVE TREATMENTS, CREATING AN URGENT NEED FOR DISEASE-PREDICTIVE BIOMARKERS TO GUIDE THEIR USE. USING CEREBROSPINAL FLUID (CSF) MEASUREMENTS OF BETA-AMYLOID AND TAU AND POSITRON-EMISSION TOMOGRAPHY TRACERS, WE CAN DETECT AD PATHOLOGY IN COGNITIVELY NORMAL INDIVIDUALS. HOWEVER, CURRENT TOOLS DO NOT ALLOW US TO PREDICT WHEN OR EVEN IF AN INDIVIDUAL WITH ASYMPTOMATIC PATHOLOGY WILL DEVELOP SYMPTOMS. TO ADDRESS THIS NEED, WE PROPOSE TO LONGITUDINALLY STUDY =3000 COGNITIVELY NORMAL INDIVIDUALS (50-75 YEARS AT ENROLLMENT) IN THE EMORY HEALTHY BRAIN STUDY TO DEFINE THE FREQUENCY OF ASYMPTOMATIC AD AND RATES OF COGNITIVE DECLINE IN A RACIALLY DIVERSE COHORT OF HEALTHY INDIVIDUALS (SPECIFIC AIM 1). AN IMPORTANT GOAL OF AIM 1 IS TO ACHIEVE =33% AFRICAN- AMERICAN PARTICIPANTS TO PROVIDE SUFFICIENT POWER TO ADDRESS QUESTIONS REGARDING RACE- AND SEX-DEPENDENT DIFFERENCES IN BIOMARKERS AND RISK OF COGNITIVE DECLINE. PARTICIPANTS WILL BE PHENOTYPED BIENNIALLY WITH COGNITIVE TESTING, CARDIOVASCULAR PHYSIOLOGY, BRAIN MRI, AND BLOOD AND CSF COLLECTION. CROSS-SECTIONAL (SPECIFIC AIM 2) AND LONGITUDINAL ANALYSES (SPECIFIC AIM 3) WILL TEST THE HYPOTHESIS THAT BIOMARKERS OF SYNAPTIC, VASCULAR, MYELINATION, GLIAL IMMUNITY, AND METABOLIC FUNCTIONS WILL IDENTIFY SUBGROUPS WHO ARE AT GREATEST RISK OF PROGRESSING TO SYMPTOMATIC AD. CANDIDATE BIOMARKERS WILL BE IDENTIFIED THROUGH STATE-OF-THE-ART PROTEOMICS, MR IMAGING, AND STATISTICAL METHODS. A HIGHLY COLLABORATIVE DATA AND BIOSPECIMEN SHARING PLAN WILL ALLOW OTHER INVESTIGATORS TO LEVERAGE THESE RESOURCES TO ADVANCE A BROAD SPECTRUM OF ADRD RESEARCH.

B AND T CELL BIOLOGY OF PROTECTION FROM AND ERADICATION OF SIV/SHIV INFECTION - ABSTRACT THE EMORY CONSORTIUM FOR INNOVATIVE HIV/AIDS VACCINE AND CURE RESEARCH IN NONHUMAN PRIMATES AIMS TO DEFINE THE MECHANISMS OF THE B AND T CELL BIOLOGY OF PROTECTION FROM AND ERADICATION OF SHIV INFECTION. THE CONSORTIUM BRINGS TOGETHER AN INTERDISCIPLINARY MIX OF HIGHLY COLLABORATIVE, AND PRODUCTIVE INVESTIGATORS IN A RANGE OF HIV VACCINE AND CURE DISCIPLINES TO ADDRESS THE OVERARCHING HYPOTHESIS THAT THE SUCCESS OF THE PROPHYLACTIC HIV VACCINE WE HAVE DEVELOPED DURING THE CURRENT PROGRAM IS DUE TO A COMBINATION OF A STRONG AND SUSTAINED SYSTEMIC AND MUCOSAL IMMUNE RESPONSE. THIS IS COMPRISED OF MULTI-FUNCTIONAL ANTIBODY AND TISSUE RESIDENT CD8 T CELL IMMUNITY, WHICH UPON ENCOUNTERING COGNATE ANTIGEN RESPONDS THROUGH CONVENTIONAL CYTOLYTIC MECHANISMS AND THROUGH MODULATION OF THE MUCOSAL ENVIRONMENT, SUCH THAT RESPONDING HIV-SPECIFIC CD4+ T CELL ARE RESISTANT TO INFECTION. MOREOVER, WE POSTULATE THAT SUCH A POTENT AND BALANCED VACCINE RESPONSE WILL, IN THE CONTEXT OF ACTIVE LATENCY REVERSING AGENTS, REDUCE VIRAL RESERVOIRS AND THUS MAINTAIN SUPPRESSION OF VIRUS REPLICATION FOLLOWING CESSATION OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPY. THE APPROACHES IN FOCUS 1, AIMED AT UNDERSTANDING THE MECHANISMS OF VACCINE PROTECTION, WILL UTILIZE STATE OF THE ART TECHNIQUES AND ANALYSES TO FULLY CHARACTERIZE AND HARNESS A NOVEL POPULATION OF TISSUE RESIDENT CD8 T CELLS INDUCED BY OUR HETEROLOGOUS VIRAL VECTOR VACCINE (HVV VACCINE) ENCODING GAG AS AN IMMUNOGEN TO EFFECTIVELY SYNERGIZE WITH THE HUMORAL IMMUNE RESPONSE INDUCED BY OUR HIV ENVELOPE TRIMER VACCINE (PROTEIN VACCINE) CO-DELIVERED WITH NOVEL ADJUVANTS TO PROVIDE LONG-TERM PROTECTION AGAINST HETEROLOGOUS SHIV CHALLENGE EVEN IN THE ABSENCE OF STRONG NEUTRALIZING ANTIBODY RESPONSE. IN THE LATER YEARS WE WILL USE THIS NOVEL, MECHANISTIC INFORMATION TO OPTIMIZE THE VACCINE AND MOVE IT CLOSER TO CLINICAL STUDIES. IN FOCUS 2 WE WILL PURSUE, IN SHIV-INFECTED ART-TREATED MACAQUES, THE “SHOCK AND KILL” APPROACH TO INDUCE VIRUS EXPRESSION FROM LATENTLY INFECTED CELLS USING LATENCY REVERSAL AGENTS (LRAS) FOLLOWING THERAPEUTIC VACCINATION AIMED AT BOOSTING VIRUS- SPECIFIC IMMUNE RESPONSES ABLE TO CLEAR CD4 T CELLS IN WHICH VIRUS PRODUCTION HAS BEEN REACTIVATED. FIRST, WILL DETERMINE HOW THE HVV+PROTEIN VACCINE BEHAVES IN ART SUPPRESSED MACAQUES AND THEN STUDY ITS ABILITY TO DEPLETE THE RESERVOIR IN THE CONTEXT OF ACTIVE LRAS AND ITS IMPACT ON CONTROL OF VIRAL REBOUND. THESE EXPERIMENTAL APPROACHES WILL BE SUPPORTED BY AN EFFECTIVE OPERATIONS AND MANAGEMENT SUPPORT COMPONENT AND THREE STATE OF THE ART CENTRALIZED RESEARCH RESOURCES TO FULLY CHARACTERIZE THE MAGNITUDE, FUNCTION, SPECIFICITY AND REPERTOIRE OF THE HUMORAL RESPONSE. SINGLE CELL ANALYSIS AND TRANSCRIPTOMICS WILL ALSO SUPPORT CHARACTERIZATION OF INNATE AND ADAPTIVE SIGNALS AT THE CELLULAR LEVEL.

HOUSEHOLD AIR POLLUTION AND HEALTH: A MULTI-COUNTRY LPG INTERVENTION TRIAL

THE DIABETES MATCH INITIATIVE: MOBILIZING ACCESS THROUGH CAPACITY BUILDING AND HEALTH EQUITY - <![CDATA[THE PURPOSE OF THIS FUNDED PROJECT, A STRATEGIC APPROACH TO ADVANCING HEALTH EQUITY FOR PRIORITY POPULATIONS WITH OR AT RISK FOR DIABETES—SUBJECT MATTER EXPERTISE, TRAINING, AND TECHNICAL ASSISTANCE (CDC-RFA-DP-23-0021) IS TO SUPPORT THE GOALS OF THE COMPANION FUNDING OPPORTUNITY, A STRATEGIC APPROACH TO ADVANCING HEALTH EQUITY FOR PRIORITY POPULATIONS WITH OR AT RISK FOR DIABETES (CDC-RFA-DP23-0020). OVER THE NEXT FIVE YEARS, THE SUBJECT MATTER EXPERTISE, TRAINING, AND TECHNICAL ASSISTANCE PROVIDED BY THE EMORY CENTERS FOR PUBLIC HEALTH TRAINING AND TECHNICAL ASSISTANCE (EMORY CENTERS) AND ASSOCIATION OF DIABETES CARE & EDUCATION SPECIALISTS (ADCES) TEAM WILL STRENGTHEN AND BUILD NEW CAPACITIES OF THE DP-23-0020 RECIPIENTS TO SUCCESSFULLY ACHIEVE THE SPECIFIC OUTCOMES OF THEIR PROJECTS AND SHARED MEASURES OF COLLECTIVE IMPACT ACROSS PROJECTS TO DECREASE THE RISK FOR TYPE 2 DIABETES AMONG ADULTS WITH PREDIABETES AND IMPROVE SELF-CARE PRACTICES, QUALITY OF CARE, AND EARLY DETECTION OF COMPLICATIONS AMONG PRIORITY POPULATIONS WITH DIABETES. OUR SPECIFIC AIM IS TO INCREASE CAPACITY AMONG DP23-0020 RECIPIENTS TO IMPROVE HEALTH EQUITY, WITH THREE 5-YEAR IMPACT GOALS: 1) INCREASING ACCESS TO AND DELIVERY OF DIABETES MANAGEMENT; 2) INCREASING ACCESS TO AND DELIVERY OF TYPE 2 DIABETES PREVENTION; AND 3) INCREASING ACCESS TO AND DELIVERY OF RISK REDUCTION INTERVENTIONS FOR PRIORITY POPULATIONS. TOGETHER, EMORY CENTERS AND ADCES BRING AN INCREDIBLY RICH DIVERSITY OF NATIONWIDE SYSTEMS, COMMUNITY PARTNERS, AND SMES THAT WILL BE JOINING OUR NETWORK. OUR ORGANIZATIONS ARE HIGHLY RESPECTED, RECOGNIZED, AND TRUSTED BY OUR FUNDERS, PEERS, AND COMMUNITIES WE SERVE. COLLECTIVELY, WE ARE COMMITTED TO ENSURING THE QUALITY OF NATIONWIDE DIABETES PROGRAMS AND THEIR DELIVERY IN ALL PRIORITY POPULATIONS AND PROVIDING THE CAPACITY BUILDING FOR RECIPIENTS TO INCREASE ACCESS, UPTAKE, AND IMPACTFUL IMPLEMENTATION THROUGH LOCAL ADAPTATION AND FLEXIBILITY. OUR ORGANIZATIONAL MODEL TO ACCOMPLISH THE AIMS OF THIS WORK IS TO CREATE THE DIABETES MATCH INITIATIVE WHICH STANDS FOR MOBILIZING ACCESS THROUGH CAPACITY BUILDING AND HEALTH EQUITY. IT EMPHASIZES OUR EXPERIENCE WITH A COLLECTIVE IMPACT APPROACH THAT INTEGRATES THE STRENGTH OF EMORY-ADCES WORKING TOGETHER WITH OTHER SME COMMUNITY PARTNERS AND SYSTEMS IN ALL ASPECTS OF THE WORK. THIS WILL BE LED BY EMORY CENTERS’ EXECUTIVE DIRECTOR, DR. LINELLE BLAIS, WHO WILL SERVE AS THE EXECUTIVE DIRECTOR FOR THE MATCH INITIATIVE AND OVERSEE THE MANAGEMENT OF THE PROJECT AND ADVISE ON OVERARCHING STRATEGIC APPROACHES. DR. LILLIAN MADRIGAL, DIRECTOR OF IMPLEMENTATION SCIENCE AND PRACTICE AT EMORY CENTERS, WILL SERVE AS THE EMORY DIRECTOR ALONG WITH PAULINA DUKER, MPH, RN, CDCES, ADCES’ VICE PRESIDENT OF PRACTICE & LEARNING AS THE ADCES DIRECTOR. THERE WILL BE SIX CORE TEAMS WITH LEADS REPRESENTING BOTH EMORY AND ADCES; THREE TEAMS ARE ALIGNED TO THE THREE STRATEGY AREAS (SME NETWORK, TRAINING & TA, GUIDANCE DOCUMENTS & RESOURCES), AND THREE TEAMS ARE ALIGNED TO CROSS STRATEGY CORES (HEALTH EQUITY FOR PRIORITY POPULATIONS, PROGRAM EVALUATION & HEALTH EQUITY STUDIES, AND COMMUNICATIONS & DESIGN). CORES WILL BE LED BY EXPERTS IN DIABETES, HEALTH EQUITY, TRAINING, AND TA (DESCRIBED IN THE POSITION DESCRIPTIONS). LASTLY, THE MATCH INITIATIVE WILL ALSO INCLUDE THE MATCH INITIATIVE ADVISORY GROUP MADE UP OF SELECT REPRESENTATIVES FROM THE DP23-0020 RECIPIENTS AND PARTNERS FROM OUR SME NETWORK.]]>

ENTERPRISE FOR RESEARCH AND ADVOCACY TO STOP AND ERADICATE HIV (ERASE-HIV) - ABSTRACT THE PRESENCE OF A RESERVOIR OF CELLS HARBOURING INTEGRATED, REPLICATION-COMPETENT VIRUS THAT PERSISTS UNDER LONG- TERM, FULLY SUPPRESSIVE ANTIRETROVIRAL THERAPY (ART) AND THE INABILITY OF THE HOST IMMUNE RESPONSES TO CONTROL THE INITIAL EVENTS OF VIRAL REPLICATION THAT FOLLOW ART INTERRUPTION ARE CRITICAL BARRIERS TO CURING HIV INFECTION. THUS, NOVEL THERAPEUTIC STRATEGIES TO REMOVE THESE BARRIERS ARE CRITICALLY NEEDED. THE OVERARCHING HYPOTHESES OF ERASE HIV ARE: (I) DECREASED AND/OR DYSFUNCTIONAL CD8+ T AND NK CELL ANTIVIRAL FUNCTIONS, COMBINED WITH THE RECENTLY-DESCRIBED CD8+ T-CELL-MEDIATED TRANSCRIPTIONAL SILENCING OF HIV, FAVOUR HIV PERSISTENCE UNDER ART AND PREVENT THE CONTROL OF VIREMIA IF ART IS STOPPED; AND (II) NOVEL APPROACHES TO ELICIT EFFECTIVE CD8+ T-CELL, NK CELL, AND ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY (ADCC) FUNCTIONS WHILE INHIBITING THE CD8+ T-CELL-MEDIATED VIRUS SILENCING WILL PROMOTE REMISSION AND/OR ERADICATION OF HIV. THE OVERARCHING GOAL OF ERASE HIV IS TO IDENTIFY NOVEL MECHANISMS OF HIV PERSISTENCE AND TO TEST THEM IN THE MOST RELEVANT PRE-CLINICAL ANIMAL MODELS THROUGH MECHANISTICALLY-ORIENTED, COMMUNITY-SUPPORTED THERAPEUTIC STRATEGIES THAT CAN BE ULTIMATELY TRANSLATED TO CURE HIV INFECTION IN HUMANS. ERASE HIV INCLUDES THREE HIGHLY INTEGRATED RESEARCH FOCI (RFS). RF1 IS AIMED AT IDENTIFYING THE MOLECULAR AND CELLULAR MECHANISMS UNDERLYING THE TWO DISTINCT ANTIVIRAL ACTIVITIES OF CD8+ T-CELLS: THE MHC-RESTRICTED, AG-SPECIFIC RESPONSE THAT DIRECTLY ELIMINATES VIRUS-INFECTED CELLS, AND THE NON-MHC RESTRICTED, NON-CYTOLYTIC SILENCING OF HIV TRANSCRIPTION. AS SUCH, RF1 WILL PROVIDE THE CONCEPTUAL BASIS FOR THE INTERVENTIONS TESTED IN RF2 AND RF3. RF2 WILL USE ANIMAL MODELS OF ART-TREATED HIV INFECTION TO (I) RESTORE CD8+ T AND NK CELL FUNCTION WITH A COMBINED A-IL-10 AND IL-15 SUPERAGONIST (N-803) STRATEGY; (II) TARGET REBOUNDING VIRUS BY USING A CD4-MIMETIC COMPOUND (CD4MC) TO ENHANCE ANTIBODY RECOGNITION OF CELLS EXPRESSING HIV ENV AND THEIR ELIMINATION VIA ADCC; AND (III) DETERMINE IF IMPROVING CD8 T AND NK CELL FUNCTION VIA A-IL-10 AND N- 803 SYNERGIZES WITH CD4MC TO CLEAR INFECTED CELLS. RF3 WILL DETERMINE IF SUPPRESSION OF THE LATENCY-PROMOTING ACTIVITY OF CD8+ T-CELLS, COUPLED WITH N-803 AND INTERVENTIONS TO PROMOTE APOPTOSIS (BCL-2 INHIBITORS) OR IMMUNE- MEDIATED REMOVAL (CD4MC) OF CELLS THAT HAVE REACTIVATED VIRUS, WILL REDUCE THE RESERVOIR SIZE. IN ALL, WE WILL EXPLOIT THE SYNERGY BETWEEN THE MECHANISTIC DATA GENERATED IN RF1 AND THE IN VIVO INTERVENTIONS IN RF2 AND RF3 TO VALIDATE A STRATEGY THAT TARGETS BOTH HIV PERSISTENCE DURING ART AND HIV RECRUDESCENCE AFTER ART INTERRUPTION. ERASE HIV IS SUPPORTED BY EXPERTS IN HIV ADVOCACY (SISTERLOVE); RECOGNITION AND KILLING OF HIV ENV-EXPRESSING CELLS (FINZI/SODROSKI); T AND NK CELL BIOLOGY (SEKALY/RIBEIRO/DELEAGE/PARSONS); RESERVOIR ASSAYS AND LATENCY MODELS (KULPA/JONES/LITCHTERFELD/HOWELL); PRE-CLINICAL ANIMAL STUDIES (PAIARDINI/SILVESTRI/GARCIA/SAEZ- CIRION/KEELE/KUMAR); MATHEMATICAL MODELLING (DAVENPORT); AND THERAPEUTICS DEVELOPMENT (MERCK AND IMMUNITYBIO) FOR HIV CURE. WE BELIEVE THAT THE PROPOSED MECHANISTICALLY-ORIENTED PRE-CLINICAL WORK WILL INFORM STRATEGIES THAT CAN BE TRANSLATED IN CLINICAL TRIALS TO ACHIEVE PROLONGED VIRAL REMISSION IN PWH.

ATLANTA CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTE (ACTSI) RENEWAL

PLASMA CELLS IN HEALTH AND DISEASE

CUREIT: CURING THE UNCURABLE VIA RNA-ENCODED IMMUNOGENE TUNING - MORE THAN 25 MILLION AMERICANS CURRENTLY LIVE WITH AUTOIMMUNE DISEASE, AND ALMOST TWO MILLION ARE PROJECTED TO BE DIAGNOSED WITH CANCER IN 2023. IMMUNE DYSREGULATION IS AN UNDERLYING COMPONENT OF NOT ONLY CANCER AND AUTOIMMUNE DISEASES, BUT ALSO INFECTIOUS DISEASES, TRANSPLANT REJECTION, AND OTHER COMMON MEDICAL CONDITIONS. CURRENT METHODS OF IMMUNE MODULATION USED TO TREAT AND MITIGATE THESE CONDITIONS ARE OFTEN EXPENSIVE OR NOT COMPLETELY EFFECTIVE. CURING THE UNCURABLE VIA RNA-ENCODED IMMUNOGENE TUNING (CUREIT) AIMS TO ADDRESS IMMUNE DYSREGULATION BY DIRECTLY PROGRAMMING IMMUNE CELL FUNCTION. ADVANCES IN GENE-ENCODED TECHNOLOGY WILL BE LEVERAGED TO DEVELOP A PLATFORM CAPABILITY ABLE TO BOTH ENHANCE PROTECTIVE IMMUNE RESPONSES AS WELL AS MODULATE INSUFFICIENT OR INEFFECTIVE IMMUNE PROFILES. CUREIT SEEKS TO DEVELOP A DISEASE-AGNOSTIC TOOLBOX OF METHODS AND TECHNOLOGIES, INCLUDING THE IN VIVO DELIVERY OF MRNA-BASED DRUGS, CELL TARGETING LIPID NANOPARTICLES, AND EX VIVO MODULATION OF IMMUNE CELLS. THIS TECHNOLOGY HAS THE POTENTIAL TO MAKE SIGNIFICANT ADVANCEMENTS TOWARDS MANAGING OR ELIMINATING MANY DISEASES AND CONDITIONS AFFECTING ALL AGES AND DEMOGRAPHICS, INCLUDING DISEASES WHICH ARE CURRENTLY UNTREATABLE.

INSTITUTIONAL RESEARCH AND ACADEMIC CAREER DEVELOPMENT

ATLANTA CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTE (UL1)

PROTECT III

SILVIO O. CONTE CENTER FOR OXYTOCIN AND SOCIAL COGNITION

ATLANTA MACS/WIHS COMBINED COHORT STUDY CLINICAL RESEARCH SITE

EMERGENCY FINANCIAL AID GRANTS TO INSTITUTIONS UNDER THE CORONAVIRUS AID, RELIEF, AND ECONOMIC SECURITY (CARES) ACT

THE EMORY ALZHEIMER'S DISEASE CENTER

B-CELL BIOLOGY OF MUCOSAL IMMUNE PROTECTION FROM SIV CHALLENGE

HERCULES: HEALTH AND EXPOSOME RESEARCH CENTER AT EMORY

CCI CENTER IN SELECTIVE C-H FUNCTIONALIZATION

DIVERSE ROLES OF REACTIVE OXYGEN SPECIES AND INFLAMMATION IN VASCULAR DISEASE

MECHANISMS OF RISK AND RESILIENCE IN ASD: ONTOGENY, PHYLOGENY AND GENE DISRUPTION

EMORY ALZHEIMER'S DISEASE RESEARCH CENTER

ROLE OF ANTIGEN-SPECIFIC T CELL RESPONSES IN THE CONTROL OF TB

NSF CENTER FOR SELECTIVE CH FUNCTIONALIZATION

EMERGENCY FINANCIAL AID GRANTS TO STUDENTS UNDER THE CORONAVIRUS AID, RELIEF, AND ECONOMIC SECURITY (CARES) ACT

CTL AND HIV POLYMORPHISMS IN HETEROSEXUAL TRANSMISSION

SERIOUS HAZARDS OF TRANSFUSION & CELLULAR THERAPIES: MECHANISMS AND INTERVENTION

AIDS EDUCATION TRAINING CENTERS

MAINTENANCE OF THE SPF BREEDING COLONIES AT YERKES NATIONAL PRIMATE RESEARCH CENTER

EMORY WIHS CRS - LONGITUDINAL COHORT

CONSTRUCTION OF A DUAL FUNCTION PRIMATE FACILITY: ABSL3 AND TRANSPLANT MEDICINE

CARDIAC ARREST REGISTRY TO ENHANCE SURVIVAL (CARES) EXPANSION AND MODERNIZATION

HARVARD/MICHIGAN PROSTATE CANCER BIOMARKER CLINICAL CTR

EMORY PREVENTION RESEARCH CENTER

MEDICAL SCIENTIST TRAINING PROGRAM

NATIONAL EBOLA TRAINING AND EDUCATION CENTER (NETEC) SUPPLEMENT

GEORGIA DIABETES TRANSLATION RESEARCH CENTER

EMORY HIV/AIDS CLINICAL TRIALS UNIT

INSTITUTIONAL CAREER DEVELOPMENT

PD-1 FUNCTION, SIGNALING, AND REGULATION DURING VIRAL INFECTION

BIOLOGICAL VARIATION IN HEMOPHILIA

MORRIS K. UDALL CENTERS OF EXCELLENCE FOR PARKINSON'S DISEASE RESEARCH AT EMORY UNIVERSITY - PROJECT SUMMARY – OVERALL CENTER THE MORRIS K. UDALL PARKINSON'S DISEASE CENTER OF EXCELLENCE FOR PARKINSON’S DISEASE RESEARCH AT EMORY UNIVERSITY IS A COLLABORATIVE RESEARCH PROGRAM THAT STUDIES THE PATHOPHYSIOLOGY OF PARKINSONISM WITH THE GOAL OF OPTIMIZING THE TREATMENT FOR PARKINSON’S DISEASE (PD). THE CENTER DRAWS UPON THE PROVEN ABILITY OF THE BASAL GANGLIA RESEARCH COMMUNITY AT EMORY TO CONDUCT COLLABORATIVE TRANSLATIONAL RESEARCH. OTHER UDALL CENTER ASSETS ARE THE AVAILABILITY OF PRIMATES FOR RESEARCH AT THE YERKES NATIONAL PRIMATE RESEARCH CENTER AT EMORY, AND THE PRESENCE OF ONE OF THE LARGEST MOVEMENT DISORDERS CLINIC IN THE US. THE CENTER CONSISTS OF FOUR PROJECTS AND THREE CORES. THE PLANNED RESEARCH WILL SHED LIGHT ON THE POORLY UNDERSTOOD PARKINSONISM-RELATED ACTIVITY CHANGES OF SPECIFICALLY IDENTIFIED GROUPS OF PROJECTION NEURONS IN THE CEREBRAL CORTEX WHICH, IN TURN, WILL HELP US TO BETTER UNDERSTAND THE PATHOPHYSIOLOGY OF PARKINSONISM, AND TO OPTIMIZE THERAPEUTIC STRATEGIES. PROJECT 1 (LED BY DR. JAEGER) WILL UTILIZE RODENT EXPERIMENTS FOR LARGE-SCALE VOLTAGE IMAGING AND BRAIN SLICE RECORDINGS AND USE NEURAL COMPUTATIONAL APPROACHES TO DEVELOP MECHANISTIC MODELS OF CORTICAL DYSFUNCTION IN PARKINSONISM. PROJECT 2 (DR. GALVAN), WILL EXPLORE THE SPONTANEOUS AND TASK-RELATED ACTIVITY OF CORTICOSTRIATAL AND CORTICOSPINAL NEURONS IN THE PRIMARY MOTOR CORTEX (M1) AND THE SUPPLEMENTARY MOTOR AREA (SMA) IN NORMAL AND PARKINSONIAN MONKEYS, USING AN OPTO-TAGGING APPROACH TO IDENTIFY THE PROJECTION TARGETS OF THE RECORDED NEURONS. PROJECT 3 (DR. SMITH) WILL EXAMINE MORPHOLOGICAL CHANGES IN THE M1 AND SMA MICROCIRCUITRY AND PARKINSONISM-ASSOCIATED CHANGES IN THE CONNECTOME OF CORTICAL PROJECTION NEURONS IN PRIMATES, A TOPIC THAT IS VIRTUALLY UNEXPLORED AND OF HIGH RELEVANCE TO THE INTERPRETATION OF DATA IN PROJECTS 1 AND 2. THE CLINICAL ‘CATALYST’ PROJECT 4 IS AN EXAMINATION OF PARKINSONISM-RELATED CHANGES IN CORTICAL ACTIVITY IN RESPONSE INHIBITION TASKS, STUDIED IN ELECTROCORTICOGRAPHY AND ELECTROENCEPHALOGRAPHY SIGNALS IN PATIENTS WITH PD. THE FUNCTIONAL EXPERIMENTS WILL ALSO STUDY THE EFFECTS OF LEVODOPA AND DEEP BRAIN STIMULATION TREATMENTS IN THESE PARADIGMS. ALL PROJECTS WILL BE SUPPORTED BY AN ADMINISTRATIVE CORE (CORE A, DR. WICHMANN, PI; DR. SMITH, ASSOCIATE DIRECTOR, MS HOLBROOK, ADMINISTRATOR), AND BY A SERVICE CORE THAT PROVIDES ANATOMICAL SERVICES TO PROJECTS 1 AND 2, BEHAVIORAL ASSESSMENTS TO PROJECTS 2 AND 3, AND STATISTICAL SERVICES TO ALL PROJECTS (CORE B, DR. GALVAN). A CLINICAL CORE (CORE C) WILL SUPPORT PROJECT 4 WITH RECRUITMENT AND LOGISTIC SERVICES FOR THE HUMAN STUDIES. IN ADDITION TO PURSUING ITS RESEARCH MISSION (AIM 1), THE CENTER WILL HELP YOUNG SCIENTISTS TO DEVELOP THEIR CAREER IN PD RESEARCH (AIM 2), AND WILL ENGAGE IN EXTENSIVE OUTREACH EFFORTS, AIMED AT COMMUNICATING THE CENTER’S (AND UDALL CENTER NETWORK) RESEARCH FINDINGS TO THE PUBLIC (AIM 3), REACHING ALL AGE GROUPS AND BACKGROUND LEVELS. AS PART OF THE OUTREACH AGENDA, THE CENTER PLANS TO ORGANIZE ANNUAL OUTREACH EVENTS FOR PATIENTS AND THEIR CAREGIVERS. GENEROUS INTERNAL SUPPORT FUNDS WILL HELP THE CENTER TO FUND SOME OF ITS EDUCATION AND OUTREACH MISSIONS, AS WELL AS ITS PILOT GRANT PROGRAM, DESIGNED TO EXPAND PD RESEARCH AT EMORY.

A HUMAN FACTORS APPROACH TO STRENGTHENING INFECTION PREVENTION AND CONTROL

TARGETING MTOR AND CD40 PATHWAYS FOR ADJUVANTING HIV VACCINES

EMORY-GSK-NIMH COLLABORATIVE MOOD DISORDERS INITIATIVE

P30- CORE GRANT FOR VISION RESEARCH

MENTAL STRESS ISCHEMIA: PROGNOSIS AND GENETIC INFLUENCES

HETERORESISTANCE INTERDISCIPLINARY RESEARCH UNIT - ABSTRACT ANTIBIOTIC RESISTANCE IS ONE OF THE MOST SERIOUS MEDICAL CHALLENGES OF OUR TIME. THIS CRISIS PUTS PATIENTS AT RISK OF UNTREATABLE BACTERIAL INFECTIONS AND THREATENS MAJOR ADVANCES OF MODERN MEDICINE THAT RELY ON ANTIBIOTICS (TRANSPLANTS, CHEMOTHERAPY, ETC). THERE ARE AT LEAST 2.8 MILLION ANTIBIOTIC RESISTANT INFECTIONS EACH YEAR IN THE US, LEADING TO OVER 35,000 DEATHS [1]. WITHOUT SIGNIFICANT ACTION, WORLDWIDE ANNUAL MORTALITY DUE TO THESE INFECTIONS IS PREDICTED TO REACH 10 MILLION BY 2050, SURPASSING THAT PREDICTED FOR CANCER [2]. UNDERSTANDING RESISTANCE MECHANISMS IS CRITICAL TO DESIGNING NOVEL APPROACHES AND THERAPEUTICS TO COMBAT RESISTANT BACTERIA. HETERORESISTANCE (HR) IS AN ENIGMATIC FORM OF ANTIBIOTIC RESISTANCE IN WHICH A BACTERIAL ISOLATE HARBORS A RESISTANT SUBPOPULATION THAT CAN RAPIDLY REPLICATE IN THE PRESENCE OF AN ANTIBIOTIC, WHILE A SUSCEPTIBLE SUBPOPULATION IS KILLED [3, 4]. NOT ONLY DO MANY SPECIES OF BACTERIA EXHIBIT THIS FORM OF PHENOTYPIC RESISTANCE, BUT IT HAS BEEN REPORTED AGAINST NEARLY ALL CLASSES OF ANTIBIOTICS [3, 5, 6]. UNFORTUNATELY, OUR UNDERSTANDING OF HR IS EXTREMELY LIMITED AND ITS RELEVANCE DURING INFECTION HAS BEEN UNCLEAR. WE RECENTLY DEMONSTRATED THAT HR TO DIVERSE ANTIBIOTICS, INCLUDING THE LAST-LINE ANTIBIOTIC COLISTIN, CAN CAUSE TREATMENT FAILURE IN AN IN VIVO MODEL [4, 5, 7]. FURTHERMORE, WHEN THE FREQUENCY OF THE RESISTANT SUBPOPULATION IS VERY LOW (<1 IN 10,000 CELLS) HR IS MISCLASSIFIED AS SUSCEPTIBLE BY CLINICAL DIAGNOSTIC TESTS, YET IS STILL ABLE TO MEDIATE TREATMENT FAILURE [4]. OUR SURVEILLANCE DATA REVEAL THAT HR TO DIVERSE CLASSES OF ANTIBIOTICS IS WIDESPREAD EVEN AMONG HIGHLY RESISTANT CARBAPENEM-RESISTANT ENTEROBACTERIACEAE (CRE) AND ACINETOBACTER BAUMANNII (CRAB). FURTHER, WE RECENTLY DISCOVERED THAT TARGETING PAN-RESISTANT BACTERIA WITH TWO ANTIBIOTICS TO WHICH A STRAIN EXHIBITS HR RELIABLY LEADS TO EFFECTIVE COMBINATION THERAPY, HIGHLIGHTING THAT KNOWLEDGE OF HR CAN BE USED TO GUIDE EFFECTIVE THERAPIES [5]. TAKEN TOGETHER, THESE DATA HIGHLIGHT A LARGELY UNAPPRECIATED AND UNDETECTED EPIDEMIC OF HR IN THE CLINIC THAT MAY CAUSE UNEXPLAINED ANTIBIOTIC TREATMENT FAILURE BUT CAN ALSO BE EXPLOITED THERAPEUTICALLY. THE HETERORESISTANCE INTERDISCIPLINARY RESEARCH UNIT (HR-IRU) BRINGS TOGETHER AN INTERDISCIPLINARY TEAM OF EXPERTS IN AN UNPRECEDENTED EFFORT TO UNDERSTAND THE MECHANISMS, DYNAMICS, AND PREVALENCE OF HR. THE PROPOSED PROJECTS, SUPPORTED BY CLINICAL ISOLATE AND SINGLE-CELL ANALYSIS CORES, WILL USE A COMBINATION OF GENETICS, SINGLE CELL MICROSCOPY, DYNAMIC FLOW AND IN VIVO INFECTION STUDIES, MODELING, AND EPIDEMIOLOGICAL ANALYSES TO MAKE FOUNDATIONAL INSIGHTS INTO HR. AT A BASIC LEVEL, THIS WORK WILL SIGNIFICANTLY BROADEN OUR UNDERSTANDING OF HOW TRAITS EXHIBITED BY SUBPOPULATIONS OF CELLS CAN IMPACT BACTERIAL PHYSIOLOGY. AT A TRANSLATIONAL LEVEL, THIS EFFORT WILL BE A CRITICAL STEP IN OUR FIGHT AGAINST ANTIBIOTIC RESISTANT BACTERIA AND LAY THE FOUNDATION FOR THE DISCOVERY OF NOVEL THERAPEUTICS, DIAGNOSTICS, AND APPROACHES TO ALLEVIATE HUMAN SUFFERING.

B CELLS IN HEALTH AND DISEASE

EMORY CENTER FOR INFECTIOUS DISEASE MODELING & ANALYTICS AND TRAINING HUB (CIDMATH)

EMORY PREVENTION RESEARCH CENTER

RAPID DEVELOPMENT AND DEPLOYMENT OF NON-PHYSICIAN PROVIDERS IN CRITICAL CARE

GENE DISCOVERIES IN SUBJECTS WITH CROHN'S DISEASE OF AFRICAN DESCENT

SPINAL CIRCUITS AND THE MUSCULOSKELETAL SYSTEM

CD40L ADJUVANTED CLADE C DNA AND MVA HIV VACCINES

PRESERVING RENAL FUNCTION & PROTECTIVE IMMUNITY VIA ANTI-LFA1-BASED CNI AVOIDANCE

EMORY UNIVERSITY LUNG CANCER SPORE

CORRELATES OF PROTECTIVE IMMUNITY TO HCV AND RATIONAL VACCINE DESIGN - ABSTRACT PREVENTION OF HCV INFECTION REMAINS AN IMPORTANT PUBLIC HEALTH OBJECTIVE EVEN WITH THE RECENT ADOPTION OF HIGHLY EFFECTIVE ANTIVIRAL THERAPIES. IMPORTANTLY, TREATMENT WITH DIRECT ACTING ANTIVIRALS (DAAS) DOES NOT PREVENT REINFECTION IN THOSE WHO HAVE SUCCESSFULLY BEEN TREATED. A VACCINE TO PREVENT HCV PERSISTENCE IS NEEDED TO STEM AN EMERGING EPIDEMIC OF INFECTION IN ADOLESCENTS AND YOUNG ADULTS WHO INJECT DRUGS THAT HAVE LIMITED ACCESS TO SCREENING AND TREATMENT. ONLY TWENTY FIVE PERCENT OF ACUTE HCV INFECTIONS RESOLVE SPONTANEOUSLY. RESOLUTION DOES, HOWEVER, SHARPLY REDUCE THE RISK OF PERSISTENT INFECTION UPON RE-EXPOSURE TO THE VIRUS. MEMORY CD4+ T HELPER AND CD8+ CYTOTOXIC T CELL RESPONSES CONTRIBUTE TO ACCELERATED CLEARANCE OF A SECOND INFECTION. HOWEVER, THE ROLE OF NEUTRALIZING ANTIBODIES DURING REINFECTION IS LESS CLEAR. IMPORTANTLY, VACCINES TO GENERATE AN EQUIVALENT T CELL RESPONSE FAILED TO THWART OFF THE RATE OF PERSISTENCE IN NAÏVE RECIPIENTS. HERE, WE WILL TEST THE CENTRAL HYPOTHESIS THAT MEMORY CD4+ T CELLS CONTRIBUTE SIGNIFICANTLY TO HCV REINFECTION OUTCOME BY PROMOTING EXPANSION OF HCV-SPECIFIC B CELLS AND PRODUCTION OF BROADLY NEUTRALIZING ANTIBODIES THAT CONTRIBUTE TO VIRAL CLEARANCE. UNIQUE FEATURES OF THIS PROPOSAL ARE (I) THE USE OF LONGITUDINAL SAMPLES FROM THE MONTREAL COHORT OF HIGH- RISK PEOPLE WHO INJECT DRUGS. PARTICIPANTS ARE MONITORED PRIOR TO, DURING, AND AFTER HCV INFECTION AND THEN SUBSEQUENTLY FOLLOWED AGAIN WHEN THEY HAVE BEEN RE-EXPOSED TO HCV A SECOND TIME AFTER RESOLVING THEIR PRIMARY INFECTION. (II) WE HAVE ASSEMBLED A TEAM OF INVESTIGATORS IN CAIRO, EGYPT WHO WILL ASSIST US WITH RECRUITING AND TREATING SUBJECTS UNDERGOING DAA TREATMENT. EGYPT HAS THE HIGHEST PREVALENCE OF HCV INFECTION IN THE WORLD. IN 2014, EGYPT'S GOVERNMENT HAS MADE DAA TREATMENT AFFORDABLE AND 2.5 MILLION SUBJECTS HAVE STARTED TREATMENT. UNDERSTANDING THE IMMUNE RESPONSES IN THESE TWO COHORTS WILL PROVIDE US WITH VALUABLE INFORMATION TO DEVELOP AN EFFICACIOUS VACCINE REGIMEN THAT WOULD EMULATE THE SUCCESSFUL RESPONSES GENERATED DURING A NATURAL CHALLENGE WITH HCV. THREE HIGHLY INTERACTIVE PROJECTS ARE PROPOSED. PROJECT 1 (N. SHOUKRY, PI) WILL COMPARE THE FREQUENCY, BREADTH, FUNCTION, AND PHENOTYPE OF CD4+ T CELLS IN HCV REINFECTIONS THAT EITHER RESOLVE OR BECOME PERSISTENT. PROJECT 2 (A. GRAKOUI, PI) WILL USE NEW STATE OF THE ART TECHNOLOGY TO ISOLATE AND CHARACTERIZE ANTIGEN-SPECIFIC B CELLS DURING HCV REINFECTION AND POST DAA TREATMENT. PROJECT 3 (R. AMARA, PI) WILL DEVELOP VACCINE MODALITIES TO INDUCE BOTH A CD4+ T HELPER RESPONSE AND A ROBUST ANTIGEN-SPECIFIC ANTIBODY RESPONSE IN BLOOD AND LIVER USING DNA, MODIFIED VACCINIA ANKARA (MVA) AND PROTEIN-BASED VACCINES AGAINST HCV PROTEINS IN NON-HUMAN PRIMATES.

MOLECULAR LEVEL STUDIES OF SOLID-LIQUID INTERFACES IN ELECTROCHEMICAL PROCESSES

ADDITIONAL EFFORT FOR DARPA GRANT ENTITLED, "DEVELOPMENT OF ANTIBODIES THERAPEUTICS AGAINST EBOLA"

SPORE IN HEAD AND NECK CANCER

?RESETTING IMMUNE HOMEOSTASIS: A NON-INVASIVE APPROACH TOWARDS HIV ERADICATION

EVOLUTION OF AGING AND DEMENTIA IN FEMALE PRIMATES

IMMUNE REGULATION OF COVID-19 INFECTION IN CANCER AND AUTOIMMUNITY

EXPANDING THE NORDP CONSULTANTS PROGRAM TO SIXTEEN MINORITY SERVING INSTITUTIONS -THE NSF GROWING RESEARCH ACCESS FOR NATIONALLY TRANSFORMATIVE EQUITY AND DIVERSITY (GRANTED) INITIATIVE SEEKS TO SUPPORT THE DEVELOPMENT OF THE RESEARCH SUPPORT AND SERVICE INFRASTRUCTURE TO ADDRESS THE COMPLEXITY OF SECURING AND MANAGING EXTERNAL FUNDING, PARTICULARLY AT EMERGING RESEARCH AND MINORITY SERVING INSTITUTIONS (ERIS AND MSIS). THIS PROJECT FROM THE NATIONAL ORGANIZATION OF RESEARCH DEVELOPMENT PROFESSIONAL (NORDP) EXPANDS ON PRIOR SUCCESSFUL EFFORTS WORKING WITH HISTORICALLY BLACK COLLEGES AND UNIVERSITIES AND FOCUSES ON PROVIDING FUNDAMENTAL RESEARCH DEVELOPMENT RESOURCES. RESEARCH DEVELOPMENT REFERS TO STRATEGIC, CATALYTIC, AND CAPACITY-BUILDING ACTIVITIES THAT ADVANCE RESEARCH. THIS PROJECT TESTS HOW THE DIVERSITY OF THE U.S. NATIONAL RESEARCH ECOSYSTEM CAN BE ENHANCED BY PROVIDING RESEARCH DEVELOPMENT SERVICES TO MSIS. IN THIS PROJECT, THE NORDP CONSULTANTS PROGRAM WILL EXTEND SUPPORT TO 16 MINORITY SERVING INSTITUTIONS ACROSS FOUR NEW COHORTS OF FOUR MSIS EACH. EACH SCHOOL WILL RECEIVE 600 HOURS OF CONSULTING TIME FROM EXPERIENCED NORDP CONSULTANTS OVER TWO YEARS AND GAIN ACCESS TO AN ARRAY OF OTHER RESEARCH DEVELOPMENT SUPPORTS FOR THE DURATION OF THE PROJECT PERIOD. THE PROGRAM WILL ALSO PROMOTE NETWORK CREATION AMONG THE INSTITUTIONS SELECTED, THROUGH COHORT COMMUNITY BUILDING EVENTS AND PARTICIPATION IN AN ANNUAL NATIONAL CONFERENCE. FORMATIVE AND SUMMATIVE EVALUATION ACTIVITIES ARE INCLUDED TO ASSESS THE EFFECTIVENESS OF THE APPROACH. THE PROJECT REPRESENTS AN INNOVATIVE, NOVEL, AND POTENTIALLY TRANSFORMATIVE MODEL OF HOW PROFESSIONAL SOCIETIES CAN WORK WITH ERIS AND MSIS, TO PROVIDE MORE EQUITABLE ACCESS TO RESOURCES THAT WILL INCREASE RESEARCH CAPACITY AND COMPETITIVENESS, ULTIMATELY STRENGTHENING THE NATION?S RESEARCH ENTERPRISE. 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 NOT PLANNED FOR THIS AWARD.

EMORY SPECIALIZED CENTER OF RESEARCH EXCELLENCE (SCORE) ON SEX DIFFERENCES

VIROLOGIC CORRELATES OF HETEROSEXUAL TRANSMISSION

TARGETING PD-1 PATHWAY FOR FUNCTIONAL CURE OF AIDS

POPULATION-BASED SURVEY OF SARS-COV-2 INFECTION AND IMMUNE RESPONSE

MODIFIERS OF FMR1-ASSOCIATED DISORDERS: APPLICATION OF HIGH THROUGHPUT TECHNOLOGI

PRECISION CARDIOVASCULAR DISEASES PHENOTYPING AND PATHOPHYSIOLOGICAL PATHWAYS IN THE CARRS COHORT (PRECISION-CARRS) - PROJECT SUMMARY / ABSTRACT (OVERALL) PRECISION-CARRS WILL REVOLUTIONIZE THE CARDIOVASCULAR DISEASE (CVD) PREVENTION AND CARE PARADIGM FROM IMPRECISE PREDICTION WITH FOCUS ON LATE STAGE DISEASE TO PERSONALIZED AND PRECISE PREDICTION WITH IMPROVED UNDERSTANDING OF EARLY-STAGE DISEASE TO MAINTAIN CARDIOVASCULAR HEALTH. ATHEROSCLEROTIC CVD (ASCVD) AND HEART FAILURE (HF) PHENOTYPES ARE HETEROGENEOUS AND RESULT FROM COMPLEX INTERACTIONS BETWEEN IMMUTABLE GENETIC FACTORS AND MUTABLE FORCES OPERATING AT ENVIRONMENTAL (E.G., AMBIENT AIR QUALITY), INDIVIDUAL (E.G., HEALTH BEHAVIORS, SOCIAL INFLUENCE), AND MOLECULAR (E, G, PROTEINS, 'OMICS) LEVELS. SOUTH ASIANS ARE AN UNDERSTUDIED POPULATION AT HIGH CVD RISK EVEN AT YOUNG AGES, AT LOW BODY WEIGHT, AND IN THE ABSENCE OF TRADITIONAL RISK FACTORS. WE WILL LEVERAGE SUBSTANTIAL MATCHED RESOURCES, AND ALSO BUILD UPON THE NHLBI- FUNDED CARRS COHORT, A REPRESENTATIVE SAMPLE OF N=21,864 SOUTH ASIANS AGED = 20 YEARS, WITH ONGOING FOLLOW-UP FOR CLINICAL ASCVD RISK FACTORS, CLINICAL DISEASE, AND MORTALITY. THE COHORT HAS HIGH RETENTION (>95% HAVE AT LEAST ONE FOLLOW-UP) AND A BIOREPOSITORY OF 360,000 STORED SAMPLES. WE WILL ADD DETAILED SUBCLINICAL AND CLINICAL CVD PHENOTYPING, REPEATED MEASURES OF TARGETED PROTEIN MARKERS AND UNTARGETED MULTI-OMICS, AND REAL-TIME ASSESSMENT OF HEALTH BEHAVIORS. BY EXTENDING FOLLOW-UP BY AN ADDITIONAL 5 YEARS, WE WILL ACCRUE 176,536 PERSON-YEARS OF FOLLOW UP, >1,000 INCIDENT ASCVD, AND NEARLY >900 CASES OF CLINICAL HF (STAGES C/D). ENABLED BY PRECISE MAPPING OF CVD AT THE GRANULAR LEVEL OF SUBCLINICAL AND CLINICAL PHENOTYPES, WE WILL INVESTIGATE THE EPIDEMIOLOGY AND CAUSES OF CVD ALONG BOTH ASCVD AND HF PATHWAYS. THREE COMPLEMENTARY CORES (ADMINISTRATIVE AND FIELD COORDINATION; CVD PHENOTYPING; AND DATA MANAGEMENT AND ANALYSIS) WILL SUPPORT FOUR INTERCONNECTED PROJECTS, ONE OF WHICH IS LED BY AN EARLY-STAGE INVESTIGATOR (ESI). ALL FOUR PROJECT EXAMINE COMMON SUBCLINICAL AND CLINICAL ENDPOINTS FROM SYNERGISTIC VANTAGE POINTS: TRADITIONAL RISK FACTORS AND TARGETED PROTEIN-BASED PATHOPHYSIOLOGICAL PATHWAYS (PROJECT 1), THE IMPACT OF AIR POLLUTION AND MEDIATING MECHANISMS (PROJECT 2), MOLECULAR SIGNALS AND MECHANISMS THROUGH INTEGRATIVE UNTARGETED MULTI-OMICS (PROJECT 3), AND SOCIO-BEHAVIORAL INFLUENCES ON CVD RISK AND OUTCOMES STUDIED VIA SPOUSAL DYADS (PROJECT 4, ESI). PRECISION-CARRS WILL UNRAVEL THE NATURAL HISTORY, PATHOPHYSIOLOGY, AND CAUSAL FACTORS OF VASCULAR AND MYOCARDIAL DISEASE AND PAVE THE WAY FOR PRECISION CVD DIAGNOSTICS, PREVENTION, AND CARE FOR SOUTH ASIANS–WHO REPRESENT ONE FIFTH OF HUMANITY AND ARE A RAPIDLY GROWING SUB- POPULATION IN THE US. IN SUMMARY, PRECISION-CARRS IS DESIGNED TO BE A POWERFUL PLATFORM TO UNDERSTAND THE NATURAL HISTORY OF CVD IN AN UNDERSTUDIED HIGH-RISK POPULATION AND TO SPUR FUTURE INNOVATIVE SCIENTIFIC COLLABORATIONS WITH OTHER CVD LONGITUDINAL COHORTS IN THE US AND GLOBALLY.

CELLULAR AND MOLECULAR MECHANISMS OF ACUTE LUNG INJURY IN SICKLE CELL DISEASE

EMORY ALCOHOL AND LUNG BIOLOGY CENTER

NONDESTRUCTIVE DIRECT DIGITAL CAPTURE OF HISTOPATHOLOGY WITH MINIMAL PROCESSING (MINUTES) COMBINED WITH A DEDICATED AI IMAGE ANALYSIS SYSTEM CAN REDUCE CURRENT RATES OF LUMPECTOMY POSITIVE MARGINS REQUIRING A SECOND SURGERY TO REEXCISE INVOLVED TISSUES FROM 25% OR MORE TO NEARLY ZERO. IN PANCREATIC RESECTIONS RATES OF DISCREPANCY AND OR DEFERRAL TO PERMANENT SECTIONS OF 10% OR MORE CAN BE REDUCED TO NEARLY ZERO BUT IMPORTANTLY ALSO WITH A CONCOMITANT DECREASE IN THE DIAGNOSTIC DIFFICULTY AND NEED FOR THE MOST HIGHLY EXPERT PATHOLOGISTS. BY THE END OF THE PROPOSED PROJECT WE WILL HAVE A FUNCTIONAL PROTOTYPE SYSTEM MARGINCALL WHICH WILL BE ABLE TO IMAGE SPECIMEN CONTOURS MARK SURGICAL RESECTION MARGINS SERIALLY CROSS SECTION TISSUE FIBI IMAGE SERIAL TISSUE SLICES PATHOLOGY IMAGE AI MAP CANCER (AND OR IN SITU NEOPLASIAS) TO EACH SLICE OF TISSUE ASSESS PROXIMITIES TO ALL MARGINS RECONSTRUCT A 3D ORIENTATION OF THE SERIAL SLICES AND HEAT MAP THE TUMOR PROXIMITY OVER THE SURFACE OF THE SPECIMEN CONTOUR IMAGE. THIS WILL PROVIDE THE SURGEON WITH PRECISE AREAS OF INVOLVEMENT AS WELL AS AREAS THAT ARE CLOSE AND WILL DISTINGUISH AREAS OF INVASIVE EXTENSION FROM AREAS OF IN SITU INVOLVEMENT OF THE GLANDS. IMPORTANTLY EXCISION OF INVASIVE VERSUS IN SITU CAN REQUIRE A DIFFERENT APPROACH SURGICALLY WITH IN SITU DISEASE REQUIRING AN EXCISION OF THE GLAND TREE OR LOBE. MARGINCALL WILL BE ABLE TO ADDRESS THESE CHALLENGES AND FUNCTION AS AN INTRAOPERATIVE END TO END SOLUTION FOR ENHANCED VISUALIZATION OF SURGICAL MARGINS WITHOUT THE NEED FOR A PATHOLOGIST. UNIVERSITY OF CALIFORNIA DAVIS INDIANA UNIVERSITY AND EINDHOVEN UNIVERSITY OF TECHNOLOGY ARE SUBRECIPIENTS PARTICIPATING IN THIS PROJECT.

QUANTUM CHEMISTRY FOR QUANTUM COMPUTERS

GH14-1419: ADVANCING NATIONAL PUBLIC HEALTH INSTITUTES GLOBALLY

ADVANCING NATIONAL PUBLIC HEALTH INSTITUTES GLOBALLY TO STRENGTHEN PUBLIC HEALTH SYSTEMS TO ENABLE BETTER PREVENTION, DETECTION, AND RESPONDTO PUBLIC HEALTH THREATS.

ANTIVIRAL ROLE OF CD8+ T CELLS IN ART-TREATED SIV-INFECTED MACAQUES

P-CARRS-BRAIN: MULTI-DOMAIN (GENETIC, SOCIO-BEHAVIORAL, VASCULAR) RISK FACTORS AND PREDICTION OF ALZHEIMER’S DISEASE CONTINUUM IN SOUTH ASIANS IN INDIA - PROJECT SUMMARY/ABSTRACT WHILE IT IS WIDELY ACKNOWLEDGED THAT ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (AD/ADRD) HAVE AN EXTENDED PRECLINICAL PHASE, THERE ARE SPARSE DATA ON THE COGNITIVE AND PATHOBIOLOGICAL CHANGES IN MIDDLE-AGES, A CRITICAL WINDOW FOR PREVENTATIVE INTERVENTION IN PEOPLE LIKELY TO PROGRESS TO FULL-BLOWN CLINICAL DISEASE. SOUTH ASIANS, A POPULATION WITH HEIGHTENED RISK OF AD/ADRD AND VASCULAR/METABOLIC RISKS AT YOUNGER AGES, OFFER A UNIQUE OPPORTUNITY TO INVESTIGATE PRECLINICAL AD/ADRD AND RELATED MODIFIABLE RISK FACTORS OF ITS PROGRESSION. PREDICTIVE MODELS LEVERAGING MULTIMODAL DATA COULD TRANSFORM PROSPECTS FOR EARLY AD/ADRD DETECTION AND PHENOTYPE IDENTIFICATION IN MIDDLE-AGED PEOPLE, BUT ARE CURRENTLY LACKING. TO ADDRESS THESE GAPS, WE PROPOSE TO EFFICIENTLY LEVERAGE THE NHLBI-FUNDED PPG, THE PRECISION-CARRS COHORT (P01HL154996; N=21,864), WHICH HAS ~15 YEARS OF DETAILED, REPEATED MEASURES OF SOCIO-BEHAVIORAL, ENVIRONMENTAL, AND VASCULAR/METABOLIC DATA. OUR SPECIFIC AIMS ARE: (AIM-1) PERFORM MULTIMODAL AD/ADRD PHENOTYPING AND GENETICALLY CHARACTERIZE THE RISK OF AD/ADRD ACROSS THE CONTINUUM; (AIM-2) INVESTIGATE MODIFIABLE RISK FACTORS (SOCIO-BEHAVIORAL AND VASCULAR/METABOLIC FACTORS) ASSOCIATED WITH THE AD/ADRD CONTINUUM; AND (AIM-3) DEVELOP AND VALIDATE A LONGITUDINAL MACHINE LEARNING NETWORK BY EMPLOYING HIGH-DIMENSIONAL DATA TO DISTINGUISH AD/ADRD RISK. WE WILL ACHIEVE THESE AIMS BY AUGMENTING THE COHORT WITH AD/ADRD PHENOTYPING AND GENOTYPING PROTOCOLS ALIGNED WITH THE NIA-FUNDED ALZHEIMER'S DISEASE RESEARCH CENTERS (P50 AG025688). THIS STUDY WILL FOCUS ON CHARACTERIZING RISKS AND OUTCOMES IN INDIVIDUALS WHO WERE ENROLLED IN P-CARRS IN TWO WAVES (2010, 2015) AT AGES ≥40 YEARS (N=8,142, 51% FEMALE, 78% LITERATE, 38% DIABETES, AND 48% HYPERTENSION). WE WILL CHARACTERIZE MIDDLE-LIFE AD/ADRD RISKS THROUGH NEWLY MEASURING: (A) USING BASELINE STORED SAMPLES (2010 OR 2015) TO PERFORM PLASMA AD/ ADRD BIOMARKERS (PTAU217, NFL, AND GFAP) AND WHOLE GENOME SEQUENCING AND (B) AT A NEW FOLLOW-UP EXAMINATION, ASSESS PLASMA AD BIOMARKERS AND ADMINISTER SENSITIVE AI-DRIVEN DIGITAL COGNITIVE MEASURES; AND C) ONLY IN THOSE >50 YEARS (N=4,132), WE WILL ADDITIONALLY OBTAIN COMPREHENSIVE COGNITIVE BATTERY, RETINAL, AND NEUROIMAGING. IN PRELIMINARY STUDIES, WE HAVE SUCCESSFULLY DEMONSTRATED THE FEASIBILITY OF ADMINISTERING NOVEL AI-ENABLED DIGITAL COGNITIVE ASSESSMENT TOOLS, COLLECTING AND PROCESSING PLASMA AD BIOMARKERS, AND PILOT STANDARDIZATION OF MRI NEUROIMAGING BIOMARKERS. THIS PROJECT WILL ADVANCE PROGRESS IN UNDERSTANDING THE NATURAL HISTORY OF THE AD/ADRD ALONG THE LIFE COURSE AND PROMOTE EARLY DETECTION, PRECISE DIAGNOSIS AND TAILORED THERAPEUTIC STRATEGIES FOR THIS HIGH-RISK, UNDERSTUDIED POPULATION AND BEYOND.

THE IMPACT OF THE INTRAUTERINE AND EARLY CHILDHOOD ENVIRONMENTS ON NEUROCOGNITIVE AND METABOLIC DEVELOPMENT IN AFRICAN AMERICAN YOUTH: FOCUS ON THE GUT-BRAIN AXIS

SOUTHERN REGIONAL DISASTER RESPONSE SYSTEM (SRDRS)

DISCOVERY OF NOVEL PROTEOMIC TARGETS FOR TREATMENT OF ALZHEIMER'S DISEASE

DYNAMICS AND EVOLUTION OF IMMUNE RESPONSES TO INFLUENZA VIRUSES

NATIONAL EXPOSURE ASSESSMENT LABORATORY AT EMORY

SPF BREEDING COLONIES AT THE YERKES NPRC

GEORGIA COMPREHENSIVE METABOLOMICS AND PROTEOMICS UNIT FOR MOTRPAC

UNRAVELING THE IMMUNE RESPONSE TO FACTOR VIII

GRADUATE AND POSTDOCTORAL TRAINING IN TOXICOLOGY

REGIONAL EMERGING SPECIAL PATHOGEN TREATMENT CENTER EMORY UNIVERSITY AND CHILDRENS HEALTHCARE OF ATLANTA - THE PURPOSE OF THIS PROPOSAL IS FOR THE AWARDEE, EMORY UNIVERSITY IN COLLABORATION WITH CHILDREN’S HEALTHCARE OF ATLANTA-EGLESTON, TO SUPPORT HHS ADMINISTRATION FOR STRATEGIC PREPAREDNESS AND RESPONSE BY MAINTAINING AN EMERGING SPECIAL PATHOGENS TREATMENT CENTER (RESPTC) FOR REGION 4. THE BIOCONTAINMENT UNIT AT EMORY UNIVERSITY HOSPITAL IS SUPPORTED BY ALL OF EMORY HEALTHCARE IN PARTNERSHIP WITH EMORY UNIVERSITY. THE EXPECTED OUTCOMES OF THIS PROJECT ARE TO: - SERVE AS REGIONAL LEADERS IN DEVELOPING, DISSEMINATING, AND MAINTAINING STANDARDS, GUIDANCE, AND PROMISING PRACTICES FOR HIGH-QUALITY, COORDINATED SPECIAL PATHOGEN CARE AND FOR DECISION-MAKING DURING A SPECIAL PATHOGEN OUTBREAK. - BUILD CAPACITY FOR THE NATIONAL SPECIAL PATHOGEN SYSTEM (NSPS) TO ACCELERATE SPECIAL PATHOGEN RESEARCH, SERVING AS A REGIONAL HUB TO CONDUCT, PARTICIPATE IN, AND SHARE INSIGHTS RELATED TO SPECIAL PATHOGEN AND CLINICAL TRIAL RESEARCH. - MAINTAIN A TRAINED, DIVERSE, AND SPECIALIZED WORKFORCE ACROSS THEIR REGION AND THE NSPS, SERVE AS A REGIONAL LEADER IN PROVIDING SPECIAL PATHOGEN TRAININGS, EXPLORE INNOVATIVE AND FLEXIBLE HEALTH CARE WORKFORCE SOLUTIONS, AND SHARE RESOURCES AND PROMISING PRACTICES TO DEVELOP AND MAINTAIN WORKFORCE CAPABILITIES TO RESPOND TO SPECIAL PATHOGENS SURGE EVENTS. AS THE FIRST BIOCONTAINMENT UNIT IN THE US, THE FIRST HOSPITAL TO CARE FOR PATIENTS WITH EBOLA, ONE OF THE LEADING INSTITUTIONS FOR THE NATIONAL EMERGING SPECIAL PATHOGENS TRAINING AND EDUCATION CENTER, AND A DESIGNATED RESPTC SINCE 2015, EMORY IS WELL POSITIONED TO REMAIN THE REGION IV RESPTC. IN ADDITION TO THE RESPTC ASSETS CURATED SINCE THE CREATION OF THE SERIOUS COMMUNICABLE DISEASES UNIT, EMORY ALSO SERVES AS THE SOUTHEASTERN REGIONAL DISASTER HEALTH RESPONSE SYSTEM.

FMRP-MEDIATED REGULATION IN HUMAN BRAIN DEVELOPMENT AND THERAPEUTIC ADVANCEMENT

GH14-1419: ADVANCING NATIONAL PUBLIC HEALTH INSTITUTES GLOBALLY

A MULTI-INSTITUTIONAL MULTIDISCIPLINARY CENTER IS PROPOSED TO ADDRESS CRITICAL ISSUES RELATING TO THE PUBLIC HEALTH IMPACTS OF AMBIENT AIR POLLUTION

STATE-OF-THE-ART HOUSING TO EXPAND THE EMORY NATIONAL PRIMATE RESEARCH CENTER SPF RHESUS MACAQUE BREEDING COLONY - ABSTRACT THE ROBUST NONHUMAN PRIMATE RESEARCH PORTFOLIO AT THE EMORY NATIONAL PRIMATE RESEARCH CENTER (ENPRC), WHICH REACHED $36.8M IN FY2022, HAS PLACED SIGNIFICANT AND UNSUSTAINABLE DEMANDS ON THE EMORY NPRC RHESUS MACAQUE SPF BREEDING COLONY. TO MEET THE CURRENT AND PROJECTED FUTURE RESEARCH DEMAND, ENPRC IS PROPOSING TO BUILD NEW ANIMAL HOUSING AT THE ENPRC FIELD STATION TO FACILITATE EXPANSION OF THE SPF BREEDING COLONY. THE NEW ANIMAL HOUSING PROPOSED WILL BE A NOVEL HOUSING DESIGN THAT INTEGRATES TRADITIONAL LARGE INDOOR/ OUTDOOR BREEDING SPACES INTO A BUILDING THAT INCLUDES SMALLER RUN HOUSING SPACE AS WELL AS ANIMAL SUPPORT SPACE. THE RUN HOUSING WILL BE COMPRISED OF TRADITIONAL INDOOR RUN SPACE WITH ACCOMPANYING ENLARGED OUTDOOR RUN SPACE TO FACILITATE LARGER SOCIAL GROUPINGS. THIS COMBINATION OF COMPOUND AND RUN SPACE WILL MAXIMIZE BREEDING POTENTIAL AND FACILITATE TARGETED GENETIC BREEDING IN RUN GROUPS TO SUPPORT SPECIFIC RESEARCH REQUESTS AND ENABLE COLONY MANAGEMENT NEEDS. THE NEW BUILDING WILL ENHANCE ANIMAL WELFARE WITH NATURAL SUBSTRATE IN THE RUNS AS WELL AS THE OUTDOOR COMPOUND AND INCLUDE FUNCTIONAL FEATURES INCORPORATED INTO THE DESIGN THAT WILL IMPROVE ANIMAL HANDLING AND INCREASE EFFICIENCY FOR PERSONNEL. THE PROPOSED NEW ANIMAL HOUSING AT THE FIELD STATION WILL ALLOW FOR SIGNIFICANT EXPANSION OF THE SPF RHESUS MACAQUE COLONY OVER THE NEXT FIVE YEARS, THUS PROVIDING ADDITIONAL ANIMALS TO SUPPORT THE CURRENT RESEARCH AND PROJECTED RESEARCH PROGRAM FOR INVESTIGATORS AT EMORY NPRC AS WELL AS FOR EXTERNAL COLLABORATORS TO ADDRESS THE NATIONWIDE SHORTAGE OF NHPS FOR RESEARCH.

RESEARCH TRAINING IN ACADEMIC CARDIOLOGY

RNA MODIFICATION AND ANTIBIOTIC RESISTANCE

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP)

4/24 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 WOMEN 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.

1/2 SICKEL CELL DISEASE TREATMENT WITH ARGININE THERAPY (START TRIAL) - PROJECT SUMMARY/ABSTRACT VASO-OCCLUSIVE PAINFUL EPISODES (VOE) IN SICKLE CELL DISEASE (SCD) ARE THE LEADING CAUSE OF HOSPITALIZATIONS, EMERGENCY ROOM (ED) VISITS, MISSED SCHOOL, & ARE ASSOCIATED WITH AN INCREASED MORTALITY RATE. THERE ARE NO CURRENT THERAPIES TO RELIEVE VASO-OCCLUSION, WITH INTERVENTIONS LIMITED TO HYDRATION AND ANALGESIA. NITRIC OXIDE (NO), PRODUCED BY THE 5-ELECTRON OXIDATION OF L-ARGININE, IS A POTENT VASODILATOR & EXERTS PLEIOTROPIC EFFECTS ON VASCULAR & CIRCULATING BLOOD CELLS, INCLUDING THE INHIBITION OF PLATELET AGGREGATION, DOWN-REGULATION OF ADHESION MOLECULES, & MODULATION OF ISCHEMIA-REPERFUSION INJURY, ALL PATHWAYS ADVERSELY AFFECTED DURING VOE. WE HAVE FOUND THAT PEDIATRIC SCD PATIENTS ADMITTED WITH VOE HAVE DEPLETED PLASMA L-ARGININE LEVELS. ADDITIONALLY, WE HAVE NOW COMPLETED A SINGLE-CENTER RANDOMIZE, DOUBLE-BLINDED, PLACEBO-CONTROLLED TRIAL OF ARGININE THERAPY IN 54 CHILDREN WITH VOE REQUIRING HOSPITALIZATION. WE OBSERVED A REDUCTION IN TOTAL OPIOID USE (MG/KG) BY 54% AND SIGNIFICANTLY LOWER PAIN SCORES AT DISCHARGE IN CHILDREN WHO RECEIVED 5 DAYS IV L-ARGININE THERAPY EVERY 8 HOURS COMPARED TO PLACEBO, AS WELL AS A CLINICALLY RELEVANT TREND IN REDUCED LENGTH OF HOSPITAL STAY OF APPROXIMATELY 17 HOURS. IN PHARMACOKINETIC STUDIES, WE FOUND THAT IV ARGININE INDUCED A DOSE-DEPENDENT IMPROVEMENT IN MITOCHONDRIAL FUNCTION IN CHILDREN WITH SCD HOSPITALIZED FOR PAIN. WE NOW PROPOSE TO EXTEND THESE RESULTS TO A PIVOTAL PHASE 3 TRIAL OF L-ARGININE FOR VOE. WE HYPOTHESIZE THAT ARGININE IS A SAFE INTERVENTION WITH NARCOTIC- SPARING EFFECTS IN PEDIATRIC SCD PATIENTS WITH VOE THAT WILL DECREASE THE TIME CHILDREN EXPERIENCE SEVERE PAIN. AIM 1 OF THIS STUDY WILL DETERMINE THE EFFICACY OF IV ARGININE THERAPY ON THE PRIMARY ENDPOINT, TIME-TO-CRISIS RESOLUTION, AS WELL AS TOTAL PARENTERAL OPIOID USE (MG/KG) AND PAIN SCORES IN CHILDREN WITH SCD & VOE COMPARED TO PLACEBO (EFFICACY). AIM 2 WILL MONITOR FOR SAFETY OF IV L-ARGININE (SAFETY). AIM 3 WILL CHARACTERIZE ALTERATIONS IN THE ARGININE METABOLOME AND MITOCHONDRIAL FUNCTION IN CHILDREN WITH SCD AND VOE, AND EVALUATE HOW IT IS IMPACTED BY IV ARGININE THERAPY, WHILE ALSO CREATING A VALUABLE BIOREPOSITORY OF SCD-VOE BLOOD SAMPLES FOR FUTURE MECHANISM STUDIES (EXPLORATORY). THIS PROPOSAL WILL PROVIDE ESSENTIAL DATA FOR PRODUCT DEVELOPMENT AND FDA REGULATORY APPROVAL FOR USE OF ARGININE IN SCD. ACUTE CARE OF PATIENTS WITH SCD & PAIN IN THE ED IS A NEGLECTED AREA OF RESEARCH. THE RESULTS OF THIS STUDY MAY ULTIMATELY LEAD TO CHANGE IN CLINICAL PRACTICE FOR CHILDREN WITH SCD IN BOTH THE ED & INPATIENT HOSPITAL WARDS. ED-BASED STUDIES AND NOVEL THERAPIES THAT TARGET MECHANISMS OF VASO-OCCLUSION AND PAIN ARE NEEDED IN SCD.

STUDIES OF NATURAL SIV INFECTION OF SOOTY MANGABEYS

PUBLIC HEALTH TRAINING CENTERS

CHARACTERIZATION OF THE LAMPREY ADAPTIVE IMMUNE SYSTEM

PERINATAL STRESS AND GENE INFLUENCES: PATHWAYS TO INFANT VULNERABILITY

J: NRSA TRAINING CORE

EMORY-GA TECH NANOTECHNOLOGY CENTER FOR PERSONALIZED AN*

AMP-AD BRAIN PROTEOMIC NETWORK ENHANCEMENT, VALIDATION, AND TRANSLATION INTO CSF BIOMARKERS

DEVELOPMENT OF TRANSPLANT STRATEGIES UNIQUELY RESPONSIVE TO THE NEEDS OF CHILDREN

RYAN WHITE PART C OUTPATIENT EIS PROGRAM

PREVENTION EPICENTER OF EMORY AND COLLABORATING HEALTHCARE FACILITIES (PEACH II)

ADENOVIRUS HEXON AND ITS ROLE IN VIRUS INTERACTION WITH THE HOST

HARNESSING IL-10 IN CART TREATED SIV INFECTED MACAQUES TO RESTORE IMMUNITY AND TO ERADICATE HIV

DYSTONIA COALITION

GUT HOMING CELLS IN SIV INFECTION

SPF BREEDING COLONIES AT THE YERKES NPRC

STRENGTHENING HEALTHCARE INFECTION PREVENTION AND CONTROL AND IMPROVING PATIENT SAFETY IN THE UNITED STATES

DYSTONIA COALITION

MECHANISMS UNDERLYING THE RISK OF HZE PARTICLE-INDUCED SOLID TUMOR DEVELOPMENTTHE EMORY UNIVERSITY-MEDICAL COLLEGE OF GEORGIA NSCOR WILL INVESTIGAT

MENTAL STRESS AND MYOCARDIAL ISCHEMIA AFTER MI: SEX DIFFERENCES AND MECHANISMS

GENETIC AND TRAUMA-RELATED RISK FACTORS FOR PTSD

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP)

EMORY NEUROSCIENCE NINDS CORE FACILITIES

MEDICAL SCIENTIST TRAINING PROGRAM - PROJECT SUMMARY/ABSTRACT THE EMORY MEDICAL SCIENTIST TRAINING PROGRAM LEVERAGES OUR INSTITUTION’S COMPREHENSIVE ACADEMIC PROGRAMS AND DIVERSE CLINICAL TRAINING SITES TO CREATE UNIQUE, INTERDISCIPLINARY TRAINING OPPORTUNITIES THAT CULMINATE IN THE AWARD OF THE DUAL MD/PHD DEGREE. UNDER THE DIRECTOR’S LEAD, CO-DIRECTORS FOCUS ON CLINICAL AND RESEARCH PHASES OF TRAINING. SIGNIFICANT CLINICAL EXPOSURE PRECEDES GRADUATE TRAINING TO (A) ENSURE ALIGNMENT OF CLINICAL AND RESEARCH OBJECTIVES AND (B) FACILITATE THE TRANSITION TO RESEARCH-INTENSIVE RESIDENCIES AND LIFELONG CAREERS AS PHYSICIAN SCIENTIST. TRAINING BEGINS WITH THIRTY MONTHS OF MEDICAL TRAINING (12 MONTHS OF WHICH CONSIST OF REQUIRED CLINICAL ROTATIONS), DURING WHICH STUDENTS ALSO PARTICIPATE IN A JOURNAL CLUB, ADVISING ACTIVITIES AND RESEARCH ROTATIONS THAT CULMINATE IN SELECTING A PHD ADVISOR AND PROGRAM. DURING THE PHD YEARS, THE MD/PHD PROGRAM TRACKS MILESTONES (PRELIMINARY EXAMS, FORMATION OF DISSERTATION COMMITTEE, COMPLETION OF TRAINING IN RESEARCH ETHICS AND REPRODUCIBILITY OF RESEARCH; PUBLICATION REQUIREMENTS; RE-ENTRY TIMELINE) TO ENSURE CONSISTENT, RIGOROUS TRAINING ACROSS ALL PHD PATHS. THE MD/PHD PROGRAM ALSO INCORPORATES MENTOR-MENTEE CHECK-INS SEVERAL TIMES A YEAR TO ENSURE SUPPORTIVE TRAINING ENVIRONMENTS AND INTERVENTIONS AS NEEDED TO ENSURE TIMELY PROGRESS TO DEGREE. PROTECTED TIME FOR LONGITUDINAL CLINICAL EXPERIENCES CLINICAL CONTINUITY DURING THE PHD; A SMOOTH POST-PHD TRANSITION TO THE FINAL YEAR OF CLINICAL TRAINING IS MANAGED THROUGH RE-ENTRY COURSE. EMORY UNIVERSITY’S COLLABORATIVE ETHOS IS REFLECTED IN OUR PROGRAM’S ACADEMIC AND ADMINISTRATIVE STRUCTURES. THE MD/PHD PROGRAM IS SITED WITHIN THE SCHOOL OF MEDICINE OFFICE OF MEDICAL EDUCATION AND STUDENT AFFAIRS SUITE FOR PROMPT ACCESS TO OUR REGISTRAR, FINANCIAL AID AND WELLNESS/SUPPORT OFFICES SUCH AS THE OFFICE OF MULTICULTURAL AFFAIRS. OUR MONTHLY CLINICAL RESEARCH CONFERENCE OFFERS OPPORTUNITIES FOR PRESENTATIONS AND PROFESSIONAL DEVELOPMENT ACTIVITIES. OUR LANEY GRADUATE SCHOOL PARTNERSHIP ENSURES SMOOTH TRANSITIONS BETWEEN THE MEDICAL AND GRADUATE PHASES AND AFFORDS TRAINING IN THE DIVISION OF BIOLOGICAL AND BIOMEDICAL SCIENCES, THE BIOMEDICAL ENGINEERING PROGRAM (JOINT PROGRAM DEPARTMENT OF BIOMEDICAL ENGINEERING OF GEORGIA TECH AND EMORY), IN ANY OF THE DOCTORAL PROGRAMS IN THE ROLLINS SCHOOL OF PUBLIC HEALTH, OR IN GRADUATE PROGRAMS OF EMORY COLLEGE (E.G., ANTHROPOLOGY, CHEMISTRY, PSYCHOLOGY, SOCIOLOGY). AN EXECUTIVE COMMITTEE (WHICH INCLUDES PARTNERS FROM OUR PARTICIPATING SCHOOLS AND PROGRAMS AS WELL AS STUDENT LEADERSHIP REPRESENTATIVES) PROVIDES OVERSIGHT. OUR ADMISSIONS COMMITTEE (WHICH INCLUDES STUDENT REPRESENTATIVES) EMBRACES HOLISTIC APPLICATION REVIEW. OUR ANNUAL TWO-DAY RETREAT PROVIDES AN OPPORTUNITY FOR SOCIALIZING AND REFLECTION ON PROGRAM GOALS AND FUTURE DIRECTIONS A GRANT-WRITING COURSE TAUGHT BY ONE OF OUR PROGRAM CO- DIRECTORS HELPS TRAINEES PREPARE NRSA AND OTHER FELLOWSHIP APPLICATIONS. OUR STUDENTS PARTNER WITH PROGRAM FACULTY AND STAFF TO SPEARHEAD NEW INITIATIVES, PARTICIPATE IN RECRUITMENT ACTIVITIES, CURRICULUM DEVELOPMENT, AND PROGRAM EVALUATION, ALL OF WHICH LEADS TO PROGRAM COHESION AND PHYSICIAN SCIENTIST LEADERSHIP DEVELOPMENT.

EMORY PREPAREDNESS AND EMERGENCY RESPONSE CENTER

EMORY MOLECULAR AND TRANSLATIONAL IMAGING CENTER

UDALL PARKINSON'S DISEASE CENTER AT EMORY UNIVERSITY: CIRCUITRY TO THERAPY

NOVEL PROTEIN BIOMARKERS OF CORTICOLIMBIC PATHOPHYSIOLOGY IN LEWY BODY DEMENTIA - PROJECT SUMMARY LEWY BODY DEMENTIA (LBD), A CLASS OF DISORDERS COMPRISING PARKINSON’S DISEASE DEMENTIA (PDD) AND DEMENTIA WITH LEWY BODIES (DLB), FEATURES AGGRESSIVE COGNITIVE AND NEUROPSYCHIATRIC DECLINE WITHOUT CURE OR EFFECTIVE MITIGATING THERAPIES. DRIVING THE CLINICAL CHALLENGES SURROUNDING LBD IS A POOR UNDERSTANDING OF THE PATHOPHYSIOLOGY UNDERLYING ITS CLINICAL DETERIORATION AND A DESPERATE LACK OF DIAGNOSTIC, PROGRESSIVE, AND THERAPEUTIC BIOMARKERS. NEUROPATHOLOGICAL EVIDENCE SUGGESTS THAT CORTICOLIMBIC SYNUCLEINOPATHY IS CLOSELY LINKED TO THE AGGRESSIVE DEMENTIA OF LBD AND THAT EFFECTIVE BIOMARKERS OF COGNITIVE AND NEUROPSYCHIATRIC DECLINE WOULD NECESSARILY REFLECT THIS CORTICOLIMBIC DYSFUNCTION. THUS, OUR CENTRAL HYPOTHESIS IS THAT THE CORTICOLIMBIC LBD BRAIN FEATURES REGIONAL AND DISEASE-SPECIFIC ALTERATIONS IN NEURONAL AND NON-NEURONAL PATHWAYS REFLECTED AS UNIQUE PROTEIN SIGNATURES IN CSF AND PLASMA. TO INVESTIGATE THIS HYPOTHESIS, WE WILL APPLY AN INTEGRATED NETWORK-BASED PROTEOMIC PIPELINE ACROSS BRAIN, CEREBROSPINAL FLUID (CSF), AND PLASMA TO IDENTIFY LBD BIOFLUID SIGNATURES ANCHORED IN CORTICOLIMBIC PATHOPHYSIOLOGY. OUR PRELIMINARY EXPERIENCE WITH THIS PIPELINE SUGGESTS IT IS A POWERFUL PROMOTER OF MULTIPLEXED BIOMARKER ASSAYS REFLECTIVE OF DIVERSE BRAIN-BASED DYSFUNCTION, INCLUDING NEURONAL, GLIAL, AND ENDOTHELIAL PATHOPHYSIOLOGY. IN ADDITION TO THESE PROTEOMIC EXPERIMENTS, WE WILL ALSO ESTABLISH AN EMORY LBD REGISTRY UNDER THE PARKINSON’S DISEASE BIOMARKER PROGRAM (PDBP) AND UTILIZE ITS CLINICAL AND BIOSPECIMEN DATA TO FUEL PROTEOMIC VALIDATION STUDIES AND PROMOTE FUTURE LBD RESEARCH. OUR SPECIFIC AIMS INCLUDE 1) BUILDING A LONGITUDINAL PDBP REGISTRY FOR LBD, 2) DEFINING THE CORTICOLIMBIC NETWORK PROTEOME OF LBD, 3) PERFORMING BRAIN-BIOFLUID PROTEOMIC INTEGRATION TO IDENTIFY PROMISING BIOFLUID MARKERS, AND 4) LONGITUDINAL BIOFLUID VALIDATION USING TARGETED PROTEOMIC STRATEGIES. IN ADDITION TO BIOSPECIMENS COLLECTED IN AIM 1, WE WILL SUPPLEMENT THESE EXPERIMENTS USING EXISTING BRAIN AND BIOFLUID SAMPLES HOUSED IN EMORY GOIZUETA ALZHEIMER’S DISEASE RESEARCH CENTER BIOREPOSITORIES. ULTIMATELY, OUR EFFORTS TO IDENTIFY MOLECULAR SIGNATURES OF COGNITIVE AND NEUROPSYCHIATRIC DECLINE IN LBD PROMISE TO DISCOVER NOVEL BIOMARKERS TO ENHANCE EARLY DIAGNOSIS, DISEASE MONITORING, AND GAUGING THERAPEUTIC RESPONSE. FURTHERMORE, SUCH MARKERS CAN SERVE AS A NECESSARY GATEWAY TO EFFECTIVE DRUG THERAPIES FOR THIS DEVASTATING SPECTRUM OF NEURODEGENERATIVE DISEASES.

UDALL PARKINSON'S DISEASE RESEARCH CENTER AT EMORY UNIVERSITY

EMORY PARKINSON'S DISEASE COLLABORATIVE ENVIRONMENTAL RESEARCH CENTER

PREDICTORS OF TREATMENT RESPONSE RELAPSE AND RECURRENCE IN MAJOR DEPRESSION

GLUTAMATE RECEPTORS AND HUMAN NEUROLOGICAL DISEASE

SIMULTANEOUS ANTIGEN RECEPTOR REPERTOIRE PROFILING AND SINGLE-CELL TRANSCRIPTOMICS IN T AND B LYMPHOCYTES FROM LIMITED CLINICAL SAMPLES

CONTRAST-ENHANCED AND IMAGE-GUIDED SURGERY OF LUNG CANCER

DECIPHERING LKB1-ASSOCIATED IMMUNOTHERAPY RESISTANCE IN LUNG ADENOCARCINOMA (LUAD) - SUMMARY LUNG CANCER IS THE LEADING CANCER KILLER IN THE UNITED STATES. OUR TEAM PROPOSES TO DEVELOP NOVEL PERSONALIZED THERAPEUTIC STRATEGIES BY EXPLOITING VULNERABILITIES AND OPPORTUNITIES CREATED BY ALTERATIONS IN TUMOR SUPPRESSORS IN LUNG CANCER. SPECIFICALLY, WE FOCUS ON THE TUMOR SUPPRESSOR LKB1, WHICH IS ONE OF THE MOST COMMONLY MUTATED GENES IN LUNG ADENOCARCINOMA (LUAD); LKB1 MUTATIONS ARE DETECTED IN 15-25% OF LUAD, REPRESENTING A MAJOR SUBPOPULATION OF LUNG CANCER PATIENTS. DESPITE THE FREQUENCY, UPWARD TRAJECTORY OF INCIDENCE, AND AGGRESSIVE NATURE OF DISEASE, PATIENTS WITH LKB1-MUTANT LUAD NOT ONLY HAVE NO TARGETED THERAPEUTICS AVAILABLE, BUT ALSO SHOW POOR RESPONSE TO IMMUNE CHECKPOINT INHIBITORS, DEMANDING URGENT DEVELOPMENT OF EFFECTIVE THERAPEUTIC OPTIONS. TO ADDRESS THIS CRITICAL GAP, OUR REVISED APPLICATION WILL CAPITALIZE ON OUR INTEGRATED UNDERSTANDING OF LKB1-LOSS–EVOKED TUMOR GROWTH REGULATORY MECHANISMS AND SUPPRESSION OF ANTICANCER IMMUNITY TO DEVELOP INNOVATIVE CLINICAL APPROACHES FOR THE TREATMENT OF PATIENTS WITH LKB1-MUTANT LUAD. NEW PRELIMINARY DATA FROM OUR TEAM SHOWED THAT 1) LKB1 LOSS ALLOWS METABOLIC DYSREGULATION, SUCH AS GLUTAMATE DEHYDROGENASE (GDH) ACTIVATION BY FAK, LEADING TO INCREASED REGULATORY T CELLS AND IMMUNE SUPPRESSION; 2) LKB1-LOSS-TRIGGERED INHIBITION OF STING, A KEY INNATE IMMUNITY REGULATOR, CAN BE REVERSED BY AN IAP INHIBITOR, LEADING TO REACTIVATED IMMUNE RESPONSE AND ITS POTENT IN VIVO IMMUNE-DEPENDENT ANTICANCER EFFECT; AND 3) FAK IS ACTIVATED IN LKB1- DEFICIENT CANCER CELLS AND SUPPORTS CELL INVASION AND INHIBITS IMMUNE INFILTRATION. THESE RESULTS LEAD TO OUR CENTRAL HYPOTHESIS THAT MUTATED LKB1 MAY EXERT ITS IMMUNE SUPPRESSION FUNCTION THROUGH A DYSREGULATED ANTI-CANCER IMMUNITY CYCLE MEDIATED BY KEY METABOLIC, INNATE IMMUNITY, AND STROMAL REGULATORY FACTORS. TARGETING THESE FACTORS MAY LEAD TO NOVEL APPROACHES TO RE-ACTIVATE ANTICANCER IMMUNITY FOR EFFECTIVE THERAPEUTIC DEVELOPMENT IN LUAD. WE WILL ADDRESS THIS HYPOTHESIS THROUGH THREE HIGHLY INTEGRATED PROJECTS. PROJECT 1 WILL EXAMINE THE ROLE OF THE FAK-GDH1 AXIS IN IMMUNOTHERAPY RESISTANCE AND TUMOR PROGRESSION OF LKB1-MUTANT LUAD. PROJECT 2 WILL EXPLOIT OUR RECENTLY DISCOVERED LKB1-REGULATED IAP-JAK-STING SIGNALING IN LUAD TO REVERSE IMMUNE SUPPRESSION WITH AN IAP INHIBITOR TO ENHANCE IMMUNOTHERAPY EFFECT. PROJECT 3 WILL FOCUS ON TARGETING FAK- MEDIATED PRIMARY TUMOR PROGRESSION IN LKB1-MUTANT LUAD BY PERFORMING A CLINICAL TRIAL WITH THE COMBINATION OF A FAK INHIBITOR AND AN IMMUNE CHECKPOINT INHIBITOR COUPLED WITH MECHANISTIC STUDIES. THE PROJECTS ARE SUPPORTED BY THREE CORES, WHOSE FUNCTIONS ARE ADMINISTRATIVE (CORE 1), MOLECULAR PATHOLOGY AND IMMUNOLOGY (CORE 2), AND BIOINFORMATICS AND BIOSTATISTICS (CORE 3). THIS HIGHLY INTEGRATED EFFORT BUILDS ON NEW DISCOVERIES FROM OUR ESTABLISHED LUNG CANCER TEAM WITH MORE THAN 100 CO-PUBLICATIONS AND WITH STRONG INSTITUTIONAL SUPPORT. WE EXPECT TO ADVANCE LUNG CANCER TREATMENT STRATEGIES BY NEW AGENT DISCOVERY (GDH1 INHIBITORS), NEW APPLICATION OF CLINICAL STAGE IAP INHIBITORS, AND A NEW PHASE II CLINICAL TRIAL OF A FAK-TARGETED COMBINATION APPROACH TO OVERCOME IMMUNOTHERAPY RESISTANCE OF LKB1-MUTANT LUAD AND BRING TREATMENT OPTIONS TO THIS PATIENT POPULATION.

CELLULAR RESPONSES TO OXIDATIVE STRESS IN MODELS OF COLON CANCER DEVELOPMENT

QUANITIFYING THE EPIDEMIOLOGICAL IMPACT OF TARGETED INDOOR RESIDUAL SPRAYING ON AEDES-BORNE DISEASES

CHROMATIN INSULATORS AND NUCLEAR ORGANIZATION

DISSECTING THE COGNITIVE ROLES OF HIPPOCAMPUS, OTHER TEMPORAL LOBE STRUCTURES

VIROLOGIC CORRELATES OF HETEROSEXUAL TRANSMISSION

ROYBAL TRANSLATIONAL RESEARCH CENTER TO PROMOTE CONTEXT-SPECIFIC CAREGIVING OF COMMUNITY-DWELLING PERSONS LIVING WITH ALZHEIMER'S DISEASE OR RELATED DISORDERS

SELF-ADMINISTERED MICRONEEDLE PATCHES FOR INFLUENZA VACCINES

2/5 INTERNATIONAL CONSORTIUM ON BRAIN AND BEHAVIOR IN 22Q11.2 DELETION SYNDROME

IMMUNE DETERMINANTS OF PEDIATRIC HIV/SIV RESERVOIR ESTABLISHMENT AND MAINTENANCE - ABSTRACT - OVERALL NEW PERINATAL HIV INFECTIONS CONTINUE, AT A RATE OF ABOUT ONE EVERY 3-4 MINUTES, 400 EVERY DAY, AND 3000 EVERY WEEK. FOR CHILDREN LIVING WITH HIV (CLWH), ANTIRETROVIRAL THERAPY (ART) GREATLY REDUCES MORTALITY AND MORBIDITY; HOWEVER, VIRAL REBOUND QUICKLY ENSUES IF ART IS STOPPED. HIV PERSISTENCE IN A LATENT RESERVOIR IN CD4+ T CELLS THAT CAN GIVE RISE TO REBOUND VIREMIA IS THE MAJOR BARRIER TO A CURE. HOWEVER, THERE REMAINS A SIGNIFICANT KNOWLEDGE GAP REGARDING HOW THE ESTABLISHMENT AND MAINTENANCE OF HIV RESERVOIRS ARE REGULATED BY THE NEONATAL AND CHILDHOOD IMMUNE SYSTEM. THE OVERALL OBJECTIVE OF THIS PROGRAM PROJECT APPLICATION IS TO GENERATE A COMPREHENSIVE UNDERSTANDING OF THE COMPLEX HOST-PATHOGEN INTERACTIONS CRITICAL FOR HIV RESERVOIR SEEDING AND PERSISTENCE SUCH THAT NOVEL CURE STRATEGIES TRULY TARGETED FOR THE UNIQUE IMMUNE ENVIRONMENT OF CLWH CAN BE CREATED. OUR CENTRAL HYPOTHESIS IS THAT THE HOST IMMUNE ENVIRONMENT DURING THE PERINATAL PERIOD AND THROUGHOUT CHILDHOOD AND ADOLESCENCE, INFLUENCED BY HOST/MICROBIAL METABOLITES AND THYMIC OUTPUT, DETERMINES THE EFFICACY OF HIV-SPECIFIC IMMUNITY AND THE NATURE OF RESERVOIR ESTABLISHMENT AND MAINTENANCE. TO TEST THIS HYPOTHESIS, WE HAVE COMPILED AN OUTSTANDING TEAM OF EXPERIENCED SCIENTISTS AND EARLY-STAGE INVESTIGATORS (ESIS) FROM THE DEPARTMENTS OF PEDIATRICS AND PATHOLOGY AT EMORY SCHOOL OF MEDICINE, WITH COLLABORATORS FROM THE NIH, KIRBY INSTITUTE, AND THE UNIVERSITE DE MONTREAL. THE RESEARCH PROPOSED BUILDS UPON THE STRONG EXISTING COLLABORATIONS THAT GENERATED THE RIGOROUS FOUNDATIONAL RESEARCH IN SUPPORT OF EACH PROJECT AND DEVELOPS LINKS BETWEEN NEW COLLABORATORS. PROGRAM OVERSIGHT, COMMUNICATION PLANS, AND MENTORING OF ESIS WILL BE COORDINATED THROUGH THE ADMINISTRATIVE CORE. WE PROPOSE MULTIOMIC EXPERIMENTS IN PROJECTS 1-3 WITH DATA CENTRALIZATION IN THE BIOINFORMATICS CORE. THE OVERALL SPECIFIC AIMS OF OUR PROGRAM ARE: 1) TO INVESTIGATE THE IMPACT OF IL-10, TGF-SS, AND THYMIC OUTPUT ON IMMUNE FUNCTION AND RESERVOIR ESTABLISHMENT AND MAINTENANCE IN PERINATAL HIV/SIV INFECTION; 2) TO DETERMINE THE ROLE OF CD8+ T CELLS IN RESERVOIR ESTABLISHMENT AND MAINTENANCE IN PERINATAL HIV/SIV INFECTION; 3) TO GENERATE INTEGRATIVE MODELS THAT DEFINE THE HOST IMMUNE DETERMINANTS OF HIV/SIV RESERVOIR ESTABLISHMENT AND MAINTENANCE AND PREDICT THE SIZE AND NATURE OF THE HIV RESERVOIR IN CLWH. THIS DEEP DIVE INTO PEDIATRIC IMMUNOLOGY WILL ALLOW FOR INSIGHTS TO EMERGE THAT WOULD NOT BE POSSIBLE IF EACH PROJECT WERE PERFORMED IN ISOLATION. A BETTER UNDERSTANDING OF THE VULNERABILITY OF HIV RESERVOIRS TO INNATE AND ADAPTIVE IMMUNE PRESSURE WILL DRIVE INFORMED APPROACHES TO A CURE FOR CLWH. THE RESEARCH PROPOSED BUILDS ON OUR TEAM’S EXPERTISE, THE RICH RESOURCES AVAILABLE AT EMORY SCHOOL OF MEDICINE, EMORY NATIONAL PRIMATE RESEARCH CENTER, EMORY CENTER FOR AIDS RESEARCH, AND GENEROUS ACCESS TO BIOSPECIMENS FROM TWO COHORTS OF CLWH. WE ARE CONFIDENT THAT THIS PROGRAM WILL LEAD TO IMPORTANT DISCOVERIES REGARDING IMMUNE REGULATION OF THE PEDIATRIC HIV RESERVOIR AND IMMUNE DYSFUNCTION. IT IS OUR MISSION TO TURN THESE DISCOVERIES INTO CLINICAL TRIAL PROTOCOLS TO ADVANCE RESEARCH TOWARDS A CURE FOR CHILDREN WITH HIV.

BRIEF INTERVENTIONS TO CREATE SMOKE-FREE HOME POLICIES IN LOW-INCOME HOUSEHOULDS

CELL THERAPY FOR DIABETIC PERIPHERAL NEUROVASCULAR COMPLICATIONS

IMPLEMENTING EVIDENCE-BASED PREVENTION INTERVENTIONS FOR KEY POPULATIONS IN THE REPUBLIC OF RWANDA UNDER THE PRESIDENT'S EMERGENCY PLAN FOR AIDS RELI

FUNCTIONAL APPROACH TO COMMUNICATION SOUND PROCESSING IN MOUSE AUDITORY CORTEX

COMMUNITY BASED ASSESSMENTS REGARDING VASCULAR CONTRIBUTIONS TO ALZHEIMERS DISEASE IN M2OVE AD CONSORTIUM

REGION IV MENTAL HEALTH TECHNOLOGY TRANSFER CENTER

TRAINING A NEW GENERATION OF VACCINOLOGISTS

ESTABLISHMENT OF A TRANSGENIC MONKEY OF HUNTINGTONS'S DIESEASE

BIOLOGY, BIOMECHANICS AND ATHEROSCLEROSIS

DEEP SPATIAL IMMUNE PROFILING OF GRANULOMAS AND M. TUBERCULOSIS ADAPTATION TO DISEASE AND TREATMENT - PROJECT SUMMARY GRANULOMAS ARE HALLMARK PATHOLOGICAL FEATURES OF PULMONARY TUBERCULOSIS (TB) AND CONTRIBUTE TO BOTH CONTAINMENT OF MYCOBACTERIUM TUBERCULOSIS (MTB) INFECTION AND PROGRESSION TO TB DISEASE. HOWEVER, WE DO NOT UNDERSTAND HOW THE GEOSPATIAL ORGANIZATION OF IMMUNE CELLS AND THEIR COMMUNICATION NETWORKS IMPACT THE HOST IMMUNE FUNCTIONS THAT RENDER A GRANULOMA FUNCTIONALLY PERMISSIVE VERSUS RESTRICTIVE TO MTB. STRESSES ENCOUNTERED BY MTB DURING INFECTION INDUCE BACTERIAL ADAPTATIONS THAT PROMOTE MTB SURVIVAL AND DRUG TOLERANCE, BUT WE KNOW LITTLE ABOUT THE BACTERIAL GROWTH AND METABOLIC CHANGES INDUCED WITHIN DIFFERENT GRANULOMA MICROENVIRONMENTS DURING DISEASE OR TREATMENT AND HOW THE GEOSPATIAL ORGANIZATION AND IMMUNE STATE OF THE GRANULOMA IMPACTS BACTERIAL PHYSIOLOGY AND KILLING. TO UNDERSTAND HOW CELLULAR NETWORKS AND GRANULOMA SPATIAL ARCHITECTURE DETERMINE THE FUNCTIONAL CAPACITIES OF MAJOR GRANULOMA TYPES, WE PROPOSE TO DEVELOP A TB GRANULOMA INFORMATION SYSTEM (TB-GIS) THAT WILL GENERATE A GEOSPATIAL MAP FOR INDIVIDUAL GRANULOMAS AND LAYER ON ADDITIONAL DATA RELATED TO IMMUNOMETABOLIC AND ANTIMICROBIAL FUNCTIONS, AS WELL AS MTB PHYSIOLOGY AND ADAPTATION. TO CHARACTERIZE GRANULOMA TOPOLOGY, WE HAVE EXPLOITED AND OPTIMIZED A NOVEL HIGH-PLEX IMAGING MODALITY, T-CYCIF (TISSUE CYCLIC IMMUNOFLUORESCENCE), WHICH ALLOWS FOR DEEP GEOSPATIAL IMMUNE PROFILING OF TISSUE (30+ MARKERS). WE WILL LEVERAGE OUR WELL-ESTABLISHED NONHUMAN PRIMATE (NHP) MODEL OF AEROGENIC MTB INFECTION WHICH RECAPITULATES THE SPECTRUM OF HUMAN LUNG PATHOLOGICAL LESIONS AND INTEGRATE ADDITIONAL CUTTING- EDGE TOOLS AND COMPUTATIONAL MODELING TO PROBE THE HOST-PATHOGEN INTERFACE IN DIFFERENT TB GRANULOMAS (AIM 1). WE WILL ALSO DETERMINE HOW PERTURBING GRANULOMA TOPOLOGY WITH HOST- OR PATHOGEN-DIRECTED THERAPIES IMPACTS IMMUNE FUNCTION AND MTB METABOLIC STATE (AIM 2). USING THE TB-GIS FRAMEWORK, WE WILL QUANTIFY THE RELATIONSHIP BETWEEN SPECIFIC GRANULOMA FEATURES AND CELLULAR NETWORKS, IMMUNE FUNCTION AND MTB PHYSIOLOGY IN TREATED AND UNTREATED ANIMALS. WE ANTICIPATE THAT THESE TB-GIS STUDIES WILL TRANSFORM OUR ABILITY TO PREDICT GRANULOMA FUNCTION AND HELP DESIGN NEW THERAPIES TO TARGET GRANULOMAS HARBORING DRUG-TOLERANT BACTERIA THAT ARE DIFFICULT TO CLEAR WITH CURRENT TREATMENT REGIMENS.

EARLY CHILDHOOD CONSTRAINT THERAPY FOR SENSORY/MOTOR IMPAIRMENT IN CEREBRAL PALSY

DYNAMICS AND EVOLUTION OF IMMUNE RESPONSES TO INFLUENZA VIRUSES

OVARIAN CANCER SURVIVAL IN AFRICAN-AMERICAN WOMEN

ROLE OF RESIDENT MESENCHYMAL STEM CELLS IN LUNG ALLOGRAFT REJECTION

UNDERSTANDING HIV/STD RISK AND ENHANCING PREP IMPLEMENTATION MESSAGING IN A DIVERSE COMMUNITY-BASED SAMPLE OF GAY, BISEXUAL, AND OTHER MEN WHO HAVE SEX WITH MEN IN A TRANSFORMATIONAL ERA

HARNESSING HOST RESPONSE TO PREVENT MYELOMA

AN UNBIASED OMICS APPROACH TO IDENTIFY MECHANISMS OF COCAINE REGULATION OF THE HIV RESERVOIR.

A PROTEOMIC COMPARISON OF SPORADIC EARLY-ONSET, LATE-ONSET, AND AUTOSOMAL DOMINANT ALZHEIMER'S DISEASE - PROJECT SUMMARY ALZHEIMER’S DISEASE (AD) IS COMMONLY CONSIDERED A DISEASE EXCLUSIVE TO THE ELDERLY. WHILE AGING IS THE LARGEST RISK FACTOR FOR THE DEVELOPMENT OF AD, APPROXIMATELY 5 TO 10 PERCENT OF AD DEVELOPS IN PEOPLE YOUNGER THAN AGE 65. IN MOST EARLY-ONSET AD CASES THERE IS NO CLEARLY IDENTIFIABLE GENETIC MUTATION THAT CAUSES THE DISEASE, AND THEREFORE SUCH CASES HAVE BEEN TERMED SPORADIC EARLY-ONSET AD (SEOAD). COMPARED TO LATE-ONSET AD (LOAD) OR AUTOSOMAL DOMINANT FORMS OF AD (ADAD), LITTLE IS KNOWN ABOUT THE PATHOPHYSIOLOGY OF SEOAD. IN CONTRAST TO LOAD AND ADAD, SEOAD MORE OFTEN PRESENTS WITH CLINICAL SYNDROMES THAT AFFECT VISUAL-SPATIAL, LANGUAGE, EXECUTIVE AND BEHAVIORAL COGNITIVE DOMAINS, AND ON AVERAGE HAS A MORE RAPIDLY PROGRESSIVE COURSE COMPARED TO LOAD. WHETHER THE UNDERLYING PATHOPHYSIOLOGY AND BIOLOGICAL PATHWAY ALTERATIONS, AND BIOFLUID BIOMARKERS THAT REFLECT THESE CHANGES, ARE THE SAME IN SEOAD AS THOSE IN LOAD AND ADAD IS UNKNOWN. OUR PREVIOUS BRAIN PROTEOMIC STUDIES ON LOAD THROUGH THE ACCELERATING MEDICINES PARTNERSHIP FOR AD (AMP-AD) HAVE REVEALED MANY DIFFERENT PATHOLOGICAL CHANGES IN LOAD BEYOND AMYLOID-Β AND TAU DYSHOMEOSTASIS. THE GOAL OF THIS PROJECT IS TO APPLY A SIMILAR PROTEOMIC APPROACH TO SEOAD TO ADVANCE OUR UNDERSTANDING OF SEOAD PATHOPHYSIOLOGY AND HOW IT IS SIMILAR OR DISTINCT FROM LOAD AND ADAD PATHOPHYSIOLOGY. WE HYPOTHESIZE THAT SEOAD WILL HAVE MORE SEVERE CHANGES IN MITOCHONDRIAL, PROTEOSTASIS, COMPLEMENT, AND RNA-ASSOCIATED PROTEIN PATHWAYS COMPARED TO LOAD AND ADAD. WE WILL LEVERAGE A MULTI-PLATFORM DISCOVERY PROTEOMIC APPROACH TO ANALYZE SEOAD AND LOAD CEREBROSPINAL FLUID (CSF) AND PLASMA TO DETERMINE WHETHER DIFFERENCES IN EOAD BRAIN PATHOPHYSIOLOGY CAN BE OBSERVED IN BIOFLUIDS, AND HOW THESE CHANGES ARE RELATED BETWEEN CSF AND PLASMA COMPARTMENTS. FROM OUR CROSS-TISSUE PROTEOMIC DATA WE WILL ASSESS WHICH BRAIN-LINKED BIOMARKERS IN SEOAD ARE MOST PREDICTIVE OF COGNITIVE DECLINE. THESE STUDIES WILL SIGNIFICANTLY INCREASE OUR UNDERSTANDING OF THE PROTEIN NETWORK CHANGES THAT CHARACTERIZE SEOAD AND HOW THEY ARE SIMILAR OR UNIQUE TO THOSE OBSERVED IN LOAD AND ADAD. SUCH KNOWLEDGE WILL BE CRITICAL TO ENSURING THAT THERAPIES AND BIOMARKERS DEVELOPED FOR LOAD ARE APPLICABLE TO THOSE WITH EARLY-ONSET FORMS OF AD.

SOLAR ENEGY-DRIVEN ROBUST MULTI-ELECTRON-TRANSFER CATALYSTS FOR WATER OXIDATION

ENTRY MECHANISMS USED BY A MODEL RETROVIRUS

THE IMPACT OF TRAUMATIC STRESS ON THE METHYLOME: IMPLICATIONS FOR PTSD

NON-INVASIVE VAGAL NERVE STIMULATION IN PATIENTS WITH OPIOID USE DISORDERS - TREATMENT OF OPIOID USE DISORDERS (OUDS) INCLUDES MEDICATIONS WITH EFFECTS ON OPIOID RECEPTORS SUCH AS BUPRENORPHINE, BUT ACCESS IS LIMITED FOR MANY PATIENTS AND OTHERS ARE OPPOSED TO TREATING ADDICTIONS WITH MEDICATIONS THAT HAVE OPIOID AGONIST PROPERTIES. NALTREXONE IS AN OPIOID ANTAGONIST THAT IS MORE ACCEPTABLE FOR MANY PATIENTS, AND RECENT STUDIES SHOW IT TO BE EQUIVALENT IN EFFICACY. INITIATION OF TREATMENT WITH LONG-ACTING NALTREXONE, HOWEVER, REQUIRES A PERIOD OF ABSTINENCE OF ABOUT SEVEN DAYS DURING WHICH TIME PATIENTS SUFFER FROM INTENSE SYMPTOMS OF WITHDRAWAL WITH A RISK OF RELAPSE THAT CAN LEAD TO OVERDOSE-RELATED DEATH. OPIOIDS HAVE AN INHIBITORY EFFECT ON NOREPINEPHRINE AND THE SYMPATHETIC NERVOUS SYSTEM, AND MANY SYMPTOMS OF WITHDRAWAL ARE DRIVEN BY REBOUND ACTIVATION OF THESE SYSTEMS. DOPAMINERGIC SYSTEMS IN BRAIN AREAS INCLUDING VENTRAL STRIATUM (NUCLEUS ACCUMBENS) AND MEDIAL PREFRONTAL CORTEX (ANTERIOR CINGULATE) PLAY AN IMPORTANT ROLE IN OPIOID ADDICTION, CRAVING AND RELAPSE, AS DO INCREASES IN INFLAMMATION. THIS PROJECT WILL ASSESS A FORM OF NEUROMODULATION INVOLVING NON-INVASIVE ELECTRICAL STIMULATION OF THE VAGUS NERVE THAT MAY PLAY A USEFUL ROLE DURING THE PERIOD OF OPIOID WITHDRAWAL BEFORE THE INITIATION OF LONG-TERM NALTREXONE TREATMENT IN BLOCKING NOREPINEPHRINE, SYMPATHETIC, AND INFLAMMATORY RESPONSES AND ENHANCING PERIPHERAL PARASYMPATHETIC AND CENTRAL BRAIN FUNCTION IN AREAS MODULATING DRUG CRAVING (VENTRAL STRIATUM, ANTERIOR CINGULATE). OUR PRELIMINARY DATA ON THE EFFECTS OF NON-INVASIVE VAGAL NERVE STIMULATION (NVNS) ON STRESS RESPONSE IN TRAUMATIZED HUMAN SUBJECTS AND PATIENTS WITH POSTTRAUMATIC STRESS DISORDER (PTSD) SHOW THAT NVNS RELIABLY BLOCKS PERIPHERAL SYMPATHETIC AND ENHANCES PARASYMPATHETIC FUNCTION, REDUCES INFLAMMATORY RESPONSES (INTERLEUKIN-6, OR IL-6), AND ENHANCES CENTRAL BRAIN RESPONSES (ANTERIOR CINGULATE) TO STRESS. WE NOW PROPOSE TO APPLY THIS TECHNOLOGY TO THE TREATMENT OF PATIENTS WITH OUDS. FOLLOWING VERIFICATION USING MODELLING AND DETERMINATION OF OPTIMAL DOSING PARAMETERS, WE WILL USE THESE PARAMETERS TO ASSESS EFFECTS OF NVNS VERSUS SHAM STIMULATION ON OPIOID CRAVING, PERIPHERAL AUTONOMIC, CARDIOVASCULAR, INFLAMMATORY, AND BRAIN FUNCTIONAL RESPONSES MEASURED WITH HIGH-RESOLUTION POSITRON EMISSION TOMOGRAPHY (HR-PET) AND RADIOLABELED WATER TO VIDEOS OF DRUG CUES IN RECENTLY TREATED PATIENTS WITH OUDS. BASED ON THE OUTCOME OF THIS RESEARCH, WE WILL PROCEED TO THE UH3 PHASE, WHICH WILL INVOLVE A RANDOMIZED, SHAM-CONTROLLED TRIAL OF NVNS IN PATIENTS WITH OUDS DURING THE ONE TO TWO WEEK PERIOD OF OPIOID WITHDRAWAL FOLLOWED BY ASSESSMENT OF CRAVING, HR-PET IMAGING OF BOTH BRAIN FUNCTION AND BRAIN DOPAMINERGIC FUNCTION, AND ASSESSMENT OF PERIPHERAL AUTONOMIC, CARDIOVASCULAR AND INFLAMMATORY RESPONSES IN CONJUNCTION WITH ADMINISTRATION OF NVNS OR SHAM. WE HYPOTHESIZE THAT NVNS WILL REDUCE OPIOID CRAVING AND INFLAMMATORY, PERIPHERAL AUTONOMIC AND CARDIOVASCULAR RESPONSES AND ENHANCE BRAIN RESPONSES (ANTERIOR CINGULATE FUNCTION AND DOPAMINE FUNCTION IN VENTRAL STRIATUM), AND PROMOTE SUCCESSFUL CONVERSION TO LONG-ACTING NALTREXONE, IN PATIENTS WITH OUDS.

PET LIGAND DISCOVERY FOR ARGININE VASOPRESSIN - PROJECT SUMMARY. THE V1A-SPECIFIC ARGININE VASOPRESSIN RECEPTOR HAS RECENTLY BECOME THE FOCUS OF CNS RESEARCH WHEN AN ASSOCIATION BETWEEN THE RECEPTOR GENE AND AUTISM SPECTRUM DISORDER (ASD) IS IDENTIFIED. DYSREGULATION OF V1A ACTIVITY HAS BEEN SUGGESTED AS A FUNDAMENTAL MECHANISM UNDERLYING ASD PATHOPHYSIOLOGY. RECENT STUDIES REVEALED THAT V1A ANTAGONISTS CAN REGULATE THE EFFECT OF THE AVP HORMONE, THEREBY TACKLING A POTENTIAL ROOT CAUSE OF ASD DEVELOPMENT. PET IS CAPABLE OF QUANTIFYING BIOCHEMICAL PROCESSES IN VIVO, AND A SUITABLE V1A PET LIGAND WOULD SUBSTANTIALLY IMPROVE OUR UNDERSTANDING OF V1A-MEDIATED AVP SIGNALING UNDER DIFFERENT PATHOPHYSIOLOGICAL CONDITIONS, OTHERWISE INACCESSIBLE BY EX VIVO (DESTRUCTIVE) ANALYSIS, PARTICULARLY IN HIGHER SPECIES. QUANTIFICATION OF V1A IN LIVING BRAIN BY PET WOULD PROVIDE THE ASSESSMENT OF DISTRIBUTION AND EXPRESSION AND TARGET ENGAGEMENT OF NEW V1A- TARGETED NEUROTHERAPEUTICS. TO DATE, NO SUCCESSFUL EXAMPLES HAVE BEEN DEMONSTRATED TO IMAGE V1A-SPECIFIC AVP FOR HUMAN USE, REPRESENTING A SIGNIFICANT DEFICIENCY OF OUR ABILITY TO STUDY THIS TARGET IN VIVO FOR V1A. THEREFORE, WE PROPOSE TO DEVELOP A NOVEL PET LIGAND THAT CAN FILL THIS VOID, AS THE FIRST TRANSLATIONAL IMAGING TOOL. THE PI HAS RECENTLY DEVELOPED A NOVEL V1A-SPECIFIC AVP LIGAND [11C]PF-184563 AT MGH IN 2021. WHILE THIS COMPOUND SHOWED HIGH POTENCY AND EXCELLENT SELECTIVITY, IT IS NOT LIKELY PURSUED DUE TO LOW BRAIN PENETRATION. IN OUR 2ND GENERATION, WE IDENTIFIED A LEAD MOLECULE, V1A-214, WHICH SHOWED SUBSTANTIALLY-IMPROVED BINDING AFFINITY AND EXCELLENT TARGET SELECTIVITY AMONG ALL OTHER MAJOR CNS TARGETS. AN 11C-ISOTOPOLOGUE OF V1A-214 WAS SYNTHESIZED AND PRELIMINARY PET IMAGING STUDIES CONFIRMED THAT WE HAVE OVERCOME TWO MAJOR OBSTACLES FOR V1A-SPECIFIC PET LIGAND DEVELOPMENT BY ACHIEVING: 1) HIGH BRAIN UPTAKE (>1 SUV) AND 2) HIGH TARGET SPECIFICITY VALIDATED BY HUMAN V1A CELL LINES AND BLOCKING STUDIES IN VIVO, AND HETEROGENOUS UPTAKE CONSISTENT WITH V1A REGIONS IN THE CNS. THOUGH V1A- 214 IS A PROMISING LEAD MOLECULE FOR THE DEVELOPMENT OF NEW V1A-TARGETED PET LIGANDS, DUE TO SPECIES DIFFERENCE, FURTHER OPTIMIZATION FOR TRANSLATIONAL CROSS-SPECIES (NAÏVE/HUMANIZED V1A MICE AND NONHUMAN PRIMATES) IMAGING STUDIES ARE SOUGHT TO ACHIEVE OPTIMAL AVP (V1A SUBUNIT) QUANTIFICATION IN THE LIVING BRAIN FOR DRUG DISCOVERY AND CLINICAL BIOMARKER FOR ASD PATIENTS. ON THE BASIS THAT V1A-214 SERVES A VALIDATED LEAD FOR MEDICINAL CHEMISTRY OPTIMIZATION, AS SPECIFIC OBJECTIVES, WE WILL DESIGN AND PREPARE A FOCUSED LIBRARY OF V1A-SPECIFIC ANTAGONISTS AMENABLE FOR LABELING WITH 11C OR 18F, AND EVALUATE THEIR ABILITY TO QUANTIFY V1A-SPECIFIC AVP ACTIVITY AND CHANGES IN CELLULAR EXPERIMENTS, NAÏVE AND HUMANIZED V1A MICE AND NONHUMAN PRIMATES, AS WELL AS AUTORADIOGRAPHY AND BIOLOGICAL VALIDATION IN POSTMORTEM NHP/HUMAN BRAIN TISSUES. THE IMPACT OF THIS WORK IS NOT ONLY TO DEVELOP THE FIRST SUCCESSFUL HIGH-AFFINITY AND SELECTIVE V1A-SPECIFIC PET LIGAND FOR THE STUDY OF ASD-RELATED BIOLOGICAL PROCESSES, BUT ALSO ULTIMATELY, VIA PET IMAGING VALIDATION IN HIGHER SPECIES, TO ADVANCE THIS LIGAND AS A POTENTIAL CLINICAL BIOMARKER AND FOR MONITORING TARGET RESPONSE OF NOVEL THERAPEUTICS FOR NEURODEVELOPMENTAL DISEASES AND NEUROPSYCHIATRIC DISORDERS, INCLUDING ASD.

MAKING IT LAST: A RANDOMIZED, CONTROLLED TRIAL OF A HOME CARE SYSTEM TO PROMOTE PERSISTENCE IN PREP CARE

USING DNA/MVA/PROTEIN IMMUNIZATION OF RHESUS MACAQUES TO INVESTIGATE HOW THE BACKGROUND OF THE HIV-1 ENVELOPE AND NATURE OF THE PROTEIN BOOST SHAPE THE GENETIC AND FUNCTIONAL ANTIBODY LANDSCAPE.

WINSHIP NATIONAL CLINICAL TRIALS NETWORK LEAD ACADEMIC PARTICIPATING SITE

HUMAN VACCINE DURABILITY USING INTEGRATED BIOINFORMATICS AND A NOVEL IN VITRO BONE MARROW MIMIC

NEUROMECHANICAL MODELING OF POSTURAL RESPONSES

DYNAMIC DNA MODIFICATIONS IN BRAIN AND DISEASES

PREDOCTORAL TRAINING PROGRAM IN GENETICS

MULTIDISCIPLINARY RESEARCH TRAINING TO REDUCE INEQUITIES IN CARDIOVASCULAR HEALTH

MDMA-ASSISTED MASSED EXPOSURE THERAPY FOR PTSD

HBV CAPSID EFFECTORS

ASSESSING THE 5-YEAR EFFECTS OF A 500-DAY LIQUEFIED PETROLEUM GAS COOKING INTERVENTION: CONTINUED FOLLOW UP OF PARTICIPANTS FROM THE HOUSEHOLD AIR POLLUTION INTERVENTION NETWORK (HAPIN) TRIAL - NEARLY 3 BILLION PEOPLE CONTINUE TO USE SOLID FUELS (COAL, BIOMASS, ANIMAL DUNG) FOR HOUSEHOLD ENERGY NEEDS, PRIMARILY IN LOW- AND MIDDLE-INCOME COUNTRIES. THE HOUSEHOLD AIR POLLUTION RESULTING FROM COOKING WITH SOLID FUELS IS RESPONSIBLE FOR AN ESTIMATED 2.3 MILLION PREMATURE DEATHS AND ADDITIONAL MORBIDITY BURDEN EACH YEAR. HOUSEHOLD AIR POLLUTION EMISSIONS FROM COOKING WITH SOLID FUELS (CARBON DIOXIDE AND BLACK CARBON) ARE ALSO MAJOR SOURCES OF CLIMATE WARMING GASES AT THE GLOBAL LEVEL. OUR HOUSEHOLD AIR POLLUTION INTERVENTION NETWORK (HAPIN) TRIAL (NIH UM1HL134590) IS EVALUATING THE EFFECT OF A FREE LPG (LIQUEFIED PETROLEUM GAS) STOVE AND FUEL INTERVENTION AMONG 800 PREGNANT WOMEN IN EACH OF 4 COUNTRIES (GUATEMALA, INDIA, PERU, RWANDA) ON BIRTH OUTCOMES AND CHILD HEALTH THROUGH AGE 1; DATA COLLECTION HAS BEEN EXTENDED THROUGH AGE 2. THE TRIAL HAS ACHIEVED EXCELLENT RETENTION (92%), HIGH ADHERENCE TO THE INTERVENTION, AND A SUBSTANTIAL REDUCTION IN PERSONAL EXPOSURE TO FINE PARTICULATE MATTER (PM2.5) AND BLACK CARBON, A CONTRIBUTOR TO CLIMATE CHANGE. PRELIMINARY RESULTS SUGGEST THE INTERVENTION IMPROVES LENGTH AND WEIGHT AT BIRTH. RESEARCH SUGGESTS THAT EXPOSURE EXPERIENCED DURING GESTATION AND EARLY LIFE IS LINKED TO A RANGE OF LONGER-TERM OUTCOMES, AND THAT THE BENEFITS OF REDUCED EXPOSURE WILL CONTINUE EVEN IF THE INTERVENTION ENDS. THEREFORE, WE PROPOSE TO CONTINUE TO FOLLOW HAPIN CHILDREN THROUGH AGE 5 TO EVALUATE THE EFFECTS OF THE ORIGINAL HAPIN INTERVENTION ON NEUROLOGIC AND PHYSICAL DEVELOPMENT (AIM 1). FURTHER, GIVEN THAT THE INTERVENTION ENDS AT AGE 1, WE WILL CONTINUE TO CHARACTERIZE THE CHILDREN’S PERSONAL EXPOSURE TO PM2.5 AND BLACK CARBON (AIM 2), ALLOWING US THE UNIQUE ABILITY TO EVALUATE EXPOSURE-RESPONSE FOR SEVERAL RELEVANT PERIODS OF GESTATION AND EARLY CHILDHOOD (AIM 3). THE HAPIN TRIAL IS UNIQUELY POSITIONED TO ADDRESS THESE QUESTIONS, WITH A LARGE EXPOSURE CONTRAST DURING THE TRIAL AND THE GENERATION OF A RICH DATASET TO EXAMINE EXPOSURE-RESPONSE GIVEN THE EXPECTED HETEROGENEITY IN EXPOSURES AMONG CONTROL HOUSEHOLDS AND ALL PARTICIPANTS POST-TRIAL AS THEY ADOPT THE VARIOUS FUELS AND COOKING PRACTICES TYPICAL IN LMIC SETTINGS. THE SELECTED HEALTH OUTCOMES ARE SUPPORTED BY PREVIOUS LITERATURE AND HAVE IMPORTANT IMPLICATIONS FOR POLICY. OUR OVERARCHING HYPOTHESES ARE THAT 1) THE ORIGINAL INTERVENTION HAS LONGER TERM BENEFITS FOR NEUROLOGIC AND PHYSICAL DEVELOPMENT AFTER THE INTERVENTION ENDS, AND 2) THAT PERSONAL EXPOSURE TO PM2.5 AND BLACK CARBON DURING CRITICAL DEVELOPMENTAL PERIODS WILL BE INVERSELY ASSOCIATED WITH NEUROLOGIC AND PHYSICAL DEVELOPMENT. WE PROPOSE TO EXPLORE THESE AIMS AND HYPOTHESES IN HAPIN CHILDREN IN GUATEMALA, INDIA, AND RWANDA (N=2,175 CHILDREN REMAINING IN THE 3 STUDY SITES). THE PROPOSED WORK BUILDS ON THE MAJOR INVESTMENT ALREADY MADE IN THE HAPIN TRIAL BY EVALUATING WHETHER THE BENEFITS OF THE INTERVENTION EXTEND BEYOND PREGNANCY AND THE CHILD’S FIRST YEAR OF LIFE, LEVERAGING A WELL-CHARACTERIZED COHORT IN 3 DIVERSE SETTINGS, PROVIDING RIGOROUS AND WIDELY GENERALIZABLE ANSWERS TO QUESTIONS IMPORTANT FOR BOTH SCIENCE AND POLICY. WE ARE MAXIMIZING POTENTIAL FOR SUCCESS BY EXTENDING OUR PRIOR RESEARCH, USING AN EXPERIENCED AND PROVEN RESEARCH TEAM, WITH STRONG AND ONGOING RELATIONSHIPS WITH PARTICIPANTS.

EARLY RISK FACTORS OF ACCELERATED NEURAL AGING TRAJECTORIES AND COGNITIVE DECLINE: A NONHUMAN PRIMATE LONGITUDINAL MODEL - ABSTRACT: A STRONG LINK BETWEEN EARLY LIFE STRESS/ADVERSITY (ELS/ELA) AND AGE-RELATED DISORDERS, SUCH AS CARDIOMETABOLIC DISEASE, COGNITIVE AND PSYCHIATRIC/NEUROLOGICAL DISORDERS, HAVE BEEN ESTABLISHED MOSTLY BASED ON RETROSPECTIVE HUMAN REPORTS. YET, PROSPECTIVE, LONGITUDINAL, STUDIES ACROSS THE LIFE SPAN ARE CRITICAL TO IDENTIFY BIOMARKERS OF ELA RISK EMBEDDED EARLIER IN LIFE, DURING MIDDLE AGE TO DEVELOP EARLY INTERVENTION STRATEGIES. ANIMAL MODELS WITH SHORT LIFE SPANS (INVERTEBRATES, RODENTS) HAVE SIGNIFICANT LIMITATIONS TO INFORM ABOUT HUMAN AGING AND THE THERAPEUTICS DEVELOPED FROM THOSE MODELS HAVE FAILED IN CLINICAL TRIALS. LONGITUDINAL NONHUMAN PRIMATE (NHP) STUDIES COULD PROVIDE SIGNIFICANT INFORMATION ON EARLY BIOLOGICAL AND NEURAL MARKERS OF ELA-RELATED COGNITIVE DECLINE DUE TO THEIR LONG LIFE SPAN AND GRADUAL AGING-RELATED COGNITIVE IMPAIRMENTS AND BRAIN PATHOLOGY SIMILAR TO THOSE IN HUMANS EMERGING IN MIDDLE AGE. THIS PROPOSAL BUILDS ON OUR DATA LINKING ELA IN MACAQUES WITH EARLY MARKERS OF ACCELERATED CELLULAR AGING (ACCELERATED DNA METHYLATION AGE, SHORTENED TELOMERE LENGTH), INFLAMMATION, AND NEUROCOGNITIVE ALTERATIONS DETECTABLE FROM INFANCY TO YOUNG ADULTHOOD. THE GOAL IS TO USE A PROSPECTIVE, LONGITUDINAL DESIGN IN NHPS TO IDENTIFY EARLY BIOMARKERS/PATHWAYS AND UNDERLYING MECHANISMS OF ELA-RELATED ACCELERATED NEURAL AGING TRAJECTORIES AND COGNITIVE DECLINE FROM YOUNG ADULTHOOD TO MIDDLE AGE. THIS UNIQUE POPULATION OF ADULT FEMALE MACAQUES WITH ELA (SOCIAL SUBORDINATION STRESS) ARE CURRENTLY LIVING IN SOCIAL GROUPS AT THE YERKES NATIONAL PRIMATE RESEARCH CENTER AND WERE LONGITUDINALLY CHARACTERIZED FROM BIRTH THROUGH PUBERTY AS PART OF NIH-FUNDED STUDIES. THESE ANIMALS (HIGH-ELA: SUBORDINATES; LOW-ELA: DOMINANT) WILL BE STUDIED LONGITUDINALLY BETWEEN 7(EARLY ADULTHOOD) AND 11 (MIDDLE AGE) YEARS OF AGE. AIM 1 WILL EXAMINE TRAJECTORIES OF ELA-ACCELERATED NEURAL AGING IN BRAIN REGIONS THAT CONTROL COGNITIVE AND STRESS/EMOTIONAL FUNCTIONS STUDIED IN AIM 2 (PREFRONTAL CORTEX -PFC-, HIPPOCAMPUS -HIPP-, AMYGDALA); IT WILL USE (A) MRI, DTI AND RESTING STATE FMRI TO EXAMINE MYELIN LOSS, CORTICAL THINNING AND LOSS OF LONG-RANGE CONNECTIVITY; (B) MEASURES OF NEUROPATHOLOGY WITH MR SPECTROSCOPY (REDUCTIONS IN N-ACETYLASPARTATE) AND MARKERS PRECEDING DEMENTIA IN HUMANS (REDUCED AMYLOID SS(ASS42)/TAU RATIO IN CSF); AND (C) MARKERS OF NEUROINFLAMMATION AND NEUROTOXICITY (CSF LEVELS OF KYNURENINE PATHWAY METABOLITES). AIM 2 WILL TEST WHETHER ELA ACCELERATES AGE- RELATED DEFICITS IN STRESS/EMOTIONAL REGULATION MEDIATED BY PFC-AMYGDALA CIRCUITS (HPA AXIS, HUMAN INTRUDER AND DOT-PROBE TASKS), AND COGNITION: ATTENTION (CONTINUOUS PERFORMANCE TASK), EXECUTIVE FUNCTION AND COGNITIVE FLEXIBILITY MEDIATED BY PFC CIRCUITS (INTRADIMENSIONAL/EXTRADIMENSIONAL DISCRIMINATION), AND SPATIAL RELATIONAL MEMORY MEDIATED BY HIPP-PFC CIRCUITS (SPATIAL MEMORY SPAN). AIM 3 WILL EXAMINE ASSOCIATIONS BETWEEN LONGITUDINAL TRAJECTORIES OF NEURAL MEASURES (AIM 1) AND COGNITIVE OUTCOMES (AIM 2); WE WILL USE INNOVATIVE LONGITUDINAL STATISTICAL APPROACHES DEVELOPING INDIVIDUALIZED TRAJECTORY BIOMARKERS OF RISK AND RESILIENCE THAT MOVE BEYOND ASSOCIATION TO ESTABLISHING STATISTICAL CAUSATION. THE HYPOTHESIS IS THAT THE ELA GROUP WILL SHOW EARLY BIOMARKERS OF STRESS AND ACCELERATED TRAJECTORIES OF BIOLOGICAL AND NEUROCOGNITIVE AGING IN MIDDLE AGE.

ATLANTA PEDIATRIC SCHOLARS PROGRAM

MOLECULAR INTERACTIONS OF HIV-1 WITH THE NUCLEAR PORE COMPLEX

RGS14 INTEGRATION OF GI/O AND RAP1/2 SIGNALING PATHWAYS

PREDICTORS OF ANTIDEPRESSANT TREATMENT RESPONSE: THE EMORY CIDAR

B-CELL BIOLOGY OF MUCOSAL IMMUNE PROTECTION FROM SIV CHALLENGE

RETINAL MECHANISMS OF REFRACTIVE DEVELOPMENT

IMAGING OF SINGLE HIV-1 UNCOATING AND TRANSPORT TO THE NUCLEUS