Duke University

CENTER FOR HIV/AIDS VACCINE IMMUNOLOGY AND IMMUNOGEN DISCOVERY

ECHO COORDINATING CENTER

(CHAVI) CENTER FOR HIV/AIDS VACCINE IMMUNOLOGY

INDUCTION OF PROTECTIVE ANTIBODIES FOR HIV VACCINE DEVELOPMENT

ANTIBACTERIAL RESISTANCE LEADERSHIP GROUP (ARLG)

CENTER FOR INNOVATIVE TRIALS IN CHILDREN AND ADULTS (TRIDENT)

DUKE COMP CANCER CTR CORE SUPPORT GRANT

RADX-UP CDCC

PRAGMATIC EVALUATION OF EVENTS AND BENEFITS OF LIPID-LOWERING IN OLDER ADULTS (PREVENTABLE)

CTRS FOR MEDICAL COUNTERMEASURES AGAINST RADIATION

STUDIES OF NUCLEAR STRUCTURE USING NEUTRONS AND CHARGED PARTICLES

DUKE CTSA

SUPERFUND CHEMICAL IMPACT ON DEVELOPMENT

DUKE CTSA (COMPOSITE)

CENTER FOR AIDS RESEARCH (CFAR)

HEART FAILURE CLINICAL RESEARCH NETWORK COORDINATING CENTER

ERROR-CORRECTED UNIVERSAL RECONFIGURABLE ION-TRAP QUANTUM ARCHETYPE (EURIQA)

DETECTION AND ELIMINATION OF ONCOGENIC SIGNALING NETWORKS IN PREMALIGNANT AND MALIGNANT CELLS WITH MAGNETIC RESONANCE IMAGING

MODULATION OF B CELL RESPONSES IN AUTOIMMUNITY

DEVELOPING A HER3 VACCINE TO PREVENT RESISTANCE TO ENDOCRINE THERAPY

ALZHEIMER'S GUT MICROBIOME PROJECT

DUKE CTSI

DESIGN AND DEVELOPMENT OF A PAN-BETACORONAVIRUS VACCINE - ABSTRACT - OVERALL COMPARED TO SARS-COV-1 AND MERS, THE CURRENT SARS-COV-2 VIRUS IS HIGHLY TRANSMISSIBLE AND TO DATE HAS CAUSED OVER 85,000,000CASES WORLDWIDEWITH OVER 1,800,000 DEATHS. WITH AN ENDEMIC POPULATION OF MULTIPLEOTHER STRAINS OF COVS IN BATS, RODENTS WITH INTERMEDIATE HOSTS, CIVETS AND PANGOLINS, AND BECAUSE OF THE ABILITY OF COVS TO RECOMBINE, IT IS A CERTAINTY THAT NEW COVS WITH INFECTIOUS POTENTIAL FOR HUMANS WILL CAUSE FUTURE HUMAN PANDEMICS. TO ADDRESS THIS PROBLEM IN A FOCUSED AND INTEGRATED WAY, THIS P01 TEAM OF VIROLOGISTS, IMMUNOLOGISTS, COMPUTATIONAL BIOLOGISTS, STRUCTURAL BIOLOGISTS, BIOPHYSICISTS, EVOLUTIONARY BIOLOGISTS, AND TRADITIONAL VACCI NOLOGISTS WILL DEVELOP PANBETACORONAVIRUS (PANBETACOV) VACCINES, INCLUDING MERBECOVIRUSES (GROUP 2C), WHICH GAVE RISE TO MERS, AND SARBECOVIRUSES (GROUP 2B), WHICH GAVE RISE TO SARS COV-1 AND SARS COV-2, THE THREE MOST DEADLY BETACOV HUMAN OUTBREAKS. THE SIGNIFICANCE OF THIS GRANT IS THAT IT WILL PROVIDE FOR PANBETACOV VACCINES FOR FUTURE EPIDEMICS THAT CAN BE IMMEDIATELY AVAILABLE AT THE ONSET OF A BETACOV PANDEMIC, AVOIDING MUCH OF THE HUMAN TRAGEDY AND SOCIAL DISRUPTION CAUSED BY A PANDEMIC. THE OVERALL SPECIFIC AIMS OF THE P01 ARE: AIM 1. DEVELOP AND CHARACTERIZE IMMUNOGENICITY OF PANBETACOV SARBECOVIRUS (GROUP 2B) VACCINE CANDIDATES. AIM 2. DETERMINE GROUP 2B VACCINE CANDIDATE PROTECTION CAPACITY AGAINST GROUP 2B PANEL OF VIRUSES. AIM 3. DEVELOP PANBETACOVMERBECOVIRUS (GROUP2C) VACCINE CANDIDATES, DETERMINETHEIR IMMUNOGENICITY, CROSS- REACTIVITY WITH OTHER BETACOVS AND PROTECTION CAPACITY AGAINST GROUP 2C PANEL OF VIRUSES. THIS PROGRAM PROJECT GRANT INCLUDES FOUR PROJECTS. PROJECT 1 WILL DESIGN VACCINES IN ALPHAVIRUS REPLICON PARTICLE (VRP) VACCINE SYSTEM, DEVELOP AND TEST P01 VACCINES IN THEIR UNIQUE MOUSE COV CHALLENGE MODELS. PROJECT 2 WILL USE STRUCTURE-BASED MOLECULAR MODELING AND MONOMER AND MULTIMER NANOPARTICLE SPIKE PROTEIN DESIGNS AND TEST IN WILD-TYPE MOUSE MODELS. PROJECT 3 WILL BOTH DESIGN COV VACCINES AND TEST VACCINE DESIGNS EXPRESSED AS MRNAS IN LIQUID NANOPARTICLES (LNPS). PROJECT 4 WILL COMPUTATIONALLY DESIGN B AND T CELL PANBETACOV VACCINES. THIS P01 PROPOSES THREE CORES: AN ADMINISTRATIVE CORE, A BIOCONTAINMENT AND IMMUNE MONITORING CORE, AND A NON-HUMAN PRIMATE CORE. WORK IN THIS P01 WILL PROVIDE PANBETACOV VACCINES TO PROTECT AGAINST ESCAPE MUTANTS OF SARS-COV-2 IN THE CURRENT EPIDEMIC, AND WILL BE AVAILABLE TO PROTECT SOCIETY AGAINST NEW BETACOVS THAT MIGHT EMERGE TO INFECT HUMANS IN THE FUTURE.

PROMISE TRIAL: CLINICAL COORDINATING CENTER

THE RISKS AND OPPORTUNITIES OF HOMEOSTATIC REPOPULATION

DUKE CENTER FOR HIV STRUCTURAL BIOLOGY - ABSTRACT – OVERALL APPROXIMATELY 40 MILLION PEOPLE WORLDWIDE ARE LIVING WITH HIV/AIDS; HOWEVER, A PROTECTIVE VACCINE OR FUNCTIONAL CURE REMAIN ELUSIVE DESPITE FOUR DECADES OF INTENSE RESEARCH. HIV-1 EVADES THE IMMUNE SYSTEM THROUGH ITS RAPID STRUCTURAL EVOLUTION DURING INFECTION AND REPLICATION. THE PROPOSED DUKE CENTER FOR HIV STRUCTURAL BIOLOGY WILL PROVIDE NEW INSIGHTS INTO THE DYNAMICS OF HIV-1 ENTRY AND FUSION WITH THE HOST MEMBRANE, THE ENV-INITIATED IMMUNE ACTIVATION OF B-CELL RECEPTORS, AND THE ROLE OF ANTI-ENV ANTIBODIES IN BLOCKING VIRAL REBOUND. THE CENTER WILL PURSUE STRUCTURAL STUDIES THAT AIM TO 1) TO DEVELOP A COMPLETE, TIME RESOLVED AND ATOMICALLY DETAILED MECHANISM OF HIV-1 ENV FUSION; 2) TO DEFINE BCR COMPLEX STRUCTURES WITH SPECIFICITY OF AUTOLOGOUS (ANAB) AND BROADLY NEUTRALIZING ANTIBODIES (BNAB); AND 3) TO ACHIEVE AN ATOMIC LEVEL UNDERSTANDING OF ANTIBODY-MEDIATED CONTROL OF REBOUND FROM LATENT HIV-1 RESERVOIRS. THE ULTIMATE GOAL OF THESE STUDIES IS TO ADVANCE STRUCTURAL BIOLOGY TECHNIQUES AND KNOWLEDGE OF HIV-1 ENV STRUCTURE-DERIVED DISEASE MECHANISMS IN HIV-1 INFECTION AND REBOUND. ADDITIONALLY, THROUGH ITS DEVELOPMENTAL CORE, THE CENTER WILL PROVIDE RESOURCES AND TRAINING OPPORTUNITIES FOR EARLY CAREER INVESTIGATORS AND TRAINEES WHO ARE PURSUING CAREERS IN THE FIELD OF HIV-1 STRUCTURAL BIOLOGY.

SOSIP-NP/MRNA COMBINATION FOR NOVEL PREVENTIVE AND THERAPEUTIC HIV-1 VACCINE REGIMENS - ABSTRACT THE ULTIMATE GOAL OF THE PROPOSED STUDIES IS TO CONTRIBUTE TO ENDING THE HIV/AIDS EPIDEMIC. IT HAS BEEN FOUR DECADES SINCE THE START OF THE HIV/AIDS EPIDEMIC AND A PROTECTIVE VACCINE OR FUNCTIONAL CURE HAS BEEN ELUSIVE. IN 2020, THERE WAS AN ESTIMATED 37.6 MILLION PEOPLE LIVING WITH HIV. DESPITE HIGHLY ACTIVE ANTI-RETROVIRAL THERAPIES, HUNDREDS OF THOUSANDS OF PEOPLE STILL DIE FROM AIDS-RELATED DISEASES AND MILLIONS OF NEW INFECTIONS CONTINUE TO EMERGE. THUS, FINDING A WAY TO END THIS PANDEMIC REMAINS A GLOBAL PRIORITY. THE OVERALL GOAL OF THE CONSORTIUM FOR INNOVATIVE HIV/AIDS VACCINE AND CURE RESEARCH (CIAVCR) IS TO DEVELOP AN EFFECTIVE COMBINED IMMUNOTHERAPEUTIC REGIMEN FOR HIV-1 PREVENTION AND CURE USING THE NON- HUMAN PRIMATE (NHP) MODEL THAT HAS A DIRECT PATH TO THE CLINIC FOR USE IN HUMANS. THERE ARE TWO FOCI PROPOSED IN THE CIAVCR: IN FOCUS 1, OUR OVERALL GOAL IS TO DEMONSTRATE THE CORRELATES AND MECHANISMS OF PROTECTION FOR A PROTECTIVE VACCINE, AND THE ROLE OF VACCINE-INDUCED IMMUNE RESPONSES IN SELECTING AND LIMITING THE LATENT RESERVOIR. THE BENEFITS OF USING NOVEL MRNA CONSTRUCTS TO DELIVER IMMUNOGENS THAT CAN ELICIT BOTH HUMORAL AND CELLULAR RESPONSES WILL BE EVALUATED. IN FOCUS 2, OUR OVERALL GOAL IS TO DETERMINE THE ROLE OF VACCINE-INDUCED IMMUNE RESPONSES TO 1) CONTROL HIV-1 INFECTION BY REDUCING THE SIZE OR ELIMINATING HIV-1 RESERVOIRS, AND/OR 2) DELAY PLASMA VIRUS LOAD REBOUND. THE PROTECTIVE VACCINES STUDIED IN FOCUS 1 WILL BE TESTED TO DEFINE THE MECHANISMS OF VACCINE-INDUCED B AND T CELL RESPONSES IN CLEARING HIV-1 RESERVOIRS. ADDITIONALLY, NOVEL THERAPIES WILL BE COMBINED WITH THE VACCINES TO AUGMENT CLEARANCE OF HIV-1 RESERVOIRS. IN BOTH FOCUS 1 AND 2, ANALYSIS OF THE BREAKTHROUGH AND LATENT RESERVOIR ENV SEQUENCES WILL INFORM THE DESIGN OF NEW VACCINE BOOSTS FOR AN IMPROVED PROTECTIVE VACCINE REGIMEN THAT CAN ALSO LIMIT REBOUND VIRUSES. THE NHP-SHIV CENTRALIZED RESEARCH RESOURCE (CRR) WILL SUPPORT THE NHP STUDIES IN FOCUS 1 AND 2 TO INVESTIGATE THE EFFECTIVENESS OF VACCINE-INDUCED POLYFUNCTIONAL RESPONSES AND NOVEL IMMUNOTHERAPIES IN CLEARING HIV-1 RESERVOIRS. THESE STUDIES WILL USE INNOVATIVE BARCODED-SHIVS TO DETERMINE THE EFFECT OF VACCINE-INDUCED RESPONSES ON ELIMINATING THE VIRAL RESERVOIRS, AND TO EVALUATE THE QUANTITY AND QUALITY OF VIRUSES THAT ARE REACTIVATED BY LATENCY REVERSING AGENTS (LRAS) FOLLOWING TREATMENT INTERRUPTION. THE MANAGEMENT AND OPERATIONS SUPPORT UNIT (MOS) WILL COORDINATE THE SCIENTIFIC AND ADMINISTRATIVE ACTIVITIES OF THIS CIAVCR PROGRAM TO ENSURE THAT THE FOCI AND NHP-SHIV CRR FUNCTION COHESIVELY. BY THE END OF THIS GRANT, WE EXPECT TO HAVE DESIGNED A COMBINED PREVENTIVE AND THERAPEUTIC APPROACH TO EFFECTIVELY PROTECT FROM INFECTION AND ELIMINATE VIRAL RESERVOIRS—A STRATEGY FOR EFFECTIVELY IMPACTING THE HIV/AIDS PANDEMIC.

THE PURPOSE OF THIS COOPERATIVE AGREEMENT IS TO FUND RESEARCH IN SUPPORT OF BTO IN THE AMOUNT OF 2,991,338 ON CONTRACT HR0011-17-2-0069.

NSF ENGINEERING RESEARCH CENTER FOR PRECISION MICROBIOME ENGINEERING (PREMIER) -MICROBES HAVE COLONIZED AND ADAPTED TO MOST EVERY ENVIRONMENT ON EARTH, INCLUDING THE BUILT ENVIRONMENTS THAT HUMANS HAVE CREATED, SUCH AS THE HOMES WHERE WE LIVE AND THE PIPES THAT BRING US DRINKING WATER. IT HAS BEEN WELL ESTABLISHED THAT MICROBIAL COMMUNITIES, OR MICROBIOMES, THAT COLONIZE PEOPLE HAVE A DIRECT INFLUENCE ON HUMAN HEALTH. THE MICROBIOME OF THE BUILT ENVIRONMENT, IN PARTICULAR, HAS GAINED INCREASING RECOGNITION FOR ITS KEY ROLE IN HUMAN HEALTH THROUGH ITS INTERACTION WITH THE HUMAN MICROBIOME. HOWEVER, DESPITE THIS KNOWLEDGE, NO SYSTEMATIC INFRASTRUCTURE EXISTS TO DECIPHER HOW MICROBIAL SYSTEMS ADAPT TO AND GROW WITHIN BUILT ENVIRONMENTS, IMPEDING OUR ABILITY TO DIAGNOSE BUILT ENVIRONMENT HEALTH AND HARNESS THE POWER INHERENT TO THOSE MICROBIOMES. THE ENGINEERING RESEARCH CENTER FOR PRECISION MICROBIOME ENGINEERING (PREMIER) WILL CREATE MICROBIOME-BASED DIAGNOSTIC TOOLS AND DEVELOP MICROBIOME ENGINEERING APPROACHES TO MONITOR AND OPERATE BUILT ENVIRONMENTS THAT MAXIMIZE HUMAN HEALTH PROTECTION. INFORMED BY SOCIETAL NEEDS AND RESEARCH-STAKEHOLDER TEAMS, PREMIER?S RESEARCH DESIGN WILL WORK TO PREVENT THE SPREAD OF INFECTIOUS AGENTS, PROMOTE THE COLONIZATION OF BENEFICIAL MICROORGANISMS, AND LEAD TO STRATEGIES FOR CONTROLLING PANDEMICS AND ANTIBIOTIC RESISTANCE?PHENOMENA THAT HAVE LED TO OVER SIX MILLION DEATHS WORLDWIDE (AS OF JUNE 2022) AND COST THE GLOBAL ECONOMY AN ESTIMATED $8 TRILLION IN THE LAST YEAR ALONE. INTEGRAL TO ITS RESEARCH VISION, PREMIER WILL CREATE DIVERSE AND INCLUSIVE INTERDISCIPLINARY RESEARCH AND TRAINING HUBS WHERE ENGINEERS, MICROBIOLOGISTS, SOCIAL SCIENTISTS, AND ETHICISTS WORK ALONGSIDE THEORISTS, MODEL BUILDERS, AND COMPUTATIONAL SCIENTISTS TO DEVELOP TECHNOLOGIES THAT ENABLE TRANSFORMATIVE ENGINEERING DISCOVERIES IN SAFE, SUSTAINABLE AND RESPONSIBLE WAYS. OUR CAPACITY TO ENGINEER MICROBIOMES REQUIRES A FUNDAMENTAL UNDERSTANDING OF CONCEPTS OF COMMUNITY ECOLOGY AND AN ABILITY TO TRACK, CONTROL, AND MODEL THOSE INTERACTIONS. TO APPLY MICROBIOME ENGINEERING TO REAL-WORLD SYSTEMS, COMMUNITY LEVEL INTERACTIONS MUST BE INTEGRATED INTO A COMPREHENSIVE, SCALABLE MODELING FRAMEWORK THAT REQUIRES ITERATIVE EVALUATION AND VALIDATION IN MODEL TESTBEDS. PREMIER?S RESEARCH ORGANIZATION IS DESIGNED TO GENERATE FUNDAMENTAL UNDERSTANDING ACROSS THESE LEVELS AND FUNCTIONALITIES, CULMINATING IN THE DEVELOPMENT OF A FRAMEWORK THAT ENABLES THE BIODESIGN OF SMART AND HEALTHY BUILT ENVIRONMENTS. PREMIER WILL LEVERAGE ADVANCES IN HIGH-THROUGHPUT GENOMIC SEQUENCING, HIGH-RESOLUTION MASS SPECTROMETRY, COMPUTATIONAL PERFORMANCE, AND STATISTICAL MODELING TO UNRAVEL PREVIOUSLY UNKNOWN MECHANISTIC INTERACTIONS. ENABLING TECHNOLOGIES WILL BE DEVELOPED TO DETECT AND DEFINE INTERACTIONS IN THE BUILT ENVIRONMENT, INCLUDING APPROACHES THAT PROBE MICROBIAL DARK MATTER FOR THE DEVELOPMENT OF BUILT-ENVIRONMENT HEALTH DIAGNOSTIC TOOLS; METHODS FOR TARGETED DELIVERY OF DESIRED GENETIC FEATURES AND MICROBIAL VECTORS; TOOLS FOR FINE IN SITU FUNCTIONAL TUNING; AND PREDICTIVE SCALABLE STATISTICAL MICROBIOME ENGINEERING MODELS THAT CONSIDER HIGH DIMENSIONALITY, SPARSITY, AND HETEROGENEITY. THESE NEW TECHNOLOGY ELEMENTS WILL ENABLE US TO TEST HYPOTHESES RELATED TO MICROBIOME ASSEMBLY AND FUNCTION. IMPORTANTLY, BY INCORPORATING SOCIAL SCIENTISTS AND ETHICISTS INTO PREMIER?S RESEARCH FRAMEWORK, NON-SOCIAL SCIENTISTS? WORK WILL BE INFORMED BY CONSIDERATION OF THE ETHICAL, SOCIETAL, AND POLICY IMPLICATIONS OF THEIR MICROBIOME ENGINEERING DISCOVERIES. THROUGH RIGOROUS EVALUATION AND ITERATIVE REFINEMENT OF CURRICULA, AND INSTITUTIONAL PRACTICES DESIGNED TO SUPPORT A CULTURE OF CONVERGENCE AND THE DISSEMINATION OF FINDINGS, PREMIER WILL CONTRIBUTE TO BEST PRACTICES IN DOMESTIC TRAINING. THE PREMIER ERC WILL INCLUDE TARGETED RECRUITMENT OF TRAINEES FROM UNDERREPRESENTED GROUPS, BUILDING UPON EXISTING PARTNERSHIPS WITH OUR NATION?S LARGEST HBCU, AND WILL PROVIDE IMMERSION IN RESEARCH AND TRAINING AT THE INTERFACE OF MULTIPLE DISCIPLINES TO ADDRESS COMPLEX CHALLENGES. PREMIER WILL TRAIN THE NEXT GENERATION OF DIVERSE AND HIGHLY MOTIVATED ENGINEERS AND SCIENTISTS IN TECHNICAL AND PROFESSIONAL SKILLS TO COMPETE IN THE EMERGING ARENAS OF MICROBIAL SCIENCE AND ENGINEERING. ULTIMATELY, OUR WORK WILL ADVANCE COLLABORATIONS AND DISCOVERY FOCUSED ON ENVIRONMENTAL MICROBIOMES TO ENGINEER HEALTHY BUILT ENVIRONMENTS. 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.

NATIONAL EVOLUTIONARY SYNTHESIS CENTER

STUDIES OF NUCLEAR STRUCTURE USING NEUTRONS AND CHARGED PARTICLES

CONJUGATE NANOPARTICLE PLATFORM DEVELOPMENT FOR HIV-1 ENVELOPE IMMUNOGENS - ABSTRACT – OVERALL HIV-1 BROADLY NEUTRALIZING ANTIBODIES (BNABS) ARE PROTECTIVE IN ANIMAL MODELS OF HIV-1 INFECTION, BUT ARE NOT ELICITED IN HUMANS BY CURRENT VACCINE REGIMENS. TO ELICIT BNABS, THE B CELL LINEAGE VACCINE DESIGN APPROACH AIMS TO ADMINISTER MULTIPLE IMMUNOGENS IN A SPECIFIC SEQUENCE TO SHEPHERD BNAB MATURATION THROUGH IMMUNOLOGIC ROADBLOCKS THAT TYPICALLY HALT BNAB DEVELOPMENT. ONE ROADBLOCK WE RECENTLY IDENTIFIED ARE SOMATIC MUTATIONS THAT ENCODE KEY AMINO ACIDS FOR ANTIBODY FUNCTION BUT THAT ARE RARELY MADE BY THE SOMATIC MUTATION ENZYME ACTIVATION-INDUCED CYTIDINE DEAMINASE. OUR CENTRAL VACCINE DESIGN HYPOTHESIS IS THAT ANTIBODIES (ABS) ENCODING THESE IMPROBABLE MUTATIONS, WILL BE RARE; THUS, VACCINE IMMUNOGENS WILL NEED TO HAVE HIGHER AFFINITY FOR ABS WITH THESE DESIRED AMINO ACID CHANGES THAN ABS WITHOUT THE AMINO ACID CHANGES IN ORDER TO SELECT FOR THEM. THE PROBLEM FACING THIS STRATEGY IS THAT THE ONLY ANTIGEN FOR HIV-1 BNABS IS HIV-1 ENVELOPE (ENV), WHICH IS POORLY IMMUNOGENIC AND FOR WHICH BNAB PRECURSORS GENERALLY HAVE LOW AFFINITY. WE AND OTHERS HAVE FOUND THESE TWO OBSTACLES CAN BE OVERCOME BY DESIGNING ENVS WITH HIGH AFFINITY FOR BNAB PRECURSORS AND BY MULTIMERIZING THESE ENVS ON NANOPARTICLES (NPS) TO PROVIDE AVIDITY AND IMPROVED ANTIGEN TRAFFICKING TO GERMINAL CENTERS. HOWEVER, ENV TRIMER NPS CAN HAVE LOW EXPRESSION AND PRESENT MISFOLDED ENV TRIMERS THAT ELICIT UNDESIRED NON-NEUTRALIZING ABS. THIS APPLICATION IS SIGNIFICANT BECAUSE IT WILL ESTABLISH A CGMP-COMPLIANT VACCINE PLATFORM THAT RAPIDLY GENERATES HIGHER QUALITY HIV-1 ENV TRIMER NP VACCINES WITHOUT TIME-CONSUMING ITERATIVE IMMUNOGEN DESIGN. THIS PLATFORM USES THE SORTASE A ENZYME TO SITE-SPECIFICALLY, COVALENTLY-LINK WELL- FOLDED HIV-1 ENV TRIMERS TO INTACT HELICOBACTER PYLORI FERRITIN NPS. THE RESULTANT HIV-1 ENV TRIMER SORTASE A- CONJUGATED NPS (SCNPS) DISPLAY ONLY WELL-FOLDED ENV TRIMERS, AND IN PRELIMINARY STUDIES, HAVE SUCCESSFULLY INITIATED CD4 BINDING SITE BNAB LINEAGES IN HUMAN BNAB PRECURSOR KNOCK-IN MICE AND CD4BS NABS IN RHESUS MACAQUES. THE SCNP PLATFORM IS UNIVERSAL IN NATURE SINCE IT CAN INCORPORATE DIVERSE VIRAL TYPE I FUSION PROTEINS BY SIMPLY ADDING A 6-AMINO ACID SORTASE A TAG TO THEIR C-TERMINUS. IN SPECIFIC AIM 1, WE WILL COMPARE THE ABILITY OF MONOVALENT AND BIVALENT HIV-1 ENV SCNPS TO GUIDE AFFINITY MATURATION OF CD4 BINDING SITE BNABS IN HUMANIZED MICE AND RHESUS MACAQUES. IN SPECIFIC AIM 2, WE WILL PRODUCE AND ASSEMBLE TWO CD4 BINDING SITE-BNAB- TARGETING HIV-1 ENV TRIMER SCNPS (CH505 TF SCNP AND A SECOND SEQUENTIAL ENV TRIMER SCNP) UNDER CGMP CONDITIONS. THIS PROGRAM WILL DELIVER AN OPTIMIZED CGMP PROCESS FOR MAKING SCNPS, TWO CGMP-PRODUCED ENV TRIMER SCNPS, AND ADDITIONAL FERRITIN AND SORTASE A COMPONENTS FOR THE MANUFACTURE OF FUTURE IMMUNOGENS. THE CH505 TF ENV TRIMER SCNPS WILL BE USED IN A PHASE I TRIAL THROUGH THE HIV VACCINE TRIAL NETWORK. ULTIMATELY, THE IMPACT OF THIS PLATFORM IS THAT IT WILL ENABLE MULTIPLE ENV TRIMER SCNPS TO BE MADE RAPIDLY UNDER CGMP, MAKING IT FEASIBLE TO DO ITERATIVE TESTING IN CLINICAL TRIALS OF COMPLETE SEQUENTIAL NANOPARTICLE VACCINES THAT TARGET BNABS.

THE GENETICS OF BIOBEHAVIORAL RISK FACTORS FOR CVD

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP)

REPRODUCTIVE SCIENTIST DEVELOPMENT PROGRAM

CO-OCCURRING ADHD IN YOUNG CHILDREN WITH ASD: PRECURSORS, DETECTION, NEURAL SIGNATURES, AND EARLY TREATMENT

IMPACT OF ANTIBODY EFFECTOR FUNCTION DIVERSITY ON ANTIVIRAL ACTIVITY IN SITU - ABSTRACT_OVERALL PREVENTING HIV-1 ACQUISITION AND EXTINGUISHING VIRUS REPLICATION IS A KEY GOAL FOR VACCINE AND IMMUNOPROPHYLAXIS STRATEGIES. DIVERSE ANTIBODY (AB) FC RECEPTOR (FCR)-MEDIATED FUNCTIONS AND MULTIPLE EFFECTOR CELL POPULATIONS ENGAGE IN VIVO IN A JOINT MERGER TO THWART INFECTION. AN IMPROVED UNDERSTANDING OF SPECIFIC FUNCTIONAL AND QUALITATIVE FEATURES OF THE HUMORAL RESPONSE AND HOW THEY CONTRIBUTE TO PROTECTIVE EFFICACY IS NEEDED. RESULTS FROM IMMUNE CORRELATES ANALYSES OF VACCINE EFFICACY TRIALS, IMMUNOPROPHYLAXIS TRIALS AND PRECLINICAL STUDIES INDICATE THAT ANTIBODY CONSTANT (FC) REGION MEDIATED ANTIVIRAL ACTIVITY IS AN UNTAPPED SOURCE OF ANTIVIRAL FUNCTIONS TO AFFORD BROAD AND POTENT PROTECTION AGAINST HIV INFECTION. FULL EXPLOITATION OF THIS POTENTIAL DEMANDS A MORE COMPLETE UNDERSTANDING OF FC-MEDIATED IMMUNE MECHANISMS IN HUMANS AND ANIMAL MODELS. RATIONAL DESIGN OF PREVENTION METHODS REQUIRES MORE INFORMATION REGARDING EPITOPE TARGETS, COGNATE POLYCLONAL ANTIBODY (AB) ISOTYPES AND SUBCLASSES, DIVERSE FCR AND EFFECTOR CELL POPULATIONS, AND MOST IMPORTANT, HOW THESE ELEMENTS CAN BE PULLED TOGETHER FOR THE GREATEST ANTIVIRAL IMPACT. THE GOAL OF THIS PROGRAM IS TO DEFINE HOW FC-MEDIATED IMMUNITY CAN BE USED FOR PREVENTING, TREATING, CURING HIV INFECTION. WE PROPOSE TO DETERMINE THE COMBINED IMPACT OF ANTIBODY FC AND EFFECTOR CELLS ON ANTIVIRAL OUTCOMES IN SITU, THUS INFORMING HOW ANTIBODY FC EFFECTOR FUNCTIONS CAN BE USED TO IMPROVE ANTIBODY- BASED VACCINE STRATEGIES, INCREASE THE RELATIVE ANTIVIRAL ACTIVITY OF HIV-1 SPECIFIC ANTIBODY SUBCLASSES, AND AUGMENT BNAB- BASED PROPHYLACTIC AND THERAPEUTIC APPROACHES. OUR CENTRAL HYPOTHESIS IS THAT ANTIBODY ANTIVIRAL POTENCY IS MAXIMAL WHEN MULTIPLE ANTIBODY SPECIFICITIES AND SUBCLASSES ARE COMBINED AND THAT THEIR ANTIVIRAL FUNCTIONS ARE MODULATED BY THE IN VIVO LOCALIZATION OF FCR-BEARING EFFECTOR CELLS AND HOST GENETIC DETERMINANTS OF FC-FCR ENGAGEMENT. HARNESSING FC FUNCTION WILL IMPROVE BNAB VACCINE STRATEGIES GIVEN THE NEED TO INCREASE THE ANTIVIRAL FUNCTIONS OF NEUTRALIZING ANTIBODIES (NABS) AT SUB-EFFICACIOUS LEVELS. TOWARD THIS END, WE PROPOSE THREE SYNERGISTIC, INTER-RELATED PROJECTS SUPPORTED BY TWO CORES AND AN ADMINISTRATIVE CORE TO ACHIEVE THE FOLLOWING OVERALL AIMS: 1. IDENTIFY COMBINATIONS OF BNAB AND NNAB ANTIBODY SPECIFICITIES WITH MAXIMAL ANTIVIRAL ACTIVITY. 2. DEFINE THE CONTRIBUTION OF ANTIBODY FC DOMAIN (SUBCLASS, ALLOTYPE) ON ANTIVIRAL FUNCTIONS. 3. DETERMINE FCR AND EFFECTOR CELL POPULATIONS RESPONSIBLE FOR MAXIMAL AB FC ANTIVIRAL FUNCTIONS IN SITU.

GRADUATE RESEARCH FELLOWSHIP PROGRAM

THE DUKE FUNCTION CENTER: PIONEERING THE COMPREHENSIVE IDENTIFICATION OF COMBINATORIAL NONCODING CAUSES OF DISEASE

RESEARCH IN HIGH ENERGY PHYSICS AT DUKE UNIVERSITY

INCREASING THE QUALITY AND EFFICIENCY OF CLINICAL TRIALS (U18)

GRADUATE RESEARCH FELLOWSHIP PROGRAM (GRFP)

DUKE SPORE IN BRAIN CANCER

AI INSTITUTE FOR EDGE COMPUTING LEVERAGING NEXT GENERATION NETWORKS (ATHENA)

NORTH CAROLINA COMMUNITY SCHOOLS COALITION (NCCSC)

MESSENGER RNA IMMUNOGENS FOR INITIATION OF HIV V3-GLYCAN NEUTRALIZING B CELL LINEAGES

DUKE TRANSDISCIPLINARY PREVENTION RESEARCH CENTER

NSF CENTER FOR THE CHEMISTRY OF MOLECULARLY OPTIMIZED NETWORKS

CLAUDE D PEPPER OLDER AMERICANS INDEPENDENCE CENTERS (OAICS)

NOVEL MECHANISMS AND THERAPIES IN HEART FAILURE

MODULAR UNIVERSAL SCALABLE ION-TRAP QUANTUM COMPUTER

NIH HEALTH CARE SYSTEMS RESEARCH COLLABORATORY - COORDINATING CENTER

MESSENGER RNA IMMUNOGENS FOR INITIATION OF PROTECTIVE HIV NON-NEUTRALIZING ANTIBODIES

MEDICAL SCIENTIST TRAINING PROGRAM

BRIDGE TRIAL

COMPARE-UF

LUNG TRANSPLANT CLINICAL TRIAL NETWORK (LT-CTN) - ABSTRACT THIS LUNG TRANSPLANT CLINICAL TRIALS NETWORK (LT-CTN) CTOT-CA CONSORTIUM INCLUDES EIGHT OF THE LEADING HIGH- VOLUME, RESEARCH-ORIENTED ADULT AND PEDIATRIC LUNG TRANSPLANT PROGRAMS IN NORTH AMERICA. LONG-TERM SURVIVAL AFTER LUNG TRANSPLANTATION IS LIMITED BY CHRONIC LUNG ALLOGRAFT DYSFUNCTION (CLAD), THE FINAL MANIFESTATION OF CHRONIC LUNG TRANSPLANT REJECTION. CLAD IS NOT EFFECTIVELY PREVENTED BY LUNG TRANSPLANT IMMUNOSUPPRESSION, AS OVER 50% OF TRANSPLANT PATIENTS DEVELOP CLAD WITHIN FIVE YEARS. GROWING EVIDENCE SUGGESTS UPREGULATION OF INFLAMMATORY CYTOKINES IN THE LUNG ALLOGRAFT CONTRIBUTES TO CLAD DEVELOPMENT THROUGH INNATE IMMUNITY AND ALLORECOGNITION- DRIVEN ADAPTIVE IMMUNE RESPONSES. OUR PRELIMINARY DATA DEMONSTRATE THAT POST-TRANSPLANT ACUTE REJECTION (AR), LYMPHOCYTIC BRONCHIOLITIS (LB), ORGANIZING PNEUMONIA (OP), OR ACUTE LUNG INJURY (ALI) INCREASE CLAD RISK AND ARE ASSOCIATED WITH ELEVATIONS OF TYPES I & II CYTOKINES IN THE LUNG FLUID. BECAUSE TYPE I/II CYTOKINES SHARE SIGNALING THROUGH THE JANUS KINASE (JAK) FAMILY, BLOCKING THE RELEVANT JAKS COULD BE AN EFFECTIVE STRATEGY TO LIMIT INFLAMMATORY CYTOKINE RESPONSES AND PREVENT CLAD. OUR DATA DEMONSTRATE THAT ITACITINIB, A SELECTIVE JAK1 AND PARTIAL JAK2 INHIBITOR BEING TESTED IN PATIENTS WITH BONE MARROW TRANSPLANT, IS EFFECTIVE IN PREVENTING AR IN A FULLY MISMATCHED MURINE ORTHOTOPIC LUNG TRANSPLANT MODEL, AND THAT JAK1 IS HIGHLY OVEREXPRESSED IN HUMAN LUNG TRANSPLANT CLAD. THUS, WE HYPOTHESIZE THAT ADDITION OF ITACITINIB TO STANDARD POST-TRANSPLANT IMMUNOSUPPRESSION WILL REDUCE INFLAMMATION DUE TO CYTOKINE SIGNALING, DIMINISH FURTHER INNATE AND ADAPTIVE IMMUNE RESPONSES, AND PREVENT CLAD. TO TEST THIS, WE PROPOSE TO COMPLETE THE INHIBIT-CLAD (ITACITINIB RANDOMIZED, MULTI-CENTER, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL TO REDUCE LUNG INFLAMMATION AND PREVENT CLAD) STUDY, ENROLLING 450 BILATERAL LUNG TRANSPLANT RECIPIENTS OVER TWO YEARS AND RANDOMIZING 280 OF THOSE AT HIGHER CLAD RISK (EVIDENCE OF AR, LB, OP, OR ALI) TO TREATMENT WITH ITACITINIB OR PLACEBO AND FOLLOW-UP OVER THREE TO FIVE YEARS, TO DETECT THE PRIMARY OUTCOME OF CLAD. WE ALSO WILL COLLECT BIOSPECIMENS FROM ALL ENROLLED PARTICIPANTS AND CONDUCT MECHANISTIC STUDIES USING LUNG FLUID AND TISSUE FROM RANDOMIZED PATIENTS TO DETERMINE HOW INNATE IMMUNITY AND ADAPTIVE IMMUNE RESPONSES THAT CONTRIBUTE TO CLAD DEVELOPMENT ARE MITIGATED BY SELECTIVE JAK INHIBITION WITH ITACITINIB. FINALLY, AS CYTOMEGALOVIRUS (CMV) IS ANOTHER KEY CLAD RISK FACTOR – AND PREVENTABLE – WE PROPOSE A MULTI-CENTER INFECTIOUS DISEASE STUDY TARGETING PREVENTION OF CMV INFECTION AFTER LUNG TRANSPLANT USING NOVEL MEASURES OF CMV-SPECIFIC IMMUNITY TO PERSONALIZE ANTIVIRAL PROPHYLAXIS DURATION. OUR HIGHLY QUALIFIED TEAM OF INVESTIGATORS BRING LONGSTANDING, COLLABORATIVE, HIGHLY RELEVANT EXPERIENCE, INCLUDING LEADING THE ADULT CTOT-20 AND-22 AND THE PEDIATRIC CTOTC-03, -05, -08, AND -11 STUDIES. SUCCESSFULLY COMPLETED, THE STUDIES NOW PROPOSED HAVE POTENTIAL TO TRANSFORM CLINICAL PRACTICE, IMPROVE LUNG TRANSPLANT OUTCOMES, AND EXPAND TREATMENT PARADIGMS FOR IMMUNE SUPPRESSION AND ANTI-VIRAL PROPHYLAXIS AFTER SOLID ORGAN TRANSPLANTATION.

THE ISCHEMIA TRIAL - SDCC

COORDINATING CENTER FOR THE DRUG INDUCED LIVER INJURY NETWORK (DILIN)

BRIDGING ANTIBODY FC-MEDIATED ANTIVIRAL FUNCTIONS ACROSS HUMANS AND NON-HUMAN PRIMATES

COORDINATING CENTER FOR CALERIE

PFCQC: STAQ: SOFTWARE-TAILORED ARCHITECTURE FOR QUANTUM CO-DESIGN

NORTH CAROLINA INTEGRATED CARE FOR KIDS MODEL

DEVELOPMENT OF NOVEL THERAPIES FOR NIDDM

MOLECULAR TRANSDUCERS OF PHYSICAL ACTIVITY AND HEALTH: NC CONSORTIUM CLINICAL SITE

CENTER FOR ENVIRONMENTAL IMPLICATIONS OF NANOTECHNOLOGY

THE IGNITE II CC: ENGAGEMENT, COORDINATION, DEMONSTRATION, AND DISSEMINATION

HEALTH CARE SYSTEMS RESEARCH COLLABORATORY - COORDINATING CENTER

LEVERAGING ARTIFICIAL INTELLIGENCE TO PREDICT MENTAL HEALTH RISK AMONG YOUTH PRESENTING TO RURAL PRIMARY CARE CLINICS - PROJECT SUMMARY THIS STUDY, IN RESPONSE TO RFA-MH-25-195, AIMS TO ENHANCE, DEPLOY, AND RIGOROUSLY VALIDATE THE DUKE PREDICTIVE MODEL OF ADOLESCENT MENTAL HEALTH (DUKE-PMA), WHICH USES A NOVEL CLINICAL SIGNATURE DERIVED FROM AFFORDABLE, ACCESSIBLE MEASURES TO IDENTIFY YOUTH AT HIGH RISK FOR PSYCHIATRIC ILLNESS IN PRIMARY CARE SETTINGS. THE DUKE-PMA, A NEURAL NETWORK-BASED PREDICTIVE TOOL, HAS ALREADY DEMONSTRATED HIGH ACCURACY IN PREDICTING PSYCHIATRIC RISK ONE YEAR IN ADVANCE IN YOUTH AGED 10-15, USING DATA FROM THE ADOLESCENT BRAIN AND COGNITIVE DEVELOPMENT (ABCD) STUDY. NOTABLY, SLEEP DISTURBANCES HAVE EMERGED AS A KEY MODIFIABLE PREDICTOR IN THE MODEL. UNLIKE MOST PREDICTIVE MODELS THAT RELY ON CURRENT SYMPTOMS TO ANTICIPATE OUTCOMES, THE DUKE-PMA BASES ITS PREDICTIONS ON UNDERLYING DISEASE MECHANISMS AND PROTECTIVE FACTORS, MAKING IT BETTER SUITED TO INFORM PREVENTIVE INTERVENTIONS. FURTHERMORE, THE MODEL IDENTIFIES AN ELEVATED P-FACTOR, A GENERAL MEASURE OF PSYCHOPATHOLOGY THAT SPANS MULTIPLE PSYCHIATRIC CONDITIONS, MAKING IT BROADLY APPLICABLE ACROSS DIVERSE YOUTH POPULATIONS. OUR PROJECT WILL BEGIN BY OPTIMIZING THE DUKE-PMA THROUGH THE INCORPORATION OF BEHAVIORAL TASKS FROM THE NIH TOOLBOX TO ENHANCE ITS PREDICTION PERFORMANCE. FOLLOWING DUKE AI HEALTH’S ALGORITHM-BASED CLINICAL DECISION SUPPORT OVERSIGHT FRAMEWORK, WE WILL ENSURE THE MODEL ADHERES TO THE HIGHEST STANDARDS OF TRANSPARENCY, QUALITY, AND EQUITY. ADDITIONALLY, WE WILL APPLY TRUSTWORTHY AI TECHNIQUES DESIGNED TO REDUCE EFFECTS OF DISTRIBUTION SHIFTS ON MODEL PERFORMANCE TO ENSURE THE MODEL REMAINS EFFECTIVE AND EQUITABLE ACROSS DIVERSE CLINICAL SETTINGS AND DEMOGRAPHIC GROUPS. AFTER OPTIMIZATION, THE DUKE-PMA WILL BE DEPLOYED IN RURAL PRIMARY CARE AND PEDIATRIC CLINICS, WHERE ACCESS TO MENTAL HEALTH SERVICES AND RESEARCH PARTICIPATION IS OFTEN LIMITED. WE WILL ENROLL 2,000 YOUTH FROM RURAL CLINICS IN THE SOUTHEAST AND MIDWEST, PARTNERING WITH THE SCIENCE, TECHNOLOGY, AND RESEARCH (STAR) CLINICAL RESEARCH NETWORK. WE WILL ALSO EXPLORE THE BENEFIT OF ADDING A MEASURE OF HOME ENVIRONMENTS TO THE DUKE-PMA THROUGH DIGITAL ENVIROTYPING, WHICH USES AN AI-DRIVEN APPROACH TO ASSESS HOME ENVIRONMENTS REMOTELY WITHOUT REQUIRING IN-PERSON VISITS, MAKING IT MUCH MORE RESOURCE-EFFICIENT AND ACCESSIBLE THAN CURRENT APPROACHES. MODEL PERFORMANCE WILL BE VALIDATED THROUGH PSYCHIATRIC DIAGNOSTICS CONDUCTED ONE YEAR AFTER THE INITIAL ASSESSMENT. IF SUCCESSFUL, THIS PROJECT HAS THE POTENTIAL TO TRANSFORM MENTAL HEALTH RESOURCE ALLOCATION PARTICULARLY IN UNDERSERVED COMMUNITIES BY OFFERING AN ACCESSIBLE, LOW-COST, DATA-DRIVEN APPROACH TO IDENTIFY VULNERABLE YOUTH AND HIGHLIGHT MODIFIABLE RISK FACTORS FOR EARLY INTERVENTION.

CENTER FOR ADAPTIVE TREATMENT OF CIGARETTE ADDICTION

EXPANSION OF ANIMAL RESOURCES FOR LARGE ANIMALS

STATISTICAL AND APPLIED MATHEMATICAL SCIENCES INSTITUTE

CENTER FOR THE ENVIRONMENTAL IMPLICATIONS OF NANOTECHNOLOGY (CEINT)

NEONATAL PORCINE ISLET XENOGRAFTS FOR THE TREATMENT OF TYPE 1 DIABETES

DUKE/UNC ALZHEIMER'S DISEASE RESEARCH CENTER - ABSTRACT - OVERALL BEFORE IT KILLS, ALZHEIMER’S DISEASE (AD) EXACTS A DEVASTATING TOLL ON PATIENTS, FAMILIES, CAREGIVERS, AND COMMUNITIES. MOREOVER, EVEN IN 2020, THERE IS STILL NO PREVENTION OR CURE FOR AD. TO MEET THIS CHALLENGE, THE NEW DUKE/UNIVERSITY OF NORTH CAROLINA ADRC IS POISED TO TRANSFORM AD-RELATED RESEARCH AND SERVICES ACROSS THE RESEARCH TRIANGLE AND EASTERN NORTH CAROLINA. THE NEW DUKE/UNIVERSITY OF NORTH CAROLINA ALZHEIMER’S DISEASE RESEARCH CENTER (DUKE/UNC ADRC)’S THEME IS IDENTIFYING AGE-RELATED CHANGES ACROSS THE LIFESPAN THAT MEDIATE DEVELOPMENT, PROGRESSION, AND EXPERIENCE OF ALZHEIMER’S DISEASE (AD). IN SUPPORT OF THIS THEME, THE DUKE/UNC ADRC CLINICAL COHORT DESIGN AND BIOMARKER COLLECTION EQUIPS INVESTIGATORS WITH DATA AND RESOURCES TO DISCOVER NEW OPPORTUNITIES TO INTERVENE IN THE YEARS BEFORE AD SYMPTOMS MANIFEST. A RELATED CENTER GOAL IS TO IDENTIFY HOW FACTORS THAT ARISE IN EARLY AND MID-LIFE CONTRIBUTE TO RACIAL AND URBAN/RURAL DISPARITIES IN DEMENTIA. THE CENTER PLANS TO PROVIDE INFRASTRUCTURE AND RESOURCES ALIGNED WITH THE FOLLOWING SPECIFIC AIMS: 1) STIMULATE AND SUPPORT RESEARCH ON AD AND ALZHEIMER’S DISEASE-RELATED DEMENTIAS (AD+ADRD) FOR INVESTIGATORS FROM MANY FIELDS BY PROVIDING ACCESS TO WELL-CHARACTERIZED SUBJECTS, CURATED DATA AND BIOSPECIMENS FROM DIVERSE INDIVIDUALS ACROSS A WIDE AGE-SPECTRUM WITH AND WITHOUT DEMENTIA, WITH EMPHASIS ON PRE-CLINICAL AND EARLY DISEASE; 2) ATTRACT AND PREPARE DIVERSE, CREATIVE, WELL-TRAINED INVESTIGATORS TO CONDUCT HIGH CALIBER RESEARCH ON AD+ADRD AND 3) IMPROVE LIVES IMPACTED BY AGE-RELATED COGNITIVE DECLINE AND INCREASE THE INCLUSIVENESS OF THIS RESEARCH. THE CENTER’S CORES (CLINICAL, BIOMARKER, NEUROPATHOLOGY, DATA MANAGEMENT AND STATISTICS (DMS), OUTREACH, RECRUITMENT, AND ENGAGEMENT (ORE), ADMINISTRATIVE) AND RESEARCH EDUCATION COMPONENT (REC) WORK COLLECTIVELY TO PURSUE THESE AIMS, AIDED BY OUR TEAM’S DECADES OF DEMENTIA OUTREACH ACROSS NORTH CAROLINA, STRONG EXISTING TIES TO MINORITY AND RURAL COMMUNITIES, AND INSTITUTIONAL RESOURCES AND EXPERTS IN DISPARITIES RESEARCH. THE CENTER’S CLINICAL, BIOMARKER, AND NEUROPATHOLOGY CORES, IN CONJUNCTION WITH THE ORE CORE WILL SUPPORT COLLECTION OF IMAGES, BIOSPECIMENS, AND FLUIDS FROM OVER 500 WELL-CHARACTERIZED PARTICIPANTS ACROSS A BROAD AGE RANGE. THE DMS CORE WILL SUPPORT DATA CURATION AND ANALYSIS BY PROVIDING INTEGRATED DATA MANAGEMENT AND STATISTICAL/BIOINFORMATICS COLLABORATIVE EXPERTISE. THE REC WILL DEVELOP A ROBUST AND DIVERSE PIPELINE OF FUTURE LEADERS IN AD+ADRD RESEARCH THROUGH AN INNOVATIVE COMBINATION OF WIDELY DISSEMINATED CURRICULAR ELEMENTS AND MORE PERSONALIZED MENTORING EXPERIENCES. THE REC’S EDUCATIONAL PLATFORMS EXTEND TO THREE ADDITIONAL UNIVERSITIES IN OUR CATCHMENT AREA, INCLUDING TWO MAJORITY MINORITY INSTITUTIONS. THE ADRC’S CORES AND THE REC, SUPPORTED BY THE ADMINISTRATIVE CORE, WILL WORK IN A COORDINATED MANNER TO GENERATE AND STORE DATA AND RESOURCES FROM PEOPLE WITH AND WITHOUT DEMENTIA OR AD RISK, SHARE DATA AND EXPERTISE AS WIDELY AS POSSIBLE, AND ULTIMATELY CONTRIBUTE BACK TO THE AD COMMUNITY THROUGH DISSEMINATION OF RESULTS, EDUCATION, AND HEALTH SERVICES.

GUIDING EVIDENCE BASED THERAPY USING BIOMARKER INTENSIFIED TREATMENT (CCC)

SOFTWARE-TAILORED ARCHITECTURE FOR QUANTUM CO-DESIGN (STAQ) -QUANTUM COMPUTERS HOLD GREAT PROMISE TO CATALYZE A NEW ERA OF COMPUTATIONAL POWER THAT WILL BENEFIT ALL OF SOCIETY. HOWEVER, QUANTUM COMPUTER PROCESSING IS BASED ON RADICAL LAWS OF PHYSICS THAT HAVE NO ANALOG IN EVERYDAY LIFE, MAKING IT A CHALLENGE TO ATTRACT THE NEEDED TECHNICAL WORKFORCE AND USER BASE. THE NSF-STAQ PROGRAM IS A UNIQUE NATIONAL QUANTUM COMPUTER RESEARCH ACTIVITY THAT DESIGNS, RUNS, AND OPTIMIZES QUANTUM ALGORITHMS ON PROGRAMMABLE QUANTUM COMPUTER SYSTEMS IN A UNIVERSITY SETTING. STAQ QUANTUM COMPUTERS ARE DESIGNED AND BUILT IN-HOUSE AT DUKE UNIVERSITY, BASED ON THE MATURE AND SCALABLE PLATFORM OF TRAPPED ATOMIC IONS ? INDIVIDUAL ATOMS SUSPENDED ABOVE A CHIP WITH ELECTROMAGNETIC FIELDS AND CONTROLLED WITH LASER BEAMS. THE DUKE QUANTUM CENTER FEATURES SEVERAL PROGRAMMABLE QUANTUM COMPUTER SYSTEMS CAPABLE OF RUNNING GENERIC QUANTUM CIRCUITS AND APPLICATIONS. THE STAQ TEAM OF 17 INVESTIGATORS FROM 8 INSTITUTIONS, INCLUDING A CORE AT DUKE UNIVERSITY, EXERCISES COMPLETE CONTROL OF ALL HARDWARE AND SOFTWARE LAYERS. STAQ WILL BRING TOGETHER SCIENTISTS, ENGINEERS, COMPUTER SCIENTISTS, AND APPLICATION EXPERTS TO HASTEN QUANTUM COMPUTER ADVANTAGE OVER CONVENTIONAL COMPUTERS, WHILE EDUCATING THE PUBLIC AND BRINGING QUANTUM COMPUTERS TO USERS WHO MAY NOT BE FAMILIAR WITH QUANTUM MECHANICS OR ITS GROWING IMPORTANCE TO SOCIETY. SECURING QUANTUM ADVANTAGE IN COMPUTATION WILL REQUIRE A VERTICAL ?FULL STACK? APPROACH, INTEGRATING APPLICATION AND ALGORITHMIC DEVELOPMENT WITH SOFTWARE OPTIMIZATION AND CONTROL DOWN TO THE HARDWARE LEVEL COMPOSED OF CONTROLLABLE QUANTUM SYSTEMS TYPICALLY EXPRESSED IN TERMS OF QUANTUM BITS (QUBITS). STAQ HARDWARE IS BASED ON TRAPPED ATOMIC IONS, OWING TO THEIR HIGH LEVEL OF PERFORMANCE, RECONFIGURABILITY, AND SOFTWARE CONTROLLABILITY, ALL DESIGNED AND FABRICATED IN STAQ FACILITIES. HOWEVER, THE GENERAL APPROACH TO QUANTUM COMPUTING IN THE STAQ PROGRAM IS EXPECTED TO CONFER TO OTHER PHYSICAL PLATFORMS. THE STAQ PROGRAM WILL CO-DESIGN QUANTUM ALGORITHMS TO STAQ MACHINES HAVING MORE THAN 50 QUBITS AND GATE FIDELITIES WELL ABOVE 99% (INCLUDING INITIALIZATION AND MEASUREMENT ERRORS), THUS REACHING A REGIME WHERE QUANTUM COMPUTATIONS WILL CHALLENGE HIGH-PERFORMANCE CLASSICAL COMPUTERS. STAQ WILL PURSUE SEVERAL FAMILIES OF QUANTUM ALGORITHMS, INCLUDING APPROXIMATE OPTIMIZATION AND VARIATIONAL ALGORITHMS, QUANTUM SIMULATIONS OF PHYSICAL MODELS IN CONDENSED MATTER, BROAD CLASSES OF LATTICE GAUGE THEORY PROBLEMS APPLICABLE TO NUCLEAR PHYSICS, AND QUANTUM COMPUTER CERTIFICATION STANDARDS. STAQ WILL ENGAGE AND EDUCATE A BROAD BASE OF USERS, STUDENTS, AND OTHER RESEARCHERS INTERESTED IN QUANTUM COMPUTER SCIENCE AND ENGINEERING, WITH A VIBRANT VISITORS PROGRAM TO STIMULATE COLLABORATIONS AND NEW AREAS OF APPLICATION EXPLORATION. THIS PROJECT ADVANCES THE OBJECTIVES OF QUANTUM INFORMATION SCIENCE AND ENGINEERING AT NSF IN RESPONSE TO THE NATIONAL QUANTUM INITIATIVE ACT FOR THE CONTINUED LEADERSHIP OF THE UNITED STATES IN QIS AND ITS TECHNOLOGY APPLICATIONS. THIS AWARD BY THE PHYSICS AT THE INFORMATION FRONTIER PROGRAM IN THE DIVISION OF PHYSICS WITHIN THE DIRECTORATE FOR MATHEMATICAL AND PHYSICAL SCIENCES IS JOINTLY SUPPORTED BY THE DIVISION OF COMPUTING AND COMMUNICATION FOUNDATIONS IN THE DIRECTORATE FOR COMPUTER AND INFORMATION SCIENCE AND ENGINEERING. 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.

PACTTE-PARTNERSHIP FOR ANEMIA: CLINICAL AND TRANSLATIONAL TRIALS IN THE ELDERLY

VACCINE IMMUNOTOXIN AND RADIOIMMUNOTHERAPY OF PRIMARY AND METASTATIC CNS TUMORS

P30-CORE GRANT FOR VISION RESEARCH

PARENT BEHAVIOR AND CHILD ADJUSTMENT ACROSS CULTURES

TRIANGLE CENTER FOR EXCELLENCE FOR MATERIALS RESEARCH AND INNOVATION: PROGRAMMABLE ASSEMBLY OF SOFT MATTER

HEART FAILURE CLINICAL RESEARCH NETWORK - DCC

AN INTEGRATED AND DIVERSE GENOMIC MEDICINE PROGRAM FOR UNDIAGNOSED DISEASES

SIGNALING ABERRATIONS AND CEREBRAL CAVERNOUS MALFORMATION PATHOGENESIS

THE LUNG TRANSPLANT CLINICAL TRIALS NETWORK (LT-CTN)

THE DUKE SENESCENT CELL EVALUATIONS IN NORMAL TISSUES (SCENT) MAPPING CENTER - ABSTRACT –SCENT– OVERALL CELLULAR SENESCENCE IS A STRESS-RESPONSE, AS WELL AS A CRITICAL COMPONENT OF CELL FATE DURING DEVELOPMENT, REPAIR, RESILIENCE AND NORMAL AGING. DEEPENING AND BROADENING OUR INVESTIGATIONS INTO CELLULAR SENESCENCE IN NORMAL CONDITION WILL ADVANCE OUR KNOWLEDGE OF HEALTHY AGING AS WELL AS AGE-RELATED DISABILITIES, THEREBY LEADING TO INTEGRATED AND INCLUSIVE APPROACHES TO GERO-PROTECTION AND GERO-THERAPEUTICS. A COMPREHENSIVE, HIGH- RESOLUTION, ATLAS OF CELLULAR SENESCENCE IN VARIOUS HUMAN TISSUES BASED ON MULTIMODAL AND MULTIDIMENSIONAL ANALYSES IS REQUIRED TO ADDRESS THIS NEED. THE DUKE SENESCENT CELL EVALUATIONS IN NORMAL TISSUES (SCENT) U54 TISSUE MAPPING CENTER (TMC) WILL LEVERAGE THE BROAD AND WORLD-LEADING EXPERTISE OF DUKE UNIVERSITY SCHOOL OF MEDICINE FACULTY TO CONTRIBUTE TO THE OVERALL GOAL OF MAPPING SENESCENT CELLS AT SINGLE CELL RESOLUTION IN NORMAL HUMAN TISSUES OF ACROSS AGE-SPAN AND DEMOGRAPHICS. WE WILL TAKE ADVANTAGE OF DUKE'S BROAD EXPERTISE IN MANY AREAS, INCLUDING PULMONARY CRITICAL CARE, LUNG AND HEART TRANSPLANT SURGERY, TRANSLATIONAL RESEARCH, AND BIOINFORMATICS, TO COLLECT HIGH-QUALITY NORMAL TISSUE SPECIMENS FOR BIOBANKING, MULTIMODAL, HIGH-RESOLUTION ANALYSIS, AND DATA INTEGRATION TO FULLY CHARACTERIZE CELLULAR SENESCENCE IN HUMAN ORGANS AND TISSUES. THE DUKE SCENT TMC WILL BE ORGANIZED AROUND 4 CORES AS REQUIRED BY SENNET: THE ADMINISTRATIVE CORE (AC) OF THIS TCM WILL PROVIDE GUIDANCE AND LEADERSHIP TO THE OTHER CORES AND COMMUNICATE WITH NIH STAFF AND THE SENNET CONSORTIUM DURING THE SET-UP PHASE TO AGREE ON COMMON PROTOCOLS. THE BIOSPECIMEN CORE WILL ESTABLISH BEST PRACTICES FOR PROSPECTIVE ACQUISITION, PRESERVATION AND PROCESSING OF DIVERSE, HIGH-QUALITY NORMAL HEALTHY HUMAN TISSUES AND ASSOCIATED BIOFLUIDS. THE BIOLOGICAL ANALYSIS CORE WILL DELIVER STATE-OF-THE-ART PROFILING, LED BY A TEAM OF HIGHLY ACCOMPLISHED RESEARCH SCIENTISTS WHO HAVE SUCCESSFULLY UTILIZED THESE SPECIFIC PLATFORMS IN CONJUNCTION WITH PREVIOUS AND/OR CURRENT SENESCENT ANALYSES. THE DATA ANALYSIS CORE (DAC) WILL MANAGE, PROCESS AND ANALYZE THE DATA GENERATED TO PROFILE SENESCENT CELL SIGNATURES AND CONSTRUCT SENESCENT CELL TISSUE MAPS, AS WELL AS COLLABORATE WITH THE ADMINISTRATIVE CORE TO COORDINATE SHARING OF DATA, METHODS AND PIPELINES WITH OTHER SENNET INSTITUTIONS.

THE SOCIAL ENTREPRENEURSHIP ACCELERATOR AT DUKE (SEAD)

BIOCHRONICITY: TIME, EVOLUTION, NETWORKS, AND FUNCTION

DUKE CENTER FOR SYSTEMS BIOLOGY

EXPERIMENTAL THERAPY FOR BRAIN TUMORS

FUNDS FOR EMERGENCY STUDENT RELIEF

INCREASING THE QUALITY AND EFFICIENCY OF CLINICAL TRIALS (R18)

TARGETING THE B CELL RESPONSE TO TREAT ANTIBODY-MEDIATED REJECTION - ABSTRACT ANTIBODY-MEDIATED REJECTION (AMR) OF SOLID ORGAN TRANSPLANTS IS THE LEADING CAUSE OF IMMUNOLOGIC GRAFT INJURY, SHORTENING THE HALF-LIFE OF TRANSPLANTS AND CONSEQUENTLY OF TRANSPLANT RECIPIENTS. THIS IMMUNOLOGICALLY MEDIATED PROCESS DEPENDS ON B LYMPHOCYTE ACTIVATION WITH DIFFERENTIATION TO PLASMA CELLS (PC) THAT PRODUCE ANTIBODIES TO THE DONOR ORGAN. ONCE ESTABLISHED, ANTIBODIES HAVE PROVEN DIFFICULT TO ERADICATE. ESTABLISHING AN EFFECTIVE AND SAFE WAY TO TREAT PATIENTS WITH ESTABLISHED AMR WOULD POTENTIALLY INCREASE THE HALF-LIFE OF TRANSPLANTED ORGANS, EXTEND THE LIVES OF PATIENTS, AND REDUCE THE NEED FOR RE-TRANSPLANTATION, ULTIMATELY INCREASING THE NUMBER OF PATIENTS WHO COULD RECEIVE LIFE-SAVING ORGAN TRANSPLANTS. OUR LAB HAS DESCRIBED AN EFFECTIVE THERAPY IN A NON- HUMAN PRIMATE (NHP) SENSITIZED MODEL OF KIDNEY TRANSPLANTATION FOR LOWERING DONOR-SPECIFIC ANTIBODY (DSA) AND PREVENTING INJURY FROM AMR. THE TREATMENT DEPENDS ON PC DEPLETION IN COMBINATION WITH GERMINAL CENTER DISORGANIZATION WHICH TOGETHER LOWER ALLOANTIBODY LEVELS. DUAL TARGETING OF THE IMMUNE SYSTEM BY COMPLEMENTARY DRUGS IS BASED ON NHP AND HUMAN DATA USING A PROTEASOME INHIBITOR AND BELATACEPT. B CELL ACTIVATION AND DIFFERENTIATION IS INHIBITED AT THE SAME TIME THAT PC ARE DEPLETED. CONSEQUENTLY, DSA DECLINES, INFLAMMATION IN THE KIDNEY RESOLVES, AND RENAL FUNCTION STABILIZES. THE IMPACT OF THIS INTERVENTION ON INFECTION RISK IS NOT WELL DEFINED BUT IS ANTICIPATED TO INCREASE. WE PROPOSE TO MEASURE THE IMPACT OF THERAPY ON BOTH HLA-SPECIFIC AND PATHOGEN-SPECIFIC B MEMORY CELLS AND PC. WE HYPOTHESIZE THAT THERE IS A HIERARCHY OF SUSCEPTIBILITY TO THERAPY, WITH PROTECTIVE IMMUNITY BEING MORE RESISTANT THAN ALLOGENEIC B CELL MEMORY. WE WILL EVALUATE THE IMPACT OF THE REGIMEN ON T-CELL FUNCTION FOCUSING ON CYTOMEGALOVIRUS (CMV). CURRENT THERAPY OF LATE AMR USING THERAPEUTIC PLASMA EXCHANGE (TPE) AND INTRAVENOUS IMMUNE GLOBULIN (IVIG) WITH OR WITHOUT RITUXIMAB HAS SHOWN VARIABLE RESULTS AND FREQUENT REBOUND OF DSA. A LOW LEVEL OF EVIDENCE SUPPORTS THE EFFICACY OF THESE TREATMENTS, IMPLYING A TREMENDOUS NEED FOR WELL-CONDUCTED CLINICAL TRIALS TO GUIDE TREATMENT OF AMR. WE PROPOSE A PHASE I/II RANDOMIZED, CONTROLLED, PROSPECTIVE INTERVENTIONAL STUDY OF AMR IN HUMAN KIDNEY TRANSPLANT PATIENTS USING COMBINED CARFILZOMIB/BELATACEPT (C/B) THERAPY WITH TPE AND IVIG COMPARED TO TPE/IVIG ALONE. OUTCOMES WILL INCLUDE THE CLINICAL IMPACT OF THERAPY ON AMR USING THE RECENTLY VALIDATED IBOX SCORE FOR AMR ASSESSMENT AND THE NUMBER AND TYPE OF INFECTIONS USING STANDARDIZED DEFINITIONS OF INFECTION. WE WILL MEASURE THE IMPACT OF THERAPY ON HLA AND PATHOGEN-ASSOCIATED B MEMORY AND PC AS WELL AS CMV-SPECIFIC POLYFUNCTIONAL T-CELLS. WE WILL ASSESS COMPUTATIONAL DIGITAL IMAGING ANALYSIS OF AMR NON-VISUAL BIOPSY FEATURES TO ASSESS WHETHER MACHINE LEARNING ALGORITHMS CAN IMPROVE ON BANFF CRITERIA OF AMR TO BETTER GUIDE TREATMENT AND PREDICT CLINICAL OUTCOME. SINCE LATE ACTIVE AND CHRONIC ACTIVE AMR HAVE SUCH A POOR PROGNOSIS FOR KIDNEY TRANSPLANT PATIENTS, WE BELIEVE THAT THIS TRIAL IS ETHICALLY JUSTIFIED AND WOULD POTENTIALLY YIELD IMPORTANT SAFETY AND PRELIMINARY EFFICACY DATA THAT MAY LEAD TO IMPROVED IMMUNE MANAGEMENT OF TRANSPLANT PATIENTS.

STUDY OF OXYTOCIN IN AUTISM TO IMPROVE RECIPROCAL SOCIAL BEHAVIORS (SOARS-B)

HIV/AIDS CLINICAL TRIALS UNIT

TARGETING PATHWAYS INVOLVED IN CARDIAC INJURY FOR NOVEL REPAIR STRATEGIES

BREAST PRE-CANCER ATLAS CENTER

DTMI-CENTER FOR THROMBOTIC AND HEMOSTATIC DISORDERS

IDIOPATHIC PULMONARY FIBROSIS CLINICAL RESEARCH NETWORK

DUKE CENTER ON THE DEMOGRAPHY OF AGING

HEAL CLINICAL COORDINATING RESOURCE CENTER FOR THE PAIN MANAGEMENT EFFECTIVENESS RESEARCH NETWORK - THE HELPING TO END ADDICTION LONG-TERM (HEAL) INITIATIVE WAS DEVELOPED TO IDENTIFY SCIENTIFIC SOLUTIONS TO THE NATIONAL OPIOID PUBLIC HEALTH CRISIS AS QUICKLY AS POSSIBLE. AS PART OF THIS INITIATIVE, THE NIH HEAL PAIN MANAGEMENT EFFECTIVENESS RESEARCH NETWORK (HEAL PAIN ERN) WILL CONTINUE TO USE THE INFRASTRUCTURE OF THE NCATS TRIAL INNOVATION NETWORK TO PROVIDE SCIENTIFIC GUIDANCE AND COORDINATION OF THE HEAL PAIN ERN TRIALS. SPECIFICALLY, THE THREE TRIAL INNOVATION CENTERS (TICS) AT DUKE/VANDERBILT, UNIVERSITY OF UTAH, AND JOHNS HOPKINS/TUFTS WILL CONTINUE TO PROVIDE INTEGRATED FUNCTIONS FOR THE CLINICAL RESOURCE COORDINATING CENTER (CRCC), DATA COORDINATION RESOURCE CENTER (DCRC), AND THE STATISTICAL AND SAFETY RESOURCE CENTER (SSRC) FOR THE HEAL PAIN ERN. TWO ADDITIONAL HEAL PAIN ERN TRIALS WILL BE SELECTED WHICH WILL REQUIRE FULL SUPPORT FROM THE HEAL PAIN ERN CCRC, DCRC, AND SSRRC. IN ADDITION, FIVE ONGOING TRIALS SUPPORTED BY THE HEAL ERN WILL CONTINUE TO RECEIVE DEDICATED SUPPORT FROM THE RESOURCE CENTERS. THE DUKE/VANDERBILT TRIAL INNOVATION CENTER IS POISED TO: SPECIFIC AIM 1. PROVIDE CLINICAL TRIAL LEADERSHIP AND EXPERTISE, ASSISTANCE IN STUDY AND PROTOCOL DESIGN, STUDY IMPLEMENTATION, AND MANAGEMENT, IN COLLABORATION WITH THE OTHER HEAL ERN RESOURCE CENTERS, FOR EXISTING AND NEW HEAL ERN TRIALS. SPECIFIC AIM 2. SERVE AS THE CLINICAL COORDINATING RESOURCE CENTER (CCRC) FOR EXISTING AND NEW HEAL ERN TRIALS. SPECIFIC AIM 3. PROVIDE SINGLE IRB SUPPORT FOR HEAL ERN TRIALS FOR EXISTING AND NEW HEAL ERN TRIALS. THROUGH COMPLETION OF THESE SPECIFIC AIMS, WE WILL HARMONIZE THE HEAL STUDIES TO ACHIEVE MAJOR INNOVATIONS IN TRIAL DESIGN AND EXECUTION, INCLUDING: COMBINATION AND REUSE OF VALUABLE DATA, EFFICIENCIES OF IMPLEMENTATION, SHARED PAIN EXPERTISE AMONG INVESTIGATIVE TEAMS, AND THE INTEGRATION OF THREE TICS AS A COHESIVE UNIT, POISED FOR FUTURE TRIAL IMPLEMENTATION.

HIGH-THROUGHPUT FUNCTIONAL ANNOTATION OF GENE REGULATORY ELEMENTS AND VARIANTS CRITICAL TO COMPLEX CELLULAR PHENOTYPES - ABSTRACT LARGE SCALE GENOME ANNOTATION CONSORTIA SUCH AS ENCODE, EPIGENOMICS ROADMAP, AND OTHERS HAVE IDENTIFIED MILLIONS OF PUTATIVE REGULATORY ELEMENTS. WE NOW NEED TO FOCUS EFFORTS ON COMPREHENSIVELY CHARACTERIZING AND QUANTIFYING THE FUNCTION OF THOSE ELEMENTS, AND NONCODING VARIANTS THAT MAP WITHIN THESE REGIONS, ON GENE EXPRESSION AND CELL PHENOTYPES. OUR LONG-TERM GOAL IS TO ASSIGN FUNCTION TO EVERY REGULATORY ELEMENT AND NONCODING VARIANT IN THE HUMAN GENOME, UNDERSTAND HOW THAT FUNCTION CHANGES IN DIFFERENT CONTEXTS, AND USE THAT INFORMATION TO BETTER UNDERSTAND CELL FITNESS, DISEASE MECHANISMS, CELL LINEAGE SPECIFICATION, AND TISSUE HOMEOSTASIS. TO ACCOMPLISH THIS GOAL, WE HAVE DEVELOPED MULTIPLE NOVEL HIGH-THROUGHPUT CRISPR-BASED TECHNOLOGIES FOR CHARACTERIZING THE FUNCTION OF PUTATIVE GENE REGULATORY ELEMENTS BY PERTURBING THEIR ACTIVITY IN THEIR ENDOGENOUS, NATIVE CONTEXT. WE HAVE COUPLED THESE METHODS WITH SINGLE-CELL RNA-SEQ TO IDENTIFY THE TARGET GENE(S) FOR EACH REGULATORY ELEMENT. WE HAVE ALSO DEVELOPED DCAS9 EFFECTOR MICE TO CHARACTERIZE ELEMENTS IN THEIR NATURAL IN VIVO CONTEXT. IN ADDITION, WE HAVE DEVELOPED POPULATION-BASED HIGH-THROUGHPUT REPORTER ASSAYS (POP-STARR) TO CHARACTERIZE THE IMPACT OF NONCODING GENETIC VARIATION ACROSS THE ENTIRE GENOME. THE OBJECTIVE OF THIS PROPOSAL IS TO APPLY AND SHARE OUR COMPENDIUM OF COMPLEMENTARY, ROBUST, SCALEABLE, AND WELL-CHARACTERIZED METHODS BY WORKING COLLABORATIVELY TO SUPPORT THE IGVF CONSORTIUM GOALS OF UNDERSTANDING HOW GENOMES AND GENOMIC VARIATION FUNCTION AND ORCHESTRATE COMPLEX PHENOTYPES. OUR TRACK RECORD IN DEVELOPING, APPLYING, AND SHARING THESE HIGH-THROUGHPUT CHARACTERIZATION METHODS, AS WELL AS PROVIDING ACCESS TO ALL DATA, SUPPORTS THAT WE WILL BE SUCCESSFUL IN ACCOMPLISHING OUR OBJECTIVE VIA THE FOLLOWING SPECIFIC AIMS: AIM 1. CHARACTERIZE ALL GENE REGULATORY ELEMENTS ESSENTIAL FOR CELL SURVIVAL. AIM 2. CHARACTERIZE ALL GENE REGULATORY ELEMENTS ESSENTIAL TO CELL LINEAGE SPECIFICATION. AIM 3. CHARACTERIZE ALL GENE REGULATORY ELEMENTS IN SELECT EQTL REGIONS. AIM 4. CHARACTERIZE ALL NON- CODING ELEMENTS ESSENTIAL TO TISSUE HOMEOSTASIS IN A MOUSE MODEL. WE WILL MAKE ALL DATA IMMEDIATELY AVAILABLE, AS WELL AS SHARE COMPREHENSIVE PROTOCOLS, REAGENTS, AND ANALYSIS TOOLS TO THE SCIENTIFIC COMMUNITY. TOGETHER, THE DIVERSE APPROACHES OF THIS CHARACTERIZATION CENTER WILL LEAD TO TRANSFORMATIVE PROGRESS IN UNDERSTANDING THE ROLE OF REGULATORY ELEMENTS AND NONCODING VARIANTS ACROSS MANY DIVERSE PHENOTYPES.

CABANA-AF TRIAL

MOLECULAR REGULATION OF CARDIOVASCULAR 7 TM RECEPTORS

NOVEL APPROACHES TO STEM CELL TRANSPLANTATION

NEURAL SIGNATURES OF HEALTHY AND UNHEALTHY AGING

A SINGLE-SHOT THERAPY WILL ACCELERATE THE ELIMINATION OF BREAST CANCER

TRIAL TO ASSESS CHELATION THERAPY 2 (TACT2) DCC

NSF INCLUDES ALLIANCE: THE ALLIANCE FOR IDENTITY-INCLUSIVE COMPUTING EDUCATION (AIICE): A COLLECTIVE IMPACT APPROACH TO BROADENING PARTICIPATION IN COMPUTING

STICHES

RELIEF ASSISTANCE FOR STUDENT SUPPORT

CTSA UM1 AT DUKE UNIVERSITY - THE MISSION OF THE DUKE CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTE (CTSI), HOME TO THE CLINICAL AND TRANSLATIONAL SCIENCE AWARD (CTSA) SINCE 2006, IS TO CATALYZE TRANSLATIONAL SCIENCE IN WAYS THAT EFFECTIVELY AND EFFICIENTLY BRING MEDICAL DISCOVERIES TO SOCIETY. IN THE NEXT PHASE OF OUR CTSA, WE ARE POISED TO BUILD ON ESTABLISHED PROGRAMS AND CAPABILITIES TO MARKEDLY INCREASE OUR IMPACT. HOWEVER, WE ARE ACUTELY AWARE OF THE CHALLENGES POSED BY THE INCREASING DOUBTS ABOUT THE CREDIBILITY OF MEDICAL SCIENCE. IN RESPONSE TO DIMINISHED TRUST IN SCIENCE AND MEDICAL INSTITUTIONS AND DRIVEN BY OUR FIERCE COMMITMENT TO IMPROVE HEALTH FOR ALL, WE WILL FOCUS THE NEXT PHASE OF OUR CTSA ON “TRUSTWORTHY PARTNERSHIPS TO IMPROVE HEALTH THROUGH TRANSLATIONAL SCIENCE.” TO ENSURE THAT THE BENEFITS OF CLINICAL AND TRANSLATIONAL RESEARCH (CTR) ARE ACCESSIBLE TO ALL, WE WILL CENTER OUR PROGRAMS ON THE FOUNDATIONAL PRINCIPLES OF TRUSTWORTHINESS AND MEANINGFUL ENGAGEMENT OF PARTNERS AND THE COMMUNITY THAT INCLUDE BIDIRECTIONAL COMMUNICATION, SHARED RESOURCES AND DECISION MAKING, ATTENTION TO BALANCING POWER DYNAMICS, AND RESPECT FOR BROAD EXPERTISE AND EXPERIENCES. TOGETHER, WITH OUR PARTNERS AND COLLABORATORS, WE WILL: (1) CATALYZE INNOVATIONS THAT ADVANCE CLINICAL AND TRANSLATIONAL SCIENCE, (2) CULTIVATE AND DISSEMINATE A SUITE OF BEST- IN-CLASS RESEARCH SERVICES AND RESOURCES THAT ENABLES INVESTIGATORS AND PARTNERS TO CONDUCT EFFICIENT, EFFECTIVE RESEARCH ACROSS THE TRANSLATIONAL SPECTRUM, (3) CREATE, NURTURE, AND ADVANCE COMMUNITY-PARTNERED RESEARCH TO IMPROVE HEALTH FOR ALL ACROSS THE LIFESPAN, (4) TRAIN AND DEVELOP AN INTERPROFESSIONAL CLINICAL AND TRANSLATIONAL RESEARCH WORKFORCE PREPARED TO IMPLEMENT TRUSTWORTHY RESEARCH PROGRAMS THAT RAPIDLY TRANSLATE DISCOVERIES TO PRACTICE, AND (5) PROPAGATE AN INFORMATICS FRAMEWORK THAT ENHANCES DATA ACCESS, DATA TRANSPARENCY, AND THE TRUSTWORTHY APPLICATION OF BIOSTATISTICS, DATA SCIENCE, AND ARTIFICIAL INTELLIGENCE. WE WILL STUDY THE IMPACT OF OUR EFFORTS AND IDENTIFY EFFECTIVE APPROACHES TO FACILITATE THE ACHIEVEMENT OF IMPROVED HEALTH FOR ALL. WE WILL ALSO IMPLEMENT NEW PROCEDURES FOR MEASURING HEALTH IN OUR COMMUNITY. WE WILL DISSEMINATE GENERALIZABLE NOVEL APPROACHES AND PRACTICES THROUGHOUT THE CTSA CONSORTIUM AND BEYOND, CATALYZING EFFORTS TO IMPROVE HEALTH ACROSS OUR NATION.

ORGANIZATION AND FUNCTION OF CELLULAR STRUCTURE

NATIONAL CONSORTIUM ON ALCOHOL AND NEURODEVELOPMENT IN ADOLESCENCE: DUKE

CENTER FOR MULTISCALE IMMUNE SYSTEMS MODELING - THE CENTER OF EXCELLENCE (COE) IS A RESEARCH INITIATIVE THAT BRINGS TOGETHER EXPERTS FROM VARIOUS FIELDS TO DEVELOP INNOVATIVE SOLUTIONS FOR MULTI-SCALE MODELING IN INFECTIOUS AND IMMUNE-MEDIATED DISEASE (IID). THE COE CONSISTS OF THE: ADMINISTRATIVE CORE (AC), COMMUNITY DEVELOPMENT AND EDUCATION CORE (CDEC), MODEL AND DATA SHARING CORE (MDSC), AND THREE RESEARCH PROJECTS (RP). EACH COMPONENT PLAYS A CRUCIAL ROLE. THE AC SERVES AS A CENTRAL HUB, CONNECTING VARIOUS ENTITIES, AND PLAYS A CRITICAL ROLE IN PIVOTING COE RESOURCES DURING DISEASE OUTBREAKS. IT ADMINISTERS THE OPPORTUNITIES FUND, SUPPORTING PROPOSALS FROM INVESTIGATORS ACROSS NIAID- SPONSORED MODELING GROUPS. THE CDEC WILL DEVELOP EDUCATIONAL RESOURCES, BUILD COMMUNITIES OF PRACTICE AND LEARNING, ORGANIZE RESEARCH EXPERIENCES FOR GRADUATE STUDENTS AND POSTDOCTORAL FELLOWS, AND SET UP DOCUMENT SHARING FACILITIES, MESSAGING PLATFORMS, AND A CENTRALIZED WEBSITE TO FACILITATE KNOWLEDGE SHARING. THE MDSC WILL DEVELOP AN INFORMATICS INFRASTRUCTURE THAT ENABLES SEAMLESS INTEGRATION OF DATA AND MODELS ACROSS DIFFERENT SCALES, FACILITATING MORE ACCURATE PREDICTIONS AND INFORMED DECISION-MAKING. THE RPS FOCUS ON BRIDGING MODELS OF HOST-VIRUS INTERACTIONS ACROSS BIOLOGICAL SCALES. RP1 MODELS HUMORAL DEFENSE AGAINST VIRAL PATHOGENS, USING ANTIBODY-ANTIGEN MOLECULAR DYNAMICS AT THE MOLECULE SCALE TO UNDERSTAND THE CONSTRAINTS LIMITING THE EVOLUTION OF IMMUNE REPERTOIRES AT THE INDIVIDUAL SCALE. RP2 MODELS THE IMMUNE CELL AS A TARGET OF VIRAL INFECTION, USING AGENT-BASED MODELS OF LYMPHOID TISSUE AT THE CELL SCALE TO INFORM HOST-PATHOGEN DYNAMICS AT THE INDIVIDUAL SCALE. RP3 MODELS THE INTERACTIONS BETWEEN INDIVIDUALS AND POPULATIONS, USING AGENT BASED MODELS OF HOST-PATHOGEN INTERACTIONS AT THE INDIVIDUAL SCALE TO INFORM STOCHASTIC EPIDEMIC MODELS AT THE POPULATION SCALE. THE RESEARCH FOCUSES ON MODELING A SET OF CLINICALLY IMPORTANT VIRUSES, INCLUDING HIV-1, SARS-COV-2, EPSTEIN BARR VIRUS (EBV), AND OTHERS. THE MODELS CAN BE USED TO STUDY DISEASE PATHOGENESIS, THE EFFECT OF MEDICAL INTERVENTIONS, AND DISEASE TRANSMISSION IN HETEROGENEOUS POPULATION NETWORKS. KEY STRENGTHS OF THE PROPOSED COE ARE (1) THE ABILITY TO COORDINATE ADMINISTRATIVE APPROACHES AND TECHNOLOGIES FOR THE INFECTIOUS DISEASE MODELING COMMUNITY; (2) A COLLABORATIVE ENVIRONMENT THAT ENCOURAGES KNOWLEDGE SHARING, INNOVATION, AND THE DEVELOPMENT OF CUTTING- EDGE SOLUTIONS; (3) BALANCED REPRESENTATION OF THE EXPERIMENTAL AND COMPUTATIONAL COMMUNITIES WITHIN EACH CORE AND RP; (4) EXTENSIVE EXPERIENCE WITH IID MODELING, TEAM SCIENCE, EDUCATION, AND COMMUNITY DEVELOPMENT; (5) ROBUST INFORMATICS INFRASTRUCTURE FOR MODEL AND DATA SHARING THAT ALREADY HOSTS LARGE-SCALE NIH- FUNDED PROJECTS; (6) EXCEPTIONAL STRENGTHS INTEGRATING GENERATIVE DEEP LEARNING WITH COMPUTATIONAL MODELING IN THE MDSC AND RPS, AND (7) THE IMPORTANCE OF THE PROPOSED RESEARCH TO DEVELOP MORE ACCURATE IID MODELS THAT CAN INFORM PUBLIC HEALTH POLICY AND DECISION-MAKING. THE UNIQUE STRENGTHS OF THE PROPOSED COE MAKE IT AN IDEAL PLATFORM FOR ADVANCING IID RESEARCH, DEVELOPING INNOVATIVE SOLUTIONS TO COMPLEX PROBLEMS, AND RESPONDING DURING INFECTIOUS DISEASE OUTBREAKS, EPIDEMICS AND PANDEMICS.

LUNG TRANSPLANT CONSORTIUM - DATA COORDINATING CENTER - ABSTRACT LUNG TRANSPLANTATION IS AN EFFECTIVE AND LIFE-EXTENDING TREATMENT FOR PATIENTS WITH ADVANCED LUNG DISEASES. HOWEVER, IMPROVEMENTS ARE NEEDED IN DONOR MANAGEMENT, CANDIDATE SELECTION, AND RECIPIENT CARE TO PREVENT EARLY POSTOPERATIVE COMPLICATIONS AND IMPROVE THE LONG-TERM SUCCESS OF LUNG TRANSPLANTATION. TO ADDRESS THESE UNMET NEEDS, THE NHLBI IS CREATING THE MULTISITE LUNG TRANSPLANT CONSORTIUM (LTC) TO CONDUCT CLINICAL AND MECHANISTIC OBSERVATIONAL RESEARCH ACROSS UP TO 8 CLINICAL CENTERS (CCS) AND UP TO 24 INDIVIDUAL SITES. CENTRAL TO THE SUCCESS OF THE LTC IS A SINGLE DATA COORDINATING CENTER (DCC) THAT WILL OVERSEE CONSORTIUM WIDE ACTIVITIES INCLUDING THE DEVELOPMENT AND IMPLEMENTATION OF A COMMON PROTOCOL THAT WILL ENROLL APPROXIMATELY 3200 LUNG TRANSPLANT SUBJECTS PROSPECTIVELY COLLECTING CLINICAL DATA AND SERIAL BIOSAMPLES TO CREATE A UNIQUE RESOURCE FOR FUTURE RESEARCH. WITH THIS APPLICATION, THE DUKE CLINICAL RESEARCH INSTITUTE (DCRI), PROPOSES TO SERVE AS THE ADMINISTRATIVE AND OPERATIONAL HOME FOR THE LTC DCC, PARTNERING WITH THE BIOREPOSITORY EXPERTISE AND RESOURCES OF THE UNIVERSITY OF PENNSYLVANIA (PENN). THE DCRI-PENN DCC BRINGS UNPARALLELED CLINICAL LUNG TRANSPLANT SUBJECT MATTER EXPERTISE, LONGSTANDING PRIOR EXPERIENCE COORDINATING MULTICENTER RESEARCH STUDIES IN LUNG TRANSPLANTATION, AND OPERATIONAL RIGOR IN RESEARCH OVERSIGHT AND BIOSAMPLE COLLECTION THAT WILL FULLY SUPPORT AND ENHANCE THE LTC COMMITTEE STRUCTURE, COMMON PROTOCOL DESIGN AND IMPLEMENTATION, AND CC STUDIES. THE DCC WILL BE LED BY THE MULTIPLE PRINCIPAL INVESTIGATOR TEAM OF DRS. PALMER, CHRISTIE, AND NEELY, WHO TOGETHER BRING CONSIDERABLE AND COMPLEMENTARY EXPERTISE IN CLINICAL AND RESEARCH ASPECTS OF LUNG TRANSPLANT, DATA AND STATISTICAL METHODOLOGY, LEADERSHIP EXPERIENCE IN THE DESIGN, COORDINATION, AND PUBLICATION OF MULTICENTER RESEARCH STUDIES IN LUNG TRANSPLANT AND LUNG DISEASES. THE DCRI-PENN DCC TEAM COMPRISES ADDITIONAL EXPERTS IN TRANSPLANT SURGERY, DATA MANAGEMENT, REGULATORY AFFAIRS, SITE-BASED RESEARCH OVERSIGHT AND MONITORING, DIGITAL HEALTH, PATIENT ENGAGEMENT, WEB DESIGN AND COMMUNICATION. THUS, THE DCC TEAM IS OPTIMALLY POISED TO COLLABORATIVELY PARTNER WITH THE NHLBI AND CCS TO COMPLETE THE FOLLOWING AIMS: 1) CREATE LTC ADMINISTRATIVE INFRASTRUCTURE THAT FACILITIES EFFICIENT TEAM COMMUNICATION, TIMELY DISSEMINATION OF STUDY RESULTS AND DATA, AND PUBLIC ENGAGEMENT, INCLUDING CREATION AND MAINTENANCE OF THE LTC WEBSITE THAT SERVES AS A FOCAL POINT FOR PROTECTED CONSORTIUM COMMUNICATION AND ENGAGEMENT OF THE BROADER LUNG TRANSPLANT COMMUNITY AND KEY STAKEHOLDERS 2) PROVIDE THOUGHT LEADERSHIP AND OPERATIONAL INPUT THAT ENSURES THE EFFICIENT DEVELOPMENT OF HIGH-IMPACT, OPERATIONALLY FEASIBLE, AND SCIENTIFICALLY RIGOROUS COMMON PROTOCOL AND CC STUDIES, 3) OVERSEE COMMON PROTOCOL CONDUCT INCLUDING USE OF A SINGLE IRB, SITE OPERATIONS, ROBUST COLLECTION OF SERIAL SUBJECT DATA AND BIOSAMPLES, MONITORING OF DATA QUALITY, AND SAFETY REPORTING IN A MANNER THAT RESULTS IN TIMELY SUBJECT ENROLLMENT AND ENSURES THE RIGOR, QUALITY, AND COMPLETENESS OF CLINICAL DATA AND BIOSAMPLES.

REFINEMENT AND EXPANSION OF THE PALLIATIVE CARE RESEARCH COOPERATIVE GROUP (PCRC)

THERAPEUTIC TARGETING OF BREAST CANCER AND HOST IMMUNE RESPONSES AT INFLECTION POINTS IN THE DISEASE TRAJECTORY

MECHANISMS OF MALADAPTATION IN HEART FAILURE

DEMOGRAPHY OF SEX DIFFERENCES IN HEALTH AND SURVIVAL

NEURAL ARCHITECTURE OF THE MURINE AND HUMAN TEMPOROMANDIBULAR JOINT - ABSTRACT: TEMPOROMANDIBULAR DISORDERS (TMDS) ARE THE MOST COMMON FORM OF CHRONIC OROFACIAL PAIN, AFFECTING 5% OF U.S. ADULTS. DESPITE SUBSTANTIAL CLINICAL AND RESEARCH INTEREST IN THIS AREA, PROGRESS TO IDENTIFY AND TARGET PATHOPHYSIOLOGICAL MECHANISMS UNDERLYING TMDS HAS BEEN SLOW. THIS LACKLUSTER PROGRESS IS OWED IN LARGE PART TO OUR RELATIVELY PRIMITIVE UNDERSTANDING OF THE BASIC NEUROANATOMICAL, MOLECULAR, AND PHYSIOLOGICAL FEATURES OF SENSORY AFFERENTS PRESENT WITHIN THE TEMPOROMANDIBULAR JOINT (TMJ) TISSUES. THE RESTORING JOINT HEALTH AND FUNCTION TO REDUCE PAIN (RE-JOIN) CONSORTIUM SEEKS TO ADDRESS THIS KNOWLEDGE GAP THROUGH THE FORMATION OF INTERDISCIPLINARY TEAMS WHICH CAN DEFINE THE INNERVATION OF ARTICULAR AND PERI-ARTICULAR TISSUES THAT COLLECTIVELY MAKE UP THE JAW JOINT. TO THIS END, PROJECT MPIS DONNELLY (DUKE UNIVERSITY SCHOOL OF MEDICINE), EMRICK (UNIVERSITY OF MICHIGAN SCHOOL OF DENTISTRY), AND CAI (UNIVERSITY OF MICHIGAN MEDICAL SCHOOL) HAVE PARTNERED TOGETHER TO COMPREHENSIVELY MAP THE PERIPHERAL NEURAL ARCHITECTURE OF THE TISSUES OF THE TEMPOROMANDIBULAR JOINT (TMJ) IN MICE AND HUMANS. USING MRI-GUIDED STEREOTACTIC APPROACHES TO DELIVER RETROGRADE DYES AND VIRAL TRACERS WITH SPATIOTEMPORAL PRECISION, WE WILL INVESTIGATE THE MOLECULAR PROPERTIES OF PERIPHERAL SENSORY NEURONS WHICH INNERVATE DISTINCT TISSUES WITHIN THE MURINE TMJ IN BOTH STEADY-STATE AND TMD CONDITIONS, USING THIS INFORMATION TO BUILD NEW INTERSECTIONAL GENETIC MOUSE MODELS TO PERMIT WHOLE-TMJ MAPPING USING LIGHTSHEET MICROSCOPY. IN ADDITION, USING INTERSECTIONAL GENETIC APPROACHES IN CONJUNCTION WITH CHEMOGENETICS, IN VIVO CA2+ IMAGING, AND BEHAVIORAL PHENOTYPING, WE WILL CHARACTERIZE THE PHYSIOLOGICAL/FUNCTIONAL PROPERTIES OF TMJ-INNERVATING SENSORY NEURONS, ALLOWING US TO IDENTIFY NEURONAL SUBPOPULATIONS WHICH CONTRIBUTE TO CHRONIC PAIN IN TMD. TO ADDRESS THE TRANSLATIONAL GAP BETWEEN MICE AND HUMANS, WE WILL ESTABLISH A BIOBANK OF TMJ TISSUES FROM TMD-FREE HEALTHY HUMAN DONORS AND FROM A COHORT OF CLINICALLY-PHENOTYPED PATIENTS PURSUING ELECTIVE TMJ SURGERIES TO MANAGE CHRONIC INTRAARTICULAR TMD CONDITIONS, FOLLOWED BY QUANTITATIVE ANALYSIS OF PERIPHERAL AFFERENT SUBTYPES ACROSS TMJ TISSUES IN EACH COHORT. FINALLY, WE WILL BUILD A FREE, USER-FRIENDLY WEB- BASED PLATFORM TO INTEGRATE THE RESULTING TRANSCRIPTOMIC, FUNCTIONAL, AND MACROSCOPIC IMAGING DATASETS TO PERMIT WIDESPREAD DISSEMINATION OF THESE DATA, WHICH WE ANTICIPATE WILL YIELD A WORKING MODEL OF THE SENSORY ARCHITECTURE OF THE TEMPOROMANDIBULAR JOINT TISSUES IN MICE AND HUMANS, INCLUDING ALTERATIONS IN TMDS COMPARED TO STEADY-STATE CONDITIONS.

IS MENTAL DISORDER A PREVENTABLE CAUSE OF AGE-RELATED DISEASE? THE DUNEDIN STUDY.

HEALTH CARE INNOVATION CHALLENGE

DUKE-UNC PREVENTION EPICENTER PROGRAM FOR PREVENTION OF HEALTHCARE-ASSOCIATED INFECTIONS

METABOLOMIC SIGNATURES FOR DISEASE SUB-CLASSIFICATION AND TARGET PRIORITIZATION IN AMP-AD

HYBRID CENTRAL TRACKING

TRANSDISCIPLINARY PROGRAM TO IDENTIFY NOVEL ANTIFUNGAL TARGETS AND INHIBITORS

INTEGRASE DEFECTIVE LENTIVIRAL VECTOR (IDLV)-ENV IMMUNOGEN STRATEGY FOR AN HIV VACCINE

SOUTHEASTERN REGIONAL CENTER OF THE NATIONAL INSTITUTE FOR CLIMATIC CHANGE RESEARCH

DUKE CENTER FOR RESEARCH TO ADVANCE HEALTHCARE EQUITY (REACH EQUITY)

EVOLUTIONARY MECHANICS OF IMPULSIVE BIOLOGICAL SYSTEMS: GUIDING SCALABLE SYNTHETIC DESIGN

RELATIONSHIPS AMONG GENETIC REGULATORS OF AGING HEALTH AND LIFESPAN

DUKE NSCOR: LUNG CANCER RISK FROM HZE IONSTHE GOAL OF THE DUKE NSCOR IS TO UNDERSTAND MECHANISMS OF HIGH CHARGE AND ENERGY (HZE) ION-INDUCED LUNG C

TRANSCRANIAL DIRECT CURRENT STIMULATION FOR POST-STROKE MOTOR RECOVER - A PHASE II STUDY (TRANSPORT 2)

CLINICAL TRIALS TRANSFORMATION INITIATIVE

RESOURCES AND WORKFORCE DEVELOPMENT FOR THE REGIONAL BIOCONTAINMENT LABORATORIES - ABSTRACT – OVERALL DUKE UNIVERSITY IS PLEASED TO RESPOND TO RFA-IP-22-075 ENTITLED “LIMITED COMPETITION: RESOURCES AND WORKFORCE DEVELOPMENT FOR THE REGIONAL BIOCONTAINMENT LABORATORIES”. DUKE IS ONE OF 12-NIH FUNDED REGIONAL BIOCONTAINMENT LABORATORIES (RBLS) IN THE COUNTRY AND HAS PLAYED AN INSTRUMENT ROLE IN THE WORLD CLASS TRANSLATIONAL RESEARCH BEING CONDUCTED AT THE DHVI AND OTHERS THROUGHOUT DUKE AND THE RESEARCH TRIANGLE REGION, BY PROVIDING BSL-3 SUITES FOR VIROLOGY, IMMUNOLOGY, MICROBIOLOGY, AND ANIMAL MODEL SERVICES. SUPPORT FROM THIS GRANT WILL STRENGTHEN THE OVERALL INFRASTRUCTURE, ONGOING FACILITY AND EQUIPMENT MAINTENANCE, ESTABLISH AN ENHANCED BSL-3 SAFETY AND TRAINING PROGRAM, AND ENHANCE ACCESS TO AND CAPABILITIES OF THE EXISTING RBL RESEARCH SUPPORT SERVICES THAT ARE LOCATED IN THE BSL-3 ENVIRONMENT. THE SIGNIFICANCE OF THIS GRANT IS THAT IT WILL ALLOW THE DUKE RBL TO BETTER RESPOND TO EMERGING INFECTIOUS DISEASES AND PLAY A LEADING ROLE IN PANDEMIC PREPAREDNESS. SPECIFIC AIMS FOR THIS PROPOSAL ARE 1) TO MAINTAIN RELIABLE AND UNINTERRUPTED FACILITY FUNCTIONALITY; 2) TO ENSURE A SAFE, SECURE, AND COMPLIANT WORK ENVIRONMENT; AND 3) PROVIDE A STATE-OF- THE-ART BIOCONTAINMENT RESEARCH ENVIRONMENT AND RELATED SUPPORT SERVICES THAT ENHANCE THE NIAID BIODEFENSE FACILITIES NETWORK. THIS GRANT WILL CONTINUE TO ALLOW DUKE TO BE A CRUCIAL RESOURCE TO A TEAM OF INTERNAL AND EXTERNAL INVESTIGATORS DEDICATED TO STUDYING AND COUNTERING SELECT AGENTS AND BSL-3/ABSL-3 INFECTIOUS AGENTS OF GLOBAL IMPORTANCE.

DUKE KURE PROGRAM

CSBE: A PLACE FOR EVOLUTIONARY SYNTHESIS IN NORTH CAROLINA'S RESEARCH TRIANGLE

COORDINATING CENTER FOR THE DRUG INDUCED LIVER INJURY NETWORK (DILIN)

EXCEPTIONAL SURVIVAL IN DANISH AND ITALIAN FAMILIES

INSTITUTIONAL CAREER DEVELOPMENT CORE

"CENTER FOR BIOMEDICAL AND MATERIALS RESEARCH WITH FREE ELECTRON LASERS", (THE RECIPIENT'S TECHNICAL PROPOSAL DATED 20 OCT 03); THE TERMS AND CONDITI

DETERMINANTS OF AAV LUNG TROPISM

BEYOND GWAS: HIGH THROUGHPUT FUNCTIONAL GENOMICS & EPIGENOME EDITING TO ELUCIDATE THE EFFECTS OF GENETIC ASSOCIATIONS FOR SCHIZOPHRENIA - PROJECT SUMMARY SCHIZOPHRENIA (SCZ) GENOMICS HAS ACHIEVED UNPRECEDENTED ADVANCES. A DECADE AGO, THERE WAS PERHAPS ONE SOLID FINDING, AND THERE ARE NOW ~270 LOCI THAT MEET CONSENSUS CRITERIA FOR SIGNIFICANCE AND REPLICATION. AS OBSERVED FOR OTHER COMPLEX PSYCHIATRIC DISORDERS, THE IDENTIFIED REGIONS ARE OVERWHELMINGLY NONCODING, STRONGLY SUGGESTING THAT GENETIC VARIATION IN GENE REGULATORY ELEMENTS IS A MAJOR MECHANISTIC CONTRIBUTOR. FURTHER INVESTIGATION OF THOSE REGULATORY MECHANISMS IS PRECLUDED BY A FUNDAMENTAL GAP IN THE ABILITY TO IDENTIFY, CHARACTERIZE, AND QUANTIFY BRAIN-RELEVANT REGULATORY ELEMENTS, AND LIMITED UNDERSTANDING OF HOW GENETIC VARIATION WITHIN THOSE ELEMENTS INFLUENCES THEIR FUNCTION. TO ADDRESS THIS KNOWLEDGE GAP, THIS PROJECT WILL COMPREHENSIVELY IDENTIFY, CHARACTERIZE, QUANTIFY, AND VALIDATE NONCODING FUNCTIONAL NONCODING REGULATORY ELEMENTS AND VARIANTS IN NEURONAL CELLS. THE CENTRAL HYPOTHESIS OF THE PROPOSAL IS THAT NONCODING VARIATION CONTRIBUTES TO PSYCHIATRIC DISORDERS BY DIRECTLY ALTERING THE FUNCTION OF REGULATORY ELEMENTS IN THE BRAIN. THE MOTIVATION FOR THE PROPOSED STUDY IS THAT IDENTIFYING REGULATORY MECHANISMS OF PSYCHIATRIC DISORDERS HAS THE POTENTIAL TO TRANSLATE INTO IMPROVED DIAGNOSIS AND TREATMENT. POWERED BY A TEAM WITH STRONG INTERDISCIPLINARY EXPERTISE IN PSYCHIATRIC DISORDERS, FUNCTIONAL GENOMICS, TECHNOLOGY DEVELOPMENT, AND STATISTICAL GENETICS, THIS HYPOTHESIS WILL BE TESTED BY COMPLETING THREE SPECIFIC AIMS: 1) COMPREHENSIVE INTEGRATION OF DIVERSE DATA TYPES TO GENERATE HYPOTHESES THAT “CONNECT” PSYCHIATRIC GENETIC RESULTS TO SPECIFIC GENES; 2) PERFORM HIGH-THROUGHPUT CRISPR EPIGENOME EDITING SCREENS TO TEST AIM 1 HYPOTHESES IN A NATURAL BIOLOGICAL CONTEXT; 3) DEVELOP MECHANISTIC UNDERSTANDING AND VALIDATE FUNCTIONAL NONCODING SCZ RISK VARIANTS USING TF BINDING ASSAYS AND IPS-DERIVED NEURONS FROM SCZ CASES WITH HIGH GENETIC RISK SCORES. OUR APPROACH IS INNOVATIVE BECAUSE IT USES A HIGHLY COMPLEMENTARY AND DIVERSE SET OF EXPERIMENTAL APPROACHES TO DRIVE TARGETED GENETIC AND FUNCTIONAL INVESTIGATION INTO REGULATORY MECHANISMS RELEVANT FOR SCZ. IN DOING SO, THE PROPOSED RESEARCH PROVIDES A MUCH-NEEDED PATH FORWARD TO UNDERSTAND HOW NONCODING VARIATION CONTRIBUTES TO COMPLEX HUMAN PHENOTYPES.

DYNAMIC CAMOUFLAGE IN BENTHIC AND PELAGIC CEPHALOPODS:AN INTERDISCIPLINARY APPROACH TO CRYPSIS BASED ON COLOR, REFLECTION, AND BIOLUMINESCENCE

FOREST-ATMOSPHERE CARBON TRANSFER AND STORAGE (FACTS)

COMPREHENSIVE IDENTIFICATION OF ACTIVE FUNCTIONAL ELEMENTS IN HUMAN CHROMATIN

HOST DEFENSE MECHANISMS IN CHRONIC LUNG DISEASE

STICH TRIAL-COORDINATING CENTER

RACE-CARS CCC 1/2 - PROJECT ABSTRACT APPROXIMATELY 350,000 PEOPLE SUFFER OUT-OF-HOSPITAL CARDIAC ARREST (OHCA) EACH YEAR, WITH AN AVERAGE SURVIVAL RATE WITH GOOD NEUROLOGICAL FUNCTION OF ONLY 9.0%. IN RESPONSE TO THE CLEAR PUBLIC HEALTH IMPERATIVE SIGNALED BY THESE STATISTICS, THE INSTITUTE OF MEDICINE IN 2015 CALLED FOR STUDIES ON IMPLEMENTATION OF INTERVENTIONS FOR OHCA AT THE COMMUNITY, EMERGENCY MEDICAL SERVICES (EMS), AND HOSPITAL LEVELS. THE LACK OF CONSISTENT USE OF EFFECTIVE INTERVENTIONS ACROSS THE COUNTRY IS LARGELY DUE TO THE LACK OF HIGH QUALITY EVIDENCE FROM RANDOMIZED TRIALS ON HOW TO IMPLEMENT THESE INTERVENTIONS AT THE SYSTEMS (COMMUNITY) LEVEL. THE PROPOSED REGIONAL APPROACHES TO CARDIOVASCULAR EMERGENCIES- CARDIAC ARREST (RACE-CARS) CLUSTER-RANDOMIZED TRIAL HAS BEEN DESIGNED TO DEVELOP NEW SYSTEMS-BASED HIGH QUALITY CLINICAL TRIAL EVIDENCE ON HOW TO IMPROVE OUTCOMES FOR OHCA. THE PREMISE FOR RACE-CARS IS BASED ON PRIOR OBSERVATIONS SHOWING SUBSTANTIAL REGIONAL HETEROGENEITY IN CARE CORRELATED WITH VARIATIONS IN OUTCOMES. IN 11 NORTH CAROLINA COUNTIES, WE OBSERVED IMPROVED RATES OF BYSTANDER CPR AND FIRST RESPONDER DEFIBRILLATION, ASSOCIATED WITH A 37% INCREASE IN SURVIVAL WITH GOOD NEUROLOGIC OUTCOME OVER A 4-YEAR PERIOD. RACE-CARS, A 7-YEAR PRAGMATIC, CLUSTER RANDOMIZED (1:1) TRIAL OF 50 COUNTIES IN NC, WILL TEST WHETHER IMPLEMENTATION OF A CUSTOMIZED SET OF STRATEGICALLY TARGETED COMMUNITY-BASED INTERVENTIONS CAN IMPROVE SURVIVAL TO HOSPITAL DISCHARGE WITH GOOD NEUROLOGIC FUNCTION IN OHCA RELATIVE TO CONTROL/STANDARD CARE. OUR INTERVENTION PROGRAM WILL CONSIST OF 4 MAIN ELEMENTS: (1) OPTIMIZED MEDICAL 911-DISPATCH PERFORMANCE WITH RAPID RECOGNITION OF CARDIAC ARREST AND DISPATCH OF EMERGENCY RESPONSE, (2) ENHANCED 911-DISPATCH TELEPHONE COACHING OF BYSTANDER CPR, (3) IMPROVED FIRST RESPONDER PERFORMANCE WITH AED USE, AND (4) COMPREHENSIVE PUBLIC TRAINING OF CPR AND AED USE. QUALITY OF LIFE AND NEUROLOGICAL FUNCTIONAL STATUS WILL BE ASSESSED AT 6 AND 12 MONTHS. RACE-CARS WILL LEVERAGE OUR STATEWIDE EMERGENCY CARE NETWORK, WHICH HAS SUCCESSFULLY COLLABORATED ON IMPROVING QUALITY OF EMERGENCY CARDIOVASCULAR CARE OVER THE PAST 14 YEARS, AND ONGOING DATA COLLECTION OF THE MAJORITY OF CARDIAC ARRESTS IN NC USING THE CARES REGISTRY. WE WILL ENROLL ~20,000 PATIENTS WITH CARDIAC ARREST OVER THE STUDY PERIOD, TO GIVE US >90% POWER TO DETECT A 30% INCREASE IN BYSTANDER CPR, AND 50% INCREASE IN BYSTANDER OR FIRST RESPONDER DEFIBRILLATION, AND > 85% POWER TO DETECT A 33% INCREASE IN SURVIVAL WITH GOOD NEUROLOGIC OUTCOME. WHILE ALL THE INTERVENTION APPROACHES HAVE EVIDENCE FOR IMPROVED OUTCOMES IN PRIOR OBSERVATIONAL STUDIES, RACE CARS IS UNIQUE IN COMBINING THESE EFFORTS INTO A PRAGMATIC RANDOMIZED SYSTEMS-BASED IMPLEMENTATION TRIAL THAT CAN BE ADJUSTED TO THE NEEDS AND ABILITIES/RESOURCES OF REGIONS THAT VARY ACCORDING TO POPULATION DENSITY, DEMOGRAPHIC AND SOCIOECONOMIC STATUS. 1

DEVELOPMENT AND PREVENTION OF SUBSTANCE USE PROBLEMS

IMMUNOGEN DESIGN FOR INDUCTION OF HIV DISTAL GP41 BROADLY NEUTRALIZING ANTIBODIES

PATHOGENESIS, PROGNOSIS, AND TREATMENT OF NAFLD PATIENTS

CARNITINE ACETYLTRANSFERASE IN DEFENDING MITOCHONDRIAL AND METABOLIC FUNCTION

TRANSFUSION MEDICINE AND RELATED AREAS

THE OBJECTIVE OF THE SOUTHERN CENTER ON ENVIRONMENTALLY-DRIVEN DISPARITIES IN BIRTH OUTCOMES (SCEDDBO) IS TO DETERMINE HOW ENVIRONMENTAL, SOCIAL, AN

PATHOLOGICAL B CELLS: NOVEL STRATEGIES TO PREVENT AND TREAT CHRONIC GVHD

SRC ON PRIMARY AND METASTATIC TUMORS OF THE CNS

A DEVELOPMENTAL MODEL OF GENE-ENVIRONMENT INTERPLAY IN SUDS

CORONARY ARTERY CALCIUM IN THE PRAGMATIC EVALUATION OF EVENTS AND BENEFITS OF LIPID LOWERING IN THE ELDERLY: CAC PREVENTABLE ANCILLARY STUDY - ABSTRACT PREDICTING RISK IS CRITICAL FOR EFFECTIVE PRIMARY PREVENTION OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE (ASCVD), HOWEVER CLASSIFYING RISK IN ADULTS =75 YEARS OF AGE REMAINS EXTREMELY CHALLENGING. CORONARY ARTERY CALCIUM (CAC) SCORING AND HIGH-SENSITIVITY TROPONIN (HS-TN) ARE PROMISING TOOLS FOR RISK STRATIFICATION IN OLDER ADULTS BECAUSE THEY PROVIDE SINGULAR AND ENDURING SNAPSHOTS THAT DIRECTLY QUANTIFY A COMPOSITE OF CUMULATIVE RISK FACTOR EXPOSURE AND INDIVIDUAL RESILIENCY OR VULNERABILITY. USED JOINTLY, WE HAVE SHOWN THAT LOW VALUES OF CAC AND HS-TN MAY BE USEFUL FOR “DE-RISKING” OLDER POPULATIONS, IDENTIFYING INDIVIDUALS WITH HIGHLY FAVORABLE PROGNOSIS IN WHOM PREVENTIVE THERAPY MAY NOT BE BENEFICIAL. HOWEVER, DESPITE PROMISING OBSERVATIONAL DATA, THE TRUE CLINICAL VALUE OF CAC AND HS-TN IN OLDER ADULTS REMAINS UNCERTAIN DUE TO LACK OF A DEDICATED, ADEQUATELY POWERED RANDOMIZED TRIAL. THE NIA/NHLBI-FUNDED PREVENTABLE (PRAGMATIC EVALUATION OF EVENTS AND BENEFITS OF LIPID-LOWERING IN OLDER ADULTS) PRAGMATIC CLINICAL TRIAL, WHICH IS CURRENTLY RANDOMIZING 20,000 ADULTS =75 YEARS OF AGE TO ATORVASTATIN 40MG OR PLACEBO AND FOLLOWING FOR ASCVD EVENTS, PROVIDES THE IDEAL SETTING TO TEST THE CRITICAL HYPOTHESIS THAT CAC AND HS-TN JOINTLY IDENTIFY OLDER ADULTS WHO WILL BENEFIT THE MOST, AND THE LEAST, FROM STATIN THERAPY. IN THIS PROPOSAL, WE SEEK TO PERFORM BASELINE CAC SCANNING AND HS-TN MEASUREMENT IN 10,000 PREVENTABLE PARTICIPANTS. AT TRIAL CONCLUSION, WE WILL CONDUCT ANALYSES STRATIFIED BY CAC, AND JOINTLY BY CAC AND HS-TN, WITH >85% POWER TO DETERMINE HETEROGENEITY OF STATIN EFFECT BY BIOMARKER STATUS. AT THE END OF THE TRIAL, WE WILL DEVELOP A COMPREHENSIVE ASCVD RISK CLASSIFICATION MODEL USING TRADITIONAL RISK FACTORS, CAC, AND HS-TN AND VALIDATE THIS IN MESA AND ARIC. WE WILL THEN CONSTRUCT AN ONLINE TOOL SIMILAR TO THE LIFE-CVD MODEL FOR CALCULATING ESTIMATED BENEFIT OF STATIN THERAPY IN THE AGE =75 PRIMARY PREVENTION POPULATION, AFTER DETAILED ACCOUNTING FOR NON-CVD COMPETING RISKS OBSERVED IN PREVENTABLE. IN SUMMARY, WE BELIEVE THAT CAC SCANNING AND HS-TN MEASUREMENT IN PREVENTABLE IS THE MOST EXPEDITIOUS AND INSTRUCTIVE WAY TO FILL CRITICAL KNOWLEDGE GAPS ABOUT SUBCLINICAL ASCVD IN AN OLDER PRIMARY PREVENTION POPULATION AND TO DETERMINE THE VALUE OF A BIOMARKER-GUIDED PRECISION MEDICINE APPROACH FOR INFORMING INDIVIDUAL BENEFIT OF PREVENTIVE STATIN THERAPY.

HIV-1 VACCINE-ELICITED ANTIBODIES TARGET ENVELOPE GLYCANS

(MURI) META-IMAGING: SENSING, PROCESSING AND COMPUTING WITH DYNAMIC METASURFACES

SPICES: SPINODAL-HARDENED HIGH-ENTROPY CERAMICS

INTERDISCIPLINARY RESEARCH TRAINING PROGRAM IN AIDS

VIA MULTI-SECTOR, TRANSDISCIPLINARY COLLABORATION, AND IN CONSULTATION WITH WIND ENERGY STAKEHOLDERS, WE WILL DEVELOP A STRUCTURED FRAMEWORK FOR COMPREHENSIVE EVALUATION OF POTENTIAL EFFECTS OF OFFSHORE WIND ENERGY ON WILDLIFE AND HABITATS, ACROSS A RANGE OF SPATIAL AND TEMPORAL SCALES. THE PROJECT GOALS ARE FRAMED AROUND DEFINED MANAGEMENT AND CONSERVATION QUESTIONS AND AIM TO IMPROVE OUR UNDERSTANDING OF THE EFFECTS OF OFFSHORE WIND ENERGY DEVELOPMENT ON WILDLIFE AND HABITATS, POSITIVE OR NEGATIVE; TO IMPROVE OUR UNDERSTANDING OF THE MECHANISMS FOR THESE EFFECTS; TO DISTINGUISH BETWEEN SHORT-AND LONG-TERM EFFECTS, AS WELL AS THEIR CUMULATIVE OR POPULATION-LEVEL RAMIFICATIONS; AND TO FURTHER DEVELOP AND VALIDATE METHODS FOR EXAMINING AND ASSESSING THESE EFFECTS. WE WILL DO THIS THROUGH STRATEGIC MONITORING AND INTEGRATED RESEARCH, SYNCHRONIZED WITH PLANNED DEVELOPMENT ACTIVITIES, THAT WILL ENABLE STATE AND FEDERAL AGENCIES AND WIND ENERGY DEVELOPERS TO INTEGRATE LOCAL-SCALE INFORMATION WITH EXISTING REGIONAL AND ECOSYSTEM-LEVEL SCIENTIFIC DATA TO INTER ALIA REDUCE UNCERTAINTY IN IMPACT ASSESSMENTS AT BOTH THE INDIVIDUAL AND POPULATION LEVELS.

SP-A AS AN IMMUNE MODULATOR

MOLECULAR ATLAS OF LUNG DEVELOPMENT - DATA COORDINATING CENTER

INTEGRATED CENTER FOR IN VIVO MICROSCOPY

CANCER CELL INTRINSIC AND EXTRINSIC ACTIONS OF STEROID HORMONES IN BREAST TUMORS

A COMPREHENSIVE RESEARCH RESOURCE TO DEFINE MECHANISMS UNDERLYING MICROBIAL REGULATION OF HOST METABOLISM IN PEDIATRIC OBESITY AND OBESITY-TARGETED T

COOPERATIVE AGREEMENT TO SUPPORT REGULATORY RESEARCH RELATED TO THE 2018 PRESCRIPTION DRUG USER FEE ACT AND THE 21ST CENTURY CURES ACT (U19)

CREATION AND DEMONSTRATION OF A PALLIATIVE CARE RESEARCH COOPERATIVE GROUP

NEW START CO-OP WITH DUKE UNIVERSITY

PRECLINICAL STUDIES OF A CRYPTOCOCCUS VACCINE FOR AIDS PATIENTS

NUCLEAR PHYSICS AT EXTREME ENERGY DENSITY

QUANTUM CONTROL BASED ON REAL-TIME ENVIRONMENT ANALYSIS BY SPECTATOR QUBITS

1/2 IMPACT-LBP CCC-ADMINISTRATIVE SUPPLEMENTS FOR COMPLEMENTARY HEALTH PRACTITIONER RESEARCH EXPERIENCE - IMPACT-LBP IS REQUESTING AN ADMINISTRATIVE SUPPLEMENTS FOR COMPLEMENTARY HEALTH PRACTITIONER RESEARCH EXPERIENCE (ADMIN SUPPLEMENTS) UNDER NOTICE OF SPECIAL INTEREST NOT-AT-22-010. IMPACT-LBP OVERARCHING GOAL REMAINS UNCHANGED, WHICH IS TO REFINE AND IMPLEMENT A MULTIDISCIPLINARY COLLABORATIVE CARE MODEL FOR LBP (MC2LBP) IN 3 ACADEMIC HEALTH CARE SYSTEMS (HCS) AND THEN EVALUATE ITS EFFECTIVENESS BY COMPARING IT TO USUAL MEDICAL CARE IN PATIENTS AGE 18 AND OLDER SUFFERING FROM LBP. WE ARE CURRENTLY IN YEAR 2/UH3 PHASE OF OUR FIVE YEAR PROJECT. THIS ADMINISTRATIVE SUPPLEMENT IS TO SUPPORT OUR IDENTIFIED CANDIDATE, ROMEO PERFECTO, DC, MS, CCSP AND WILL SERVE AS A SUITABLE VEHICLE FOR HIS ONGOING TRAINING IN METHODOLOGY, THEORIES, AND CONCEPTS NEEDED TO CONDUCT RESEARCH IN COMPLEMENTARY AND INTEGRATIVE HEALTH.

GENETIC REGULATION OF GENOME STABILITY IN YEAST

IMPROVING NEONATAL HEALTH THROUGH RAPID MALARIA TESTING IN EARLY PREGNANCY WITH HIGH-SENSITIVITY DIAGNOSTICS (INTREPID) - PROJECT SUMMARY/ABSTRACT NEWBORN HEALTH HAS IMPROVED GLOBALLY BUT THERE REMAINS A CRITICAL NEED IN RESOURCE-LIMITED SETTINGS TO REDUCE NEONATAL MORTALITY. NEARLY ALL INFANT DEATHS IN SUB-SAHARAN AFRICA OCCUR IN BABIES THAT ARE SMALL OR LOW BIRTHWEIGHT, WHICH OFTEN RESULT FROM ANTENATAL INFECTIONS WITH PLASMODIUM FALCIPARUM. THESE MALARIA EFFECTS CAN BE PARTIALLY MITIGATED BY PREGNANCY-SPECIFIC MEASURES INCLUDING THE ADMINISTRATION OF MONTHLY ANTENATAL DOSES OF SULFADOXINE-PYRIMETHAMINE AS INTERMITTENT PREVENTIVE THERAPY DURING PREGNANCY (IPTP-SP), BUT THESE ARE NOT TYPICALLY IMPLEMENTED UNTIL THE 2ND TRIMESTER, AND SO DO NOT MITIGATE THE RISKS OF INFECTION IN THE 1ST TRIMESTER. IT IS NOW FEASIBLE TO INCLUDE 1ST TRIMESTER SCREENING FOR MALARIA PARASITES OWING TO: I) UPDATED WHO GUIDELINES THAT RECOMMEND AN EXPENDED SCHEDULE OF 8 ANC CONTACTS, WITH THE FIRST PRIOR TO 12 WEEKS GESTATION, II) THE AVAILABILITY OF HIGH-SENSITIVITY MALARIA RAPID DIAGNOSTIC TESTS (HS-RDT) WITH ENHANCED DETECTION OF LOW-DENSITY INFECTIONS, AND III) ACCUMULATED SAFETY DATA THAT ENABLE THE USE OF ARTEMETHER-LUMEFANTRINE (AL) FOR MALARIA TREATMENT IN THE 1ST TRIMESTER. WE HYPOTHESIZE THAT, COMPARED TO WOMEN WHO ENTER ANC AND RECEIVE USUAL CARE, WOMEN WHO ARE SCREENED IN THE 1ST TRIMESTER WITH AN HS-RDT WILL HAVE A LOWER PREVALENCE OF A POOR PREGNANCY OUTCOME, AND WE WILL TEST THIS THROUGH THE IMPROVING NEONATAL HEALTH THROUGH RAPID MALARIA TESTING IN EARLY PREGNANCY WITH HIGH-SENSITIVITY DIAGNOSTICS (INTREPID) STUDY IN WESTERN KENYA AND THE DEMOCRATIC REPUBLIC OF THE CONGO (DRC). IN AIM 1, THE INTREPID STUDY WILL ENROLL WOMEN IN THE 1ST TRIMESTER AND RANDOMIZE THEM 1:1 TO USUAL CARE OR TO SCREENING WITH AN HS-RDT FOLLOWED BY TREATMENT OF POSITIVES WITH AL, AND THEN FOLLOW THEM THROUGH DELIVERY. FOLLOWING THE 1ST TRIMESTER INTERVENTION, ALL WOMEN WILL RECEIVE USUAL ANC, INCLUDING IPTP-SP. THE PRIMARY OUTCOME WILL BE THE COMPOSITE OUTCOME OF LOW BIRTHWEIGHT, SMALL-FOR- GESTATIONAL AGE, PRETERM BIRTH, FETAL LOSS, OR NEONATAL DEATH. IN AIM 2, WE WILL MEASURE THE THERAPEUTIC EFFICACY AND PHARMACOKINETICS OF AL ADMINISTRATION IN THE 1ST TRIMESTER THROUGH A POPULATION PK STUDY FOLLOWING STANDARD AL DOSING AND COMPARE PK PARAMETERS WITH HISTORICAL CONTROLS. IN AIM 3, WE WILL USE TRIAL DATA TO MODEL THE POTENTIAL INCREMENTAL BENEFITS OF ENHANCED-SENSITIVITY DIAGNOSTICS AND ALTERNATE TREATMENT REGIMENS ON THE RISK OF AN ADVERSE PREGNANCY OUTCOME IN ORDER TO MAXIMIZE THE IMPACT OF OUR TRIAL DATA. COLLECTIVELY THESE DATA WILL GUIDE THE DEVELOPMENT AND IMPLEMENTATION OF FRESH APPROACHES TO INTERCEPT PARASITES EARLY IN PREGNANCY AND THEREBY ENHANCE PREGNANCY OUTCOMES AND NEWBORN HEALTH.

MID SOUTHERN PRIMARY CARE NETWORKS NODE

MEDIUM ENERGY PHYSICS AT DUKE UNIVERSITY

SAFETY OF SILDENAFIL IN PREMATURE INFANTS WITH SEVERE BRONCHOPULMONARY DYSPLASIA - PULMONARY HYPERTENSION IS A DEADLY COMPLICATION OF BRONCHOPULMONARY DYSPLASIA (BPD), THE MOST COMMON PULMONARY MORBIDITY OF PREMATURITY. UP TO 40% OF PREMATURE INFANTS WITH PULMONARY HYPERTENSION AND BPD WILL DIE, AND SURVIVORS SUFFER LONG-TERM MORBIDITIES. DESPITE THESE CATASTROPHIC CONSEQUENCES, NO DRUGS ARE LABELED OR EVIDENCE BASED FOR THE PREVENTION OF PULMONARY HYPERTENSION IN THIS POPULATION. SILDENAFIL IS A POTENT PULMONARY VASODILATOR APPROVED BY THE FDA FOR THE TREATMENT OF PULMONARY HYPERTENSION IN ADULTS. PRECLINICAL BPD MODELS SUGGEST A BENEFICIAL EFFECT ON LUNG AND VASCULAR DEVELOPMENT, WHICH MAY PREVENT PULMONARY HYPERTENSION. REAL WORLD EVIDENCE SHOWS THAT NEONATOLOGISTS ARE INCREASINGLY USING SILDENAFIL IN PREMATURE INFANTS DESPITE LACK OF DATA ON DOSING, SAFETY, AND THE EXPOSURE-RESPONSE RELATIONSHIP. LED BY DRS. LAUGHON, A NEONATOLOGIST AND TRIALIST, AND DR. HORNIK, A PEDIATRIC CARDIOLOGIST AND CLINICAL PHARMACOLOGIST, OUR MULTI- INSTITUTIONAL AND MULTIDISCIPLINARY TEAM IS DEDICATED TO DEVELOPING DRUGS FOR THE PREVENTION AND TREATMENT OF CARDIOPULMONARY MORBIDITIES IN INFANTS, AN AREA OF URGENT AND UNMET PUBLIC HEALTH NEED. TO MEET THIS NEED, WE PROPOSE AN ADAPTIVE, RANDOMIZED, PLACEBO CONTROLLED, DOUBLE-BLIND, DOSE-ESCALATION, PREVENTION TRIAL OF 4 WEEKS OF STUDY DRUG (SILDENAFIL: PLACEBO 3:1 RANDOMIZATION) IN 120 PREMATURE INFANTS <29 WEEKS GESTATION WITH SEVERE BPD AT RISK FOR PULMONARY HYPERTENSION AT 30 CLINICAL SITES UNDER IND (IND#112,374, HOLDER LAUGHON). CONSISTENT WITH THE GOALS OF PAR-18-683, THE PROPOSED TRIAL WILL PROVIDE THE NECESSARY DOSING, SAFETY, AND PRELIMINARY EFFICACY DATA NEEDED TO DESIGN A PIVOTAL PHASE II/III TRIAL, AND MOVE THE DRUG FORWARD TOWARD LABELING FOR THIS INDICATION. LEVERAGING PARTNERSHIPS WITH THE NICHD FUNDED PEDIATRIC TRIALS NETWORK, AND THE NCATS FUNDED TRIAL INNOVATION NETWORK, WE WILL TRANSLATE SEVERAL STUDY DESIGN AND OPERATIONAL INNOVATIONS NOT ROUTINELY UTILIZED IN INFANT TRIALS INCLUDING ADAPTIVE CONTINUAL REASSESSMENT METHODS, RISK-ADJUSTED ENDPOINTS, PARENT-ENGAGEMENT STUDIOS, AND SITE BASED CLINICAL OPTIMIZATION INTO THE FRAMEWORK OF AN EARLY PHASE STUDY CONDUCTED UNDER REGULATORY OVERSIGHT. THESE INNOVATIONS WILL BE IMPLEMENTED DURING THE R61 AWARD PHASE. OUR TEAM HAS THE EXPERTISE, ACCESS TO PARTICIPANTS, AND ENVIRONMENT NECESSARY TO CONDUCT THE PROPOSED RESEARCH. IN PARTICULAR, WE HAVE COMPLETED A PRELIMINARY OPEN-LABEL PHARMACOKINETIC STUDY TO IDENTIFY SAFE STARTING DOSES FOR THIS STUDY, AND CONDUCTED A COHORT STUDY TO VALIDATE AN ECHOCARDIOGRAM BASED SCORE AS A SURROGATE ENDPOINT FOR PULMONARY HYPERTENSION IN PREMATURE INFANTS, THEREBY AVOIDING THE RISKS ASSOCIATED WITH INVASIVE CARDIAC CATHETERIZATION IN THIS VULNERABLE POPULATION. THIS PRELIMINARY WORK, COMBINED WITH THE UNPARALLELED EXPERIENCE OF OUR TEAM TO COMPLETE EARLY PHASE INFANT CLINICAL TRIALS ON TIME AND ON BUDGET, WILL ENSURE THE SUCCESS OF THE PROPOSED STUDY, AND DIRECTLY IMPROVE THE PUBLIC HEALTH OF PREMATURE INFANTS BY PROVIDING EVIDENCE FOR THE ONLY THERAPEUTIC TO PREVENT PULMONARY HYPERTENSION IN PREMATURE INFANTS.

GTPASE ACTIVATING COMPLEX FROM ROD PHOTORECEPTORS

ENGINEERED GLUCOSE METABOLISM IN INSULIN SECRETING CELLS

A GLOBAL SYPHILIS VACCINE TARGETING OUTER MEMBRANE PROTEINS OF TREPONEMA PALLIDUM - PROJECT ABSTRACT - A GLOBAL SYPHILIS VACCINE TARGETING OUTER MEMBRANE PROTEINS OF TREPONEMA PALLIDUM THE SCIENTIFIC PREMISE OF THIS CRC PROPOSAL RESTS UPON OUR THREE DECADES OF WORK DEFINING THE MOLECULAR ARCHITECTURE OF THE OUTER MEMBRANE (OM) OF TREPONEMA PALLIDUM SUBSP. PALLIDUM (TPA), COUPLED WITH OUR SUCCESSES COMBINING BIOINFORMATICS, BIOPHYSICAL TECHNIQUES, AND LOCALIZATION METHODS WITH LIVE TPA TO TOPOLOGICALLY CHARACTERIZE TPA OUTER MEMBRANE PROTEINS (OMPS) AND DEFINE THE SYPHILIS SPIROCHETE’S ‘OMPEOME’--ITS REPERTOIRE OF OMPS. THE CENTRAL HYPOTHESIS IS THAT THE PRINCIPAL TARGETS FOR A SYPHILIS VACCINE RESIDE WITHIN TPA’S REPERTOIRE OF RARE OMPS. THE CURRENT APPLICATION BUILDS UPON THE WORK OF THE CURRENT CRC U19 GRANT AWARDED TO THE TWO MPIS OF THIS PROPOSAL (MOODY AND RADOLF). THIS PROPOSAL BRINGS TOGETHER THE EXPERTISE IN SPIROCHETOLOGY (UNIV. OF CONNECTICUT) AND VACCINE DEVELOPMENT (DUKE HUMAN VACCINE INSTITUTE) TO DEVELOP VACCINES TARGETING TPA OMPS. THE OVERARCHING HYPOTHESIS IS THAT VACCINES TARGETING TPA OMPS WILL ELICIT ANTIBODIES THAT CAN RECOGNIZE INTACT TREPONEMES, PROVIDE PROTECTION IN ANIMAL MODELS, AND BE PRODUCIBLE USING GOOD MANUFACTURING PRACTICES (GMP) AT THE SCALE NEEDED TO PERFORM A PHASE 1 CLINICAL TRIAL. THIS CRC PROPOSAL WILL FOCUS ON TWO MAIN AIMS: AIM 1) SELECTION OF AN ECL VACCINOGEN PANEL AND PRODUCTION OF ECL MABS WITH FUNCTIONAL ACTIVITY, WITH SUBAIM 1.1 OF FINALIZING THE ECL VACCINOGEN PANEL THROUGH ROBUST PRECLINICAL ANIMAL STUDIES (UNIV. OF CONNECTICUT) AND SUBAIM 1.2 OF PRODUCING ECL MABS WITH FUNCTIONAL ACTIVITY (DUKE HUMAN VACCINE INSTITUTE), AND AIM 2) SELECTION AND OPTIMIZATION OF AN ECL VACCINE PLATFORM, WITH SUBAIM 2.1 OF GENERATING FUNCTIONAL ECL-SPECIFIC ABS USING MRNA-LNP IMMUNOGENS (UNIV. OF PENNSYLVANIA), AND SUBAIM 2.2 OF GENERATING FUNCTIONAL ECL-SPECIFIC ABS USING SPYVLPS (UNIV. OF CONNECTICUT), TO BE COMPARED IN ANIMAL PROTECTION STUDIES IN SUBAIM2.3. SUCCESSFUL COMPLETION OF THE AIMS OF THIS CRC U01 PROPOSAL WILL PROVIDE THE PRECLINICAL DATA NEEDED FOR AN IND SUBMISSION TO THE FDA, COMPLETE THE PROCESS DEVELOPMENT FOR GMP PRODUCTION, AND WILL RESULT IN THE FULL DESIGN OF A GMP CAMPAIGN STRATEGY AND A PLAN FOR TOXICOLOGY TESTING.

CK20-004, DUKE-UNC PREVENTION EPICENTER PROGRAM FOR PROTECTING PATIENTS FROM INFECTIONS, ANTIBIOTICS RESISTANCE AND OTHER ADVERSE EVENTS

URINARY STONE DISEASE RESEARCH NETWORK: SCIENTIFIC DATA RESEARCH CENTER

CARRA: ACCELERATING TOWARD AN EVIDENCE BASED CULTURE IN PEDIATRIC RHEUMATOLOGY

UNDERSTANDING HOW CELLS INVADE THROUGH BASEMENT MEMBRANE IN VIVO

IMPLEMENTATION, ADOPTION, AND UTILITY OF FAMILY HISTORY IN DIVERSE CARE SETTINGS

BUILDING INTERDISCIPLINARY RESEARCH CAREERS IN WOMEN'S HEALTH

COLLABORATIVE CENTER TO DEVELOP IMPROVED DIAGNOSTIC AND THERAPEUTIC APPROACHES TO ENDOMETRIOSIS - COLLABORATIVE CENTER TO DEVELOP IMPROVED DIAGNOSTIC AND THERAPEUTIC APPROACHES TO ENDOMETRIOSIS ABSTRACT THE OVERARCHING GOAL OF THIS CENTER IS TO DEVELOP ADVANCED TOOLS AND INSIGHTS FOR IMPROVED UNDERSTANDING OF THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS, A DISEASE IN WHICH ENDOMETRIAL TISSUE GROWS OUTSIDE THE UTERUS AND CAN CAUSE SEVERE DYSMENORRHEA, PAIN, INFERTILITY AND OTHER SEQUELAE. WE PURSUE THIS GOAL TO ENHANCE THE DIAGNOSIS, ASSESSMENT, AND TREATMENT OF WOMEN SUFFERING FROM THIS COMMON AND DEVASTATING DISEASE. A CLEAR PATHOPHYSIOLOGIC UNDERSTANDING OF ENDOMETRIOSIS HAS BEEN DIFFICULT TO ACHIEVE DUE, IN PART, TO THE RELIANCE ON SURGERY FOR DIAGNOSIS AND LESION ASSESSMENT. RELIANCE ON SURGERY DELAYS DIAGNOSIS AND PREVENTS FREQUENT OR REPEATED EVALUATION. IN RECENT YEARS, HOWEVER, COLLABORATIONS BETWEEN SCIENTISTS IN OUR TEAM HAVE ADVANCED A UNIFYING PATHOPHYSIOLOGICAL PRINCIPLE--THAT OF PROGESTERONE RESISTANCE. MOST OTHER PATHOPHYSIOLOGICAL FEATURES OF ENDOMETRIOSIS, INCLUDING PERSISTENT EPITHELIAL ESTROGEN RECEPTOR ACTION, PERSISTENT ESTROGEN RECEPTOR AND PROGESTERONE RECEPTOR EXPRESSION, CELLULAR PROLIFERATION, INFLAMMATION, PAIN, AND INFERTILITY, CAN BE ASCRIBED TO PROGESTERONE RESISTANCE. RECENTLY, IMPORTANT FINDINGS BY THIS CONSORTIUM SHOW THAT SIRTUIN 1 (SIRT1), AN EPIGENETIC MODULATOR, CAN CAUSE PROGESTERONE RESISTANCE, RESULTING IN EXACERBATION OF DOWNSTREAM EFFECTS. SIRT1 IS A HISTONE DEACETYLASE THAT ALSO DIRECTLY REGULATES THE FUNCTION OF PROTEINS DIRECTING INFLAMMATORY AND METABOLIC SIGNALING. WE FIND CONSISTENT OVEREXPRESSION OF ENDOMETRIAL SIRT1 ACROSS ALL SPECIES THAT WE HAVE TESTED, INCLUDING HUMANS, NON-HUMAN PRIMATES, AND MICE, HIGHLIGHTING A LIKELY CENTRAL ROLE FOR SIRT1 IN ENDOMETRIOSIS PATHOPHYSIOLOGY. FURTHERMORE, PRELIMINARY STUDIES INDICATE THAT SIRT1 OVEREXPRESSION PLAYS A DIRECT ROLE IN LESION SURVIVAL AS WELL AS INFERTILITY AND HAS A POTENTIAL ROLE AS A THERAPEUTIC TARGET. WE PRESENT THREE KEY PROJECTS BASED ON OUR BURGEONING PATHOPHYSIOLOGICAL DATA TO DEEPEN OUR KNOWLEDGE, CATALYZE THE DEVELOPMENT OF NOVEL, NON-INVASIVE DIAGNOSTIC AND ASSESSMENT METHODS AND PROMOTE NON-HORMONAL THERAPEUTIC OPTIONS FOR AFFECTED WOMEN. THE IMPACT OF THESE THREE PROJECTS ON WOMEN WILL BE ENHANCED BY PATIENT AND PROVIDER EDUCATIONAL INITIATIVES FROM THE ENDOMETRIOSIS OUTREACH AND EDUCATION (EOE) CORE AND DEEP INTEGRATION OF SYNERGISTIC DATA FROM HUMAN, NON-HUMAN PRIMATE, MOUSE, AND IN VITRO SYSTEMS, ENHANCED BY THE COMPARATIVE GENOMICS AND BIOINFORMATICS (CGB) CORE. COLLECTIVELY, THE PROJECTS AND CORES CONTRIBUTE TO THREE SYNERGISTIC AIMS: 1) ENHANCE EARLY DIAGNOSIS AND ASSESSMENT OF ENDOMETRIOSIS LESIONS BY DEVELOPING NON-INVASIVE IMAGING TECHNIQUES AND PROMOTING PUBLIC AWARENESS; 2) DETERMINE INFLAMMATORY AND METABOLIC CHANGES THAT UNDERLIE THE DISEASE PROCESS; AND 3) DEVELOP NEW MOLECULAR TARGETS FOR NON-HORMONAL, NON-SURGICAL TREATMENTS FOR ENDOMETRIOSIS; THE SUCCESSFUL COMPLETION OF THESE AIMS WILL LEAD TO A LONG-LASTING IMPROVEMENT IN THE LIVES OF WOMEN SUFFERING FROM ENDOMETRIOSIS.

AIM BACK UH3 TRANSITION

CENTER FOR VIRTUAL IMAGING TRIALS - ABSTRACT – CENTER FOR VIRTUAL IMAGING TRIALS THE ACCELERATING COMPLEXITY OF MEDICAL IMAGING DEVICES AND METHODS HAS LARGELY OUTPACED THE FIELD'S ABILITY TO EVALUATE AND OPTIMIZE THEIR DESIGN AND CLINICAL USE. DOING SO THROUGH CLINICAL TRIALS IS OFTEN NOT FEASIBLE OR DEFINITIVE DUE TO ETHICAL LIMITATIONS, EXPENSE, TIME REQUIREMENTS, AND/OR A FUNDAMENTAL LACK OF GROUND TRUTH (EXACT PATIENT ANATOMY AND CONDITION). MOST CURRENT APPROACHES TO ASSESS IMAGING TECHNOLOGIES OUTSIDE OF CLINICAL TRIALS RELY ON SIMPLISTIC MODELS AND SUBJECTIVE PERCEPTION OF IMAGE AESTHETICS, AND RESULTS CANNOT READILY PREDICT CLINICAL EFFICACY. TO FILL THIS GAP, THE BROAD OBJECTIVE OF THE CENTER FOR VIRTUAL IMAGING TRIALS IS TO DEVELOP A VIRTUAL PLATFORM FOR ASSESSING THE EFFECTIVENESS OF MEDICAL IMAGING SYSTEMS AND METHODS FOR SPECIFIC CLINICAL TASKS. THE INITIAL FOCUS IS ON COMPUTED TOMOGRAPHY (CT), BOTH DUE TO ITS WIDESPREAD MEDICAL UTILITY AND ITS STATUS AS THE LARGEST SOURCE OF MEDICAL RADIATION. VIRTUAL IMAGING TRIALS OFFER AN EFFICIENT MEANS TO EVALUATE IMAGING CONCEPTS AND TECHNOLOGIES IN SILICO BY SIMULATING THE PATIENT, IMAGING SYSTEM, AND IMAGE EVALUATION. SUCH VIRTUAL TRIALS CAN BE CONDUCTED QUICKLY AND COST EFFECTIVELY ON A COMPUTER, PROVIDING RESEARCHERS A PRACTICAL WAY TO ANSWER FUNDAMENTAL QUESTIONS USING THE PRECISE CONTROLS AND THE EXACT KNOWLEDGE OF A MODELED PATIENT. THEY ALSO ENABLE OBJECTIVE OPTIMIZATION OF CURRENT AND EMERGING IMAGING TECHNOLOGIES (HARDWARE AND SOFTWARE) TO MINIMIZE RADIATION RISK AND PROVIDE QUANTITATIVE ACCURACY. BY ACCELERATING AND IMPROVING IMAGING TECHNOLOGIES' EVALUATION AND OPTIMIZATION, VIRTUAL TRIALS SUPPORT QUALITY, SAFETY, AND EFFECTIVE PRACTICE OF PATIENT-CENTERED CARE. TO ACHIEVE ITS OBJECTIVE, THE CENTER WILL DEVELOP, REFINE, AND DISSEMINATE THE ESSENTIAL RESOURCES TO REALISTICALLY MODEL AND REPRESENT A) PATIENTS, B) IMAGING SYSTEMS, AND C) IMAGE EVALUATION. THESE RESOURCES COMPRISE THE THREE TECHNOLOGY RESEARCH AND DEVELOPMENT (TRD) PROJECTS, WHICH WORK SYNERGISTICALLY WITH AND PROVIDE RESOURCES TO COLLABORATIVE PROJECTS (CPS) AND SERVICE PROJECTS (SPS). A TECHNOLOGY TRAINING AND DISSEMINATION (TTD) COMPONENT WILL DISTRIBUTE THE CENTER'S RESOURCES AND PROVIDE THE NECESSARY TRAINING. ADMINISTRATION PROVIDES INFRASTRUCTURE, OVERSIGHT, AND INTEGRATION. THE OVERALL SPECIFIC AIMS ARE TO (1) DEVELOP, CONSOLIDATE, AND STREAMLINE THE REQUIRED COMPONENTS TO ENABLE VIRTUAL IMAGING TRIALS OF EXISTING AND EMERGING CT IMAGING METHODS, (2) POSITION VIRTUAL TRIALS AS AN ALTERNATIVE METHODOLOGY TO QUANTIFY, EVALUATE, AND OPTIMIZE CT IMAGING, AND (3) DISSEMINATE TO THE RESEARCH COMMUNITY VALIDATED TOOLS FOR EFFICIENT VIRTUAL TRIALS IN CT AND TRAIN RESEARCHERS TO USE THEM EFFECTIVELY. USING STATE-OF-THE-ART SIMULATION AND ANALYSIS METHODS, THE CENTER WILL PROVIDE THE FIRST COMPREHENSIVE PLATFORM TO ASSESS THE DIAGNOSTIC CAPABILITY OF IMAGING TECHNOLOGIES IN THEIR COMPLETE TRAJECTORY FROM DESIGN TO USE. THE CENTER WILL HAVE A NOTABLE IMPACT ON RIGOROUS AND REPRODUCIBLE SCIENTIFIC DESIGN, PREDICTION, AND PRACTICE OF MEDICAL IMAGING, STARTING WITH CT, LEADING TO MEASURED REDUCTIONS IN RADIATION DOSE, IMPROVEMENTS IN IMAGE QUALITY, AND ADVANCEMENT OF PRECISION IMAGING.

ANTIGEN RECOGNITION AND ACTIVATION OF B-CELL RECEPTORS OF HIV-1 BROADLY NEUTRALIZING ANTIBODIES

DUKE-UNC-WASH U PARTNERSHIP FOR EARLY PHASE CLINICAL TRIALS IN CANCER

MOLECULAR MYCOLOGY AND PATHOGENESIS TRAINING PROGRAM

TRAINING PROGRAM IN DEVELOPMENTAL BIOLOGY

NEUROVASCULAR DYSFUNCTION IN DELIRIUM SUPERIMPOSED ON DEMENTIA