George Washington University

GLYCEMIA REDUCTION APPROACHES IN DIABETES: A COMPARATIVE EFFECTIVENESS STUDY

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

STATISTICS CENTER FOR PEDIATRIC TYPE 2 DIABETES THERAPY

AIDS AND CANCER SPECIMEN RESOURCE (ACSR)

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

POST DPP FOLLOW UP STUDY: DATA COORDINATING CENTER

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

CPCRA CLINICAL TRIALS UNIT

EPIDEMIOLOGY OF DIABETES INTERVENTIONS AND COMPLICATIONS DATA COORDINATING CENTER

DISTRICT OF COLUMBIA CENTER FOR AIDS RESEARCH (DC CFAR)

CPCRA CLINICAL TRIALS UNIT

CARES ACT EMERGENCY FINANCIAL AID GRANT FUNDING

CARES ACT EMERGENCY FINANCIAL AID GRANT FUNDING

COMPREHENSIVE REGIONAL ASSISTANCE CENTERS - COMPREHENSIVE REGIONAL ASSISTANCE CENTERS

OPER & MAINT OF FHWA AND NHTSA NATL CRASH A C

TYPE 1 DIABETES TRIALNET: OPERATIONS COORD. CENTER

NEW TOOLS FOR COMPARATIVE SYSTEMS BIOLOGY OF THREAT AGENT ACTION MECHANISMS

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

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

MEDICAL EDUCATION PARTNERSHIP INITIATIVE COORDINATING CENTER

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

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

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

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

MOLECULAR ASPECTS OF CORNEAL EPITHELIAL MIGRATION

RARE DISEASE NETWORK FOR MYASTHENIA GRAVIS

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

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

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

CONSORTIUM ON NAVAL ENTERPRISE PATHWAYS (CONEP)

THE EAST COAST AIDS AND CANCER SPECIMEN RESOURCE

MATERNAL FETAL MEDICINE NETWORK: DATA COORDINATING CENT*

A FOLLOW-UP OF CHILDREN ENROLLED IN THE MANAGEMENT OF MYELOMENINGOCELE STUDY

THE ROLE OF ASTROGLIAL-NF-KB IN SCI

PATHOLOGY, DEVELOPMENTAL ORIGINS, AND PREVENTION OF PEDIATRIC DYSPHAGIA

LEPTIN SIGNALING IN THE CAROTID BODY: MECHANISMS AND CONSEQUENCES

PISCES 2019: PARTNERSHIP IN SECURING CYBERSPACE THROUGH EDUCATION AND SERVICE: RENEWAL

METHOTREXATE TREATMENT OF ARTHRITIS CAUSED BY CHIKUNGUNYA VIRUS (MARCH): A RANDOMIZED CONTROLLED TRIAL OF METHOTREXATE VERSUS PLACEBO IN THE TREATMENT OF CHRONIC ARTHRITIS AFTER CHIKUNGUNYA INFECTION - ABSTRACT CHIKUNGUNYA VIRUS (CHIKV) IS AN ALPHAVIRUS SPREAD BY MOSQUITOS THAT CAUSES PERSISTENT ARTHRITIS IN APPROXIMATELY 25% OF PEOPLE TWO YEARS AFTER INITIAL INFECTION. THERE IS CURRENTLY NO STANDARD EVIDENCE-BASED TREATMENT FOR CHIKV CHRONIC ARTHRITIS. THE FRENCH GUIDELINES SUGGEST THE USE OF METHOTREXATE IN THE TREATMENT OF CHRONIC CHIKV ARTHRITIS HOWEVER THERE ARE NO RANDOMIZED PLACEBO-CONTROLLED TRIALS OF METHOTREXATE TO SUPPORT THIS RECOMMENDATION. OUR LONG-TERM GOAL IS TO GUIDE THE EVIDENCE-BASED TREATMENT OF CHIKV ARTHRITIS. THE MAIN GOAL OF THIS PROPOSAL IS TO DETERMINE THE EFFICACY AND HISTOPATHOLOGIC EFFECTS OF 6 MONTHS OF METHOTREXATE (N=100) VERSUS PLACEBO (N=50) ON SYNOVITIS IN CHRONIC CHIKV ARTHRITIS IN COLOMBIA IN A RANDOMIZED CONTROLLED TRIAL. OUR CENTRAL HYPOTHESIS IS THAT METHOTREXATE WILL SIGNIFICANTLY DECREASE CHRONIC CHIKV ARTHRITIS DISEASE SEVERITY COMPARED TO PLACEBO AND SUPPRESS LEUKOCYTE ACCUMULATION AND INFLAMMATORY CYTOKINE EXPRESSION IN SYNOVIAL TISSUE. THIS HYPOTHESIS WILL BE EVALUATED IN 2 SPECIFIC AIMS. IN AIM 1, WE WILL DETERMINE THE EFFICACY OF ORAL METHOTREXATE TREATMENT VERSUS PLACEBO FOR 6 MONTHS IN CHRONIC CHIKV ARTHRITIS. IN AIM 2, WE WILL DETERMINE THE EFFECT OF METHOTREXATE ON SYNOVIAL INFLAMMATION BY OBTAINING SYNOVIAL BIOPSY SAMPLES BEFORE AND DURING TREATMENT. RATIONALE: THIS WORK WILL DEFINE THE ROLE AND MECHANISM OF METHOTREXATE IN THE TREATMENT OF CHRONIC CHIKV ARTHRITIS WITH THE GOAL OF ADVANCING THE FIELD TOWARDS AN EVIDENCE-BASED STANDARD TREATMENT. THE POTENTIAL BROADER IMPACT OF THIS WORK IS THE POTENTIAL IDENTIFICATION OF THE PATHOLOGIC MECHANISM OF CHRONIC VIRAL ARTHRITIS AND A POSSIBLE THERAPEUTIC OPTION.

(MURI) UNIFIED LARGE-SCALE THEORETICAL AND COMPUTATIONAL FRAMEWORKS FOR INVARIANCE AND COMPOSITION OF OPEN HYBRID DYNAMICAL SYSTEMS.

WORKFORCE RESILIENCY TECHNICAL ASSISTANCE CENTER

THE FUNCTIONAL SIGNIFICANCE OF CTL ESCAPE

EMERGENCE OF VISUAL ALERTNESS IN CORTICAL NETWORKS

DOPAMINE-1 RECEPTOR DEFECT IN HYPERTENSION

TREATMENT OF SLEEP APNEA BY TARGETING LEPTIN SIGNALING

PISCES 2023 - PARTNERSHIP IN SECURING CYBERSPACE THROUGH EDUCATION AND SERVICE (RENEWAL)

NIMHD RESEARCH CENTER ON LATINO IMMIGRANT/REFUGEE HEALTH DISPARITIES

2/2: A RANDOMIZED CONTROLLED TRIAL OF PRAVASTATIN FOR THE PREVENTION OF PREECLAMPSIA IN HIGH RISK WOMEN

GESTATIONAL HYPERTENSION AND PREECLAMPSIA BLOOD PRESSURE (BP) TREATMENT GOALS <140/90 VS. <160/110 MMHG: THE GOALPOST TRIAL - ABSTRACT HYPERTENSIVE DISORDERS OF PREGNANCY (HDP) AFFECT UP TO 1 IN 8 PREGNANCIES AND LEAD TO SIGNIFICANT SHORT AND LONG- TERM MORBIDITY AND MORTALITY FOR MOTHERS AND NEONATES. HDPS ARE CLASSIFIED AS NON-SEVERE AND SEVERE. IN NON-SEVERE FORMS OF HDP, SPECIFICALLY GESTATIONAL HYPERTENSION OR PREECLAMPSIA WITHOUT SEVERE FEATURES, PREGNANT INDIVIDUALS HAVE ELEVATED SYSTOLIC BLOOD PRESSURE (BP) BETWEEN 140 – 159 MMHG AND/OR ELEVATED DIASTOLIC BP 90 – 109 MMHG WITHOUT EVIDENCE OF END-ORGAN DYSFUNCTION. IN CONTRAST, SEVERE HDP, INCLUDING PREECLAMPSIA WITH SEVERE FEATURES AND ECLAMPSIA, IS CHARACTERIZED BY SEVERE HYPERTENSION DEFINED AS BP ≥160/110 MMHG OR EVIDENCE OF END-ORGAN DAMAGE SUCH AS LIVER OR KIDNEY DYSFUNCTION OR SEIZURES. ALTHOUGH DELIVERY MINIMIZES RISKS TO THE MOTHER, DEPENDING ON THE GESTATIONAL AGE, DELIVERY MAY LEAD TO INCREASED RISKS FOR THE NEONATE, PARTICULARLY ADVERSE OUTCOMES ASSOCIATED WITH PREMATURITY. FIVE PERCENT OR MORE OF ALL PREGNANCIES ARE AFFECTED BY NON-SEVERE HDP AT <370 WEEKS. THE STANDARD OF CARE IS TO EXPECTANTLY MANAGE PATIENTS WITH NON-SEVERE HDP WITH CLOSE OBSERVATION AND SERIAL SURVEILLANCE UNTIL 370 WEEKS GESTATION OR WHEN SEVERE DISEASE DEVELOPS, WHICHEVER OCCURS FIRST, AT WHICH TIME DELIVERY IS INDICATED. UNFORTUNATELY, NON-SEVERE HDP PROGRESSES TO SEVERE HDP IN 30 - 50% OF CASES <370 WEEKS GESTATION. AS SUCH, IT IS CRITICAL TO IDENTIFY INTERVENTIONS TO SAFELY REDUCE THE PROGRESSION FROM NON-SEVERE TO SEVERE HDP. A RECENT TRIAL IN PREGNANT WOMEN WITH CHRONIC HYPERTENSION DEMONSTRATED THAT TREATMENT OF BP TO A GOAL OF <140/90 DECREASES THE RISK OF PREECLAMPSIA AND IMPROVES OUTCOMES FOR MOTHER AND BABY. BASED ON THIS, CLINICAL GUIDELINES WERE CHANGED AND NOW RECOMMEND A BP GOAL <140/90 FOR ALL PREGNANT INDIVIDUALS WITH CHRONIC HYPERTENSION. HOWEVER, NO DEFINITIVE TRIAL HAS BEEN PERFORMED DEMONSTRATING THAT BP GOALS <140/90 IN NON-SEVERE HDP ARE BENEFICIAL AND SAFE, LEAVING THE CLINICAL QUESTION: DOES STARTING ORAL ANTIHYPERTENSIVE MEDICATION WHEN A PATIENT DEVELOPS A NON- SEVERE HDP PROLONG GESTATION AND BENEFIT THE MOTHER AND INFANT WITHOUT INCREASING MATERNAL OR FETAL RISKS? THEREFORE, WE PROPOSE THE GOALPOST TRIAL, A PHASE III, OPEN-LABEL RANDOMIZED CONTROL TRIAL (N=4,120) OF ANTIHYPERTENSIVE TREATMENT IN PREGNANT INDIVIDUALS WITH NON-SEVERE HDP CONDUCTED THROUGH THE NICHD MATERNAL- FETAL MEDICINE UNITS NETWORK. PARTICIPANTS WILL BE RANDOMIZED 1:1 TO 1) INTERVENTION – ORAL ANTIHYPERTENSIVE THERAPY TO TARGETED BP GOALS <140/90 MMHG OR 2) USUAL CARE – NO ANTIHYPERTENSIVE THERAPY UNLESS BP ≥160/110 MMHG. WE WILL EVALUATE WHETHER THE INTERVENTION REDUCES ADVERSE PREGNANCY (PRIMARY AIM) AND NEONATAL OUTCOMES (SECONDARY AIM). A COMPREHENSIVE SAFETY PLAN WILL ENSURE CLOSE CLINICAL MONITORING OF MOTHER AND FETUS TO ENHANCE SAFETY. THE GOALPOST TRIAL HAS THE POTENTIAL TO CHANGE MANAGEMENT GUIDELINES FOR THE TREATMENT OF NON-SEVERE HYPERTENSIVE DISORDERS OF PREGNANCY IN THE US AND WORLDWIDE AND TO IMPROVE OUTCOMES FOR COUNTLESS WOMEN AND CHILDREN.

BIOSENSOR-MAGNETOELECTRONICS INTEGRATION

NSF CONVERGENCE ACCELERATOR TRACK F: EXPERT VOICES TOGETHER: BUILDING TRUST IN COMMUNICATION SYSTEMS BY ADDRESSING ONLINE ABUSE AND HARASSMENT -THIS PROJECT ADDRESSES THE LINKS BETWEEN TWO SIGNIFICANT PROBLEMS IMPACTING TRUST IN CONTEMPORARY COMMUNICATION SYSTEMS: (1) THE BROAD AND RAPID SPREAD OF MISINFORMATION AND (2) ABUSE AND HARASSMENT DIRECTED AT MEMBERS OF EXPERT COMMUNITIES. MISINFORMATION-DRIVEN HARASSMENT CAMPAIGNS HAVE PARTICULARLY LARGE IMPACTS ON THOSE AT THE FOREFRONT OF EFFORTS TO ACCURATELY INFORM THE PUBLIC, INCLUDING JOURNALISTS, SCIENTISTS, AND PUBLIC HEALTH OFFICIALS. AS A RESULT, THIS HARASSMENT UNDERMINES CONFIDENCE IN PIVOTAL SOURCES OF KNOWLEDGE AND REDUCES EXPERT PARTICIPATION IN THE INFORMATION ECOSYSTEM. THIS PROJECT WILL DEVELOP EXPERT VOICES TOGETHER (EVT), A SOCIO-TECHNICAL SYSTEM THAT PROVIDES REAL-TIME SUPPORT TO EXPERTS EXPERIENCING ONLINE HARASSMENT. THE PROJECT WILL INITIALLY FOCUS ON SUPPORTING JOURNALISTS, LATER EXPANDING ITS REACH TO OTHER EXPERT COMMUNITIES. EVT AIMS TO SUPPORT EXPERTS IN MOMENTS OF CRISIS, WHILE ALSO BUILDING INDIVIDUAL, ORGANIZATIONAL, AND SOCIETAL CAPACITY TO PREVENT AND MITIGATE HARMS FROM ONLINE ABUSE AND HARASSMENT IN THE LONG TERM. THE TEAM OF SCIENTISTS, TECHNICAL SPECIALISTS, PSYCHOLOGISTS, AS WELL AS CIVIL SOCIETY AND MEDIA REPRESENTATIVES WILL BRING TOGETHER THEIR EXPERTISE IN A WIDE RANGE OF FIELDS?INCLUDING MIS-/DISINFORMATION STUDIES, DATA ETHICS, SYSTEMS ENGINEERING, EXPERIMENTAL AND CLINICAL PSYCHOLOGY, HUMAN-COMPUTER INTERACTION, CASE MANAGEMENT, JOURNALISM AND MASS COMMUNICATION PRACTICE AND RESEARCH?TO CREATE A RAPID-RESPONSE SOCIO-TECHNICAL SYSTEM THAT SUPPORTS JOURNALISTS AND OTHER EXPERTS FACING ONLINE ABUSE AND HARASSMENT. THE SYSTEM WILL COMPRISE A SECURE, RAPID-RESPONSE TECHNICAL PLATFORM, SUPPORT FROM TRAINED CASE MANAGERS, AND AN INTERVENTION ?TOOLKIT?. TAILORED TO MEET THE SPECIFIC NEEDS OF EACH USER, THE EVT TOOLKIT WILL OFFER A MENU OF OPTIONS, INCLUDING: (1) PERSONALIZED ASSISTANCE WITH DIGITAL SAFETY AND SECURITY, (2) SUPPORT MONITORING AND REPORTING ABUSE, AND (3) HELP IDENTIFYING AND BUILDING A COMMUNITY CARE SYSTEM. GROUNDED IN BEST PRACTICES FROM TRAUMA-INFORMED CARE, THE COMMUNITY CARE SYSTEM IN PARTICULAR IS DESIGNED TO BRING TOGETHER PEERS, FRIENDS, FAMILY, COLLEAGUES, AND MENTAL HEALTH CARE SPECIALISTS WHO CAN PROVIDE SUPPORT FOR THE EXPERT FACING ONLINE ABUSE, WHILE ALSO HELPING TO BUILD LONG-TERM RESILIENCE WITHIN SOCIAL NETWORKS, INSTITUTIONS, AND SOCIETY AS A WHOLE 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.

TEEN PREVENTION PROGRAM - TIER 2

PHASE 1/2B TESTING OF THE SM-TSP-2 SCHISTOSOMIASIS VACCINE IN UGANDA

ROLE OF LIVER FLUKE GRANULIN IN CHOLANGIOCARCINOGENESIS

RANDOMIZED TRIAL OF ANTENATAL LATE PRETERM STEROIDS (ALPS) - DCC

LONG-TERM IMMUNITY AGAINST TOXOPLASMOSIS

THREE YEAR AWARD TO CREATE NEW PROGRAMMING MODELS FOR NON-GENDER BASED VIOLENCE SERVICE ORGANIZATIONS TO SUPPORT SURVIVORS OF GENDER BASED VIOLENCE.

MULTI-CENTER STUDY OF TAMSULOSIN FOR URETERAL STONES IN THE EMERGENCY DEPARTMENT

TACE

RECREATIONAL MARIJUANA MARKETING AND YOUNG ADULT CONSUMER BEHAVIOR - SUMMARY/ABSTRACT THE PAST DECADE IN THE US MARKED PIVOTAL CHANGES IN THE POLICY AND RETAIL ENVIRONMENTS REGARDING MARIJUANA (MJ), THE MOST COMMONLY USED FEDERALLY ILLICIT DRUG, PARTICULARLY PREVALENT IN YOUNG ADULTS AND RACIAL AND SEXUAL/GENDER MINORITIES (SGM). DESPITE CONTROVERSY REGARDING RECREATIONAL MJ, FURTHER LEGALIZATION IS LIKELY, AND STATES WILL CONTINUE TO NAVIGATE ITS IMPLEMENTATION. THUS, STATES WITH LEGALIZED RECREATIONAL MJ PROVIDE AN OPPORTUNITY AND A NEED TO MONITOR RECREATIONAL MJ RETAIL AND IMPACT ON VARIOUS SUBGROUPS, AS MJ REGULATORY FRAMEWORKS ARE IN THEIR INFANCY AND REQUIRE ADVANCEMENTS GIVEN THE NUANCES OF MJ RETAIL (E.G., SPECIALTY STORES, UNIQUELY DIVERSE PRODUCTS, PROGRESSIVE PROMOTIONAL STRATEGIES). THE OVERALL GOAL OF THIS RESEARCH IS TO INFORM REGULATORY EFFORTS TO MINIMIZE MJ USE IN VULNERABLE POPULATIONS, IN STATES WITH LEGALIZED RECREATIONAL MJ AND THOSE THAT SUBSEQUENTLY LEGALIZE IT. THE IMMEDIATE OBJECTIVE OF THIS PROPOSAL IS TO EXAMINE THE RECREATIONAL MJ MARKET, MJ USE, AND RELATED PERCEPTIONS IN CONSUMER SEGMENTS OF DISPROPORTIONATELY-IMPACTED GROUPS, PARTICULARLY DIVERSE YOUNG ADULTS. OUR SCIENTIFIC PREMISE BUILDS ON LITERATURE INDICATING THAT LICIT DRUG RETAIL MARKETING – BOTH BRICK-AND-MORTAR AND ONLINE – TARGET CERTAIN POPULATIONS (E.G., RACIAL/ETHNIC MINORITIES, SGM, YOUNG ADULTS) AND THE CONSEQUENCES OF SUCH MARKETING ON SUBSTANCE USE IN THESE GROUPS. THE MJ RETAIL HAS LARGELY LACKED STANDARDIZED INDUSTRY MARKETING SURVEILLANCE TOOLS, WHICH HAVE BEEN CRITICAL IN ESTABLISHING THE IMPACT OF TOBACCO AND ALCOHOL RETAIL MARKETING AND INFORMING REGULATION. THIS PROPOSAL LEVERAGES OUR TEAM’S PRIOR WORK; WE DEVELOPED SURVEILLANCE TOOLS TO CHARACTERIZE POINT-OF-SALE PRACTICES (E.G., AGE VERIFICATION), PRODUCT AVAILABILITY, PROMOTIONAL STRATEGIES, AND PRODUCT PRICING AT BRICK- AND-MORTAR SHOPS AND ONLINE – NOW USED BROADLY IN RESEARCH AND PRACTICE. FINDINGS INDICATED SEVERAL ISSUES WITH POLICY COMPLIANCE (E.G., AGE VERIFICATION), PROMOTIONAL STRATEGIES APPEALING TO YOUNG PEOPLE AND MINORITIES, VARIOUS HEALTH CLAIMS, AND MINIMAL HEALTH WARNINGS. OUR TEAM HAS ALSO SHOWN THE UTILITY OF IDENTIFYING YOUNG ADULTS AT HIGH-RISK FOR SUBSTANCE USE AND LIKELY MARKETING EXPOSURE BY USING INDUSTRY MARKET SEGMENTATION BASED ON PSYCHOGRAPHICS (E.G., VALUES, ATTITUDES, LIFESTYLE); THE EXTENT TO WHICH PSYCHOGRAPHICS VS. SOCIODEMOGRAPHICS INFORM INDUSTRY MARKETING STRATEGIES, PARTICULARLY AMONG TARGETED POPULATIONS, IS NOT WELL KNOWN. USING A SOCIOECOLOGIC FRAMEWORK AND DIFFUSION OF INNOVATIONS, WE AIM TO: 1) DETERMINE WHETHER NEIGHBORHOOD DEMOGRAPHY IS ASSOCIATED WITH MARKETING AND POS PRACTICES AMONG RECREATIONAL MJ RETAILERS OVER TIME, ACCOUNTING FOR POLICY CONTEXT; AND 2) COMPARE YOUNG ADULT MARKET SEGMENTS DEFINED BY AGE AND MINORITY STATUS VS. PSYCHOGRAPHICS IN RELATION TO MJ USE, PERCEPTIONS, ACCESS, AND ADVERTISING EXPOSURE IN STATES WITH DIFFERING MJ POLICY CONTEXTS (RECREATIONAL, MEDICINAL, NO LEGALIZED MJ POLICY) OVER TIME. LED BY A BY UNIQUELY-POISED RESEARCH TEAM, THIS PROPOSAL IS: A) RESPONSIVE TO NOT-DA-19-065 (PUBLIC HEALTH RESEARCH ON CANNABIS); B) BASED ON A STRONG SCIENTIFIC PREMISE AND RATIONALE; C) HIGHLY INTEGRATIVE ACROSS AIMS/DATA SOURCES; AND D) BASED ON RIGOROUS METHODS INTEGRATING INNOVATIVE APPLICATIONS. WE INCLUDE A ROBUST DISSEMINATION PLAN INVOLVING REPRESENTATIVES FROM STATE/LOCAL AGENCIES OVERSEEING MJ RETAIL IMPLEMENTATION TO SPEED RESEARCH TRANSLATION TO PRACTICE.

BUILDING CANCER CONTROL CAPACITY: FOCUS ON RURAL CANCER CONTROL

EXPERIMENTAL INVESTIGATIONS OF HADRON SPECTROSCOPY AT ACCELERATOR FACILITIES

REPURPOSING FDA-APPROVED OXYTOCIN TO TREAT OPIOID-INDUCED RESPIRATORY DEPRESSION - OPIOID ADDICTION AND MISUSE IS A SERIOUS NATIONAL CRISIS THAT AFFECTS PUBLIC HEALTH, AS WELL AS SOCIAL AND ECONOMIC WELFARE. THE OPIOID CRISIS HAS BEEN GREATLY EXACERBATED BY THE INCREASED AVAILABILITY OF SYNTHETIC OPIOIDS, SUCH AS FENTANYL, AND BY THE INCREASED PRESCRIBING OF OPIOID PAIN RELIEVERS. OPIOID OVERDOSE KILLS 130 PEOPLE IN THE UNITED STATES EVERY DAY. THE PRIMARY CAUSE OF DEATH ASSOCIATED WITH OPIOIDS IS OPIOID-INDUCED RESPIRATORY DEPRESSION (OIRD). NALOXONE, A COMPETITIVE ANTAGONIST OF MU-OPIOID RECEPTORS (MORS), HAS A RAPID ONSET AND HELPS REVERSE OIRD BUT IS SHORT ACTING AND RE-DOSING IS OFTEN NECESSARY. A RECENTLY APPROVED MOR ANTAGONIST, NALMEFENE, IS LONG-ACTING, HOWEVER BOTH NALOXONE AND NALMEFENE REVERSE OPIOID MEDIATED ANALGESIA AND INDUCE ACUTE WITHDRAWAL LEADING TO LOW ADHERENCE THAT LIMIT THEIR USE FOR OIRD PREVENTION PARTICULARLY IN HIGHLY VULNERABLE POPULATIONS SUCH AS PATIENTS CHRONICALLY RECEIVING HIGH DOSES OF OPIOIDS FOR PAIN. IN ADDITION, NALOXONE DOES NOT REVERSE OPIOID INDUCED MUSCLE RIGIDITY, UPPER AIRWAY OBSTRUCTION IN PATIENTS WITH UNDERLYING OBSTRUCTIVE SLEEP APNEA, AND MAY CAUSE PULMONARY EDEMA. ALTERNATIVE, NON-OPIOID RECEPTOR ANTAGONIST-BASED APPROACHES FOR BOTH OIRD TREATMENT AND PREVENTION ARE NEEDED. OUR APPROACH TARGETS OXYTOCIN (OXT), AS OUR WORK HAS SHOWN OXT IS EFFECTIVE FOR TREATMENT OF SLEEP DISORDERED BREATHING BY INCREASING RESPIRATORY RATE AND DECREASING THE DURATION OF THE APNEIC/HYPOPNEIC EVENTS AND SEVERITY OF HYPOXEMIA IN PATIENTS WITH OBSTRUCTIVE SLEEP APNEA. OXT IS FDA APPROVED FOR OTHER USES. OUR OVERARCHING HYPOTHESIS, BASED ON OUR EXCITING PRELIMINARY DATA, IS THAT OXT PREVENTS FENTANYL ASSOCIATED MORTALITY, AND REDUCES FENTANYL EVOKED RESPIRATORY DEPRESSION AND INCREASED INCIDENCE OF APNEAS. IN RESPONSE TO PAR-22-200, WE PROPOSE TO CONDUCT STUDIES THAT WILL EVALUATE THE POTENCY, EFFICACY, AND DURATION OF ACTION OF OXT IN REVERSING OIRD AND REDUCING OPIOID LETHALITY. IN SPECIFIC AIM 1: WE WILL IDENTIFY, VALIDATE AND OPTIMIZE OXT DOSE, ROUTES OF ADMINISTRATION (INTRANASAL (IN), SUBCUTANEOUS (SUB- Q), AND INTRAVENOUS (IV)), AND NEED FOR REDOSING, TO REVERSE ACUTE OIRD INDUCED BY FENTANYL. IN SPECIFIC AIM 2: WE WILL USE AN ANIMAL MODEL OF CHRONIC PAIN AND DAILY ED50 ADMINISTRATION OF FENTANYL TO TEST IF OXT PROVIDES ADDITIONAL ANALGESIA AND HELPS PREVENT THE RISK OF OVERDOSE LETHALITY AND OIRD THAT OCCURS WITH CHRONIC OPIOID USE AND OPIOID TOLERANCE. IN SPECIFIC AIM 3: WE WILL TEST THE HYPOTHESIS THAT SELECTIVE CHEMOGENETIC ACTIVATION OF OXT NEURONS IN THE PARAVENTRICULAR NUCLEUS OF THE HYPOTHALAMUS WILL PREVENT AND TREAT OIRD. IN SPECIFIC AIM 4: WE WILL OBTAIN THE APPROVALS REQUIRED FOR TWO CLINICAL TRIALS. IN SPECIFIC AIM 5: WE WILL QUANTIFY, IN A DOUBLE BLINDED, PLACEBO-CONTROLLED PHASE 2 CLINICAL TRIAL, THE THERAPEUTIC EFFICACY OF OXT IN DECREASING APNEAS, RESPIRATORY DEPRESSION AND OXYGEN DESATURATIONS IN PATIENTS GIVEN OPIOIDS UPON IN-HOSPITAL RECOVERY FROM LAPAROSCOPIC BARIATRIC SURGERY. IN SPECIFIC AIM 6: WE WILL TEST IN A DOUBLE BLINDED, PLACEBO-CONTROLLED PHASE 2 CLINICAL TRIAL, THE THERAPEUTIC EFFICACY OF OXT IN DECREASING A) THE SEVERITY OF SLEEP DISORDERED BREATHING; B) PAIN PERCEPTION, C) OPIOID DOSE AND D) DRUG LIKING IN PATIENTS ON CHRONIC OPIOID THERAPY FOR CHRONIC PAIN.

CHANGING THE NARRATIVE ON FIREARMS VIOLENCE: A COMMUNITY COLLABORATIVE INTERVENTION - ABSTRACT HOMICIDE, TYPICALLY WITH A FIREARM, IS THE THIRD LEADING CAUSE OF DEATH FOR YOUNG PEOPLE AGES 10-24 IN THE U.S., DISPROPORTIONALLY AFFECTING AFRICAN-AMERICAN AND OTHER MINORITY YOUTH, PARTICULARLY YOUNG MALES. IN THE DISTRICT OF COLUMBIA, VIOLENT CRIME IS UP 28% FROM 2021, AND HOMICIDE RATES ROSE 14% BETWEEN 2020 AND 2021, WITH THE HIGHEST IMPACT IN SOCIOECONOMICALLY CHALLENGED COMMUNITIES. TO ADDRESS THIS SERIOUS PUBLIC HEALTH ISSUE, THE PREVENTION AND COMMUNITY HEALTH DEPARTMENT WITHIN THE GEORGE WASHINGTON UNIVERSITY MILKEN INSTITUTE SCHOOL OF PUBLIC HEALTH (GWSPH), TOGETHER WITH MINT, INC., DON’T SHOOT GUNS, SHOOT CAMERAS, DC HOUSING AUTHORITY/HIGHLANDS ADDITION COMMUNITY CENTER, THE DC OFFICE OF THE ATTORNEY GENERAL, AND THE DC OFFICE ON GUN VIOLENCE PREVENTION/BUILDING BLOCKS, PROPOSE TO COLLABORATIVELY FINALIZE, IMPLEMENT AND EVALUATE A HIGHLY UNIQUE, COMMUNITY-LEVEL YOUTH FIREARMS PREVENTION INTERVENTION IN TWO PHASES – A DEVELOPMENTAL UG3 PHASE ONE, AND AN IMPLEMENTATION UH3 PHASE TWO. THE PROPOSED INTERVENTION, CALLED “CHANGING THE NARRATIVE ON FIREARMS VIOLENCE,” INVOLVES A UNIQUE, THEORY-DRIVEN EFFORT TO DEVELOP AND DISSEMINATE MULTIPLE MEDIA FEATURING ALTERNATIVE, NON-VIOLENT IDENTITY TRAJECTORIES, WITH ACTUALIZATION OF THOSE TRAJECTORIES FACILITATED THROUGH A COMMUNITY SUPPORT PROCESS. SPECIFICALLY, THE PROPOSED PROJECT WILL: 1) COLLABORATE IN ALL PHASES WITH THE CLIF- VP AS A COOPERATIVE AGREEMENT; 2) IN PHASE ONE (UG3), CONDUCT FORMATIVE RESEARCH TO FINALIZE INTERVENTION ELEMENTS, INCLUDING IDENTIFICATION OF POTENTIAL NON-VIOLENT IDENTITY AND BRANDING ATTRIBUTES AND IDENTIFICATION OF KEY COMMUNITY COMMUNICATION CHANNELS; FINALIZE COMPOSITION OF THE COMMUNITY STEERING COMMITTEE; AND DEVELOPMENT/PILOT TESTING OF DATA COLLECTION INSTRUMENTS AND PROTOCOLS; 3) IN PHASE TWO, IMPLEMENT THE INTERVENTION, COLLECT BASELINE AND TWO ROUNDS OF FOLLOW-UP SURVEY DATA IN A COMMUNITY SAMPLE OF YOUTH AGES12- 16 AND A PARENT/GUARDIAN FOR EACH SURVEYED YOUTH, COLLECT QUALITATIVE DATA TO UNDERSTAND INTERVENTION EFFECTS, ANALYZE THE DATA, SHARE DATA AND RESULTS THROUGH THE CLIF-VP, AND DISSEMINATE RESULTS IN COLLABORATION WITH COMMUNITY PARTNERS AND THE CLIF-VP.

SECURING HIGH DENSITY URBAN AIRSPACES

HIV DISEASE AND IMPAIREMENT OF HIGH DENSITY LIPOPROTEIN METABOLISM

PLATELET-MEDIATED NEUROINFLAMMATORY RESPONSE TO HIV

RENAL DOPAMINE RECEPTOR AND REGULATION

NICOTINE MODULATION OF PARASYMPATHETIC CARDIAC NEURONS

REVEALING THE ROLE OF PLATELETS IN PROMOTING HIV RESERVOIR SEEDING AND PERSISTENCE IN THE CNS-RESIDENT MYELOID CELLS - SUMMARY DESPITE THE DEVELOPMENT OF POTENT ANTI-RETROVIRAL THERAPY (ART) THAT SUCCESSFULLY SUPPRESSES VIRUS REPLICATION IN THE MAJORITY OF PEOPLE LIVING WITH HIV (PLWH), THERE IS NO TREATMENT THAT CAN CURE THIS INFECTION ENTIRELY. THE MAJOR OBSTACLE IN ERADICATING HIV IS THE PERSISTENCE OF VARIOUS ANATOMICAL VIRAL RESERVOIRS (VRS), INCLUDING THE CENTRAL NERVOUS SYSTEM (CNS), THAT HAVE THE CAPACITY TO PRODUCE INFECTIOUS VIRUS AND SYSTEMICALLY SPREAD WITHIN A SHORT PERIOD UPON CESSATION OF ART IN ALL, WITH FEW EXCEPTIONAL CASES. THEREFORE, DEVELOPING NOVEL INTERVENTIONS AIMED AT REDUCING OR ELIMINATING THE VRS IS ONE OF THE KEY PRIORITIES FOR HIV RESEARCH. IN RESPONSE TO RFA-MH- 20-701, OUR APPLICATION PROPOSES BASIC SCIENCE AND PRECLINICAL RESEARCH IN SIV-INFECTED RHESUS MACAQUES (RMS) TO MODEL ASPECTS OF VR IN THE CNS-RESIDENT MYELOID CELLS OF PLWH, AND TO INVESTIGATE THE EFFICACY OF THE NOVEL PHARMACOLOGIC STRATEGY TO PREVENT ESTABLISHMENT OF HIV PERSISTENCE IN THE CNS. THUS, BASED ON THE OBSERVATIONS OUTLINED IN THIS APPLICATION WE HYPOTHESIZE THAT THE DISRUPTION OF PMC FORMATION DURING ACUTE PHASE OF INFECTION WILL LIMIT THE SEEDING AND MAINTENANCE OF VR AND, AS A CONSEQUENCE, THE EXTENT OF VIRAL REBOUND IN THE CNS FOLLOWING ANALYTICAL THERAPY INTERRUPTION (ATI). THREE AIMS ARE PROPOSED: (1) TO INVESTIGATE WHETHER THE SYSTEMIC DISRUPTION OF PMC FORMATION DURING ACUTE PHASE OF INFECTION, REGULATES VIRAL PERSISTENCE IN THE CNS; (2) TO INVESTIGATE WHETHER THE SYSTEMIC DISRUPTION OF PMC FORMATION DURING ACUTE PHASE OF INFECTION, REGULATES THE KINETICS AND EXTENT OF VIRAL REBOUND AFTER ATI; AND (3) TO INVESTIGATE WHETHER THE SYSTEMIC DISRUPTION OF PMC FORMATION DURING ACUTE PHASE OF INFECTION, REGULATES THE NEUROINFLAMMATION AND SYNAPTODENDRITIC DAMAGES ASSOCIATED WITH LONG-TERM ART AND ATI. THESE AIMS WILL BE ACHIEVED BY (I) USING A WELL-ESTABLISHED MODEL OF SIV-INFECTED RMS TREATED WITH SUPPRESSIVE ART, AND (II) PERFORMING IN VIVO AB-MEDIATED DISRUPTION OF PMC FORMATION DURING ACUTE PHASE OF UNTREATED INFECTION. REVEALING THE MECHANISMS THROUGH WHICH PLATELETS REGULATE THE PERSISTENCE OF HIV IN MYELOID CELLS WILL PROVIDE A CRITICAL UNDERSTANDING OF HOW THESE CELLULAR INTERACTIONS FUNCTION IN MAMMALIAN CELLS, AND AN INSIGHT INTO HOW A POTENTIAL HIV CURE CAN BE ACHIEVED IN PLWH.

TRAINING AND TECHNICAL ASSISTANCE NATIONAL COOPERATIVE AGREEMENTS (NCAS)

TEACHER QUALITY ENHANCEMENT GRANTS FOR STATE AND PARTNERSHIPS - PARTNERSHIP GRANTS

MULTILEVEL STRATEGIES TO UNDERSTAND AND MODIFY THE ROLE OF STRUCTURAL AND ENVIRONMENTAL CONTEXT ON HIV INEQUITIES FOR SEXUAL AND GENDER MINORITIES OF COLOR - PROJECT SUMMARY/ABSTRACT BLACK, LATINO/A/E/X, AND MULTIRACIAL (BLM) SEXUAL AND GENDER MINORITIES WHO HAVE SEX WITH MEN (SGMSM) IN THE U.S. CONTINUE TO EXPERIENCE A HIGH AND DISPROPORTIONATE BURDEN OF HIV, PARTICULARLY YOUNGER BLM SGMSM FOR WHOM HIV INCIDENCE CONTINUES TO RISE DESPITE ADVANCES IN HIV PREVENTION. EVIDENCE SUGGESTS THAT DIFFERENCES IN INDIVIDUAL RISK BEHAVIORS DO NOT ACCOUNT FOR HIV INEQUITIES, AND UNDERSCORE THE NEED TO MOVE BEYOND MODELS OF INDIVIDUAL-LEVEL RISK FACTORS TO IDENTIFY AND INTERVENE UPON THE SOCIO-STRUCTURAL FACTORS THAT CREATE AND MAINTAIN INEQUITABLE RISK ENVIRONMENTS. HOWEVER, MUCH OF THE RESEARCH TO DATE IS LIMITED IN SCOPE AND FOCUSES INDIVIDUAL-LEVEL RISK OR ON CROSS-SECTIONAL HIV PREVALENCE, WHICH LIMITS THE ABILITY TO TREAT SOCIO- STRUCTURAL FACTORS AS DYNAMIC OR TO INVESTIGATE THE ENVIRONMENTS WITHIN WHICH RISK BEHAVIORS OCCUR. WE ARE SUBMITTING THIS APPLICATION IN RESPONSE TO RFA-AI-21-018 LIMITED INTERACTION TARGETED EPIDEMIOLOGY TO ADVANCE HIV PREVENTION (UG3/UH3). WE PROPOSE TO ENROLL A COHORT OF APPROXIMATELY 5,500 BLM SGMSM AGES 16 AND OLDER IN THE U.S. AND PUERTO RICO WHO ARE AT HIGH RISK FOR HIV INFECTION. WE WILL USE A COMBINED APPROACH TO RECRUITMENT (SEXUAL NETWORKING APPS, SOCIAL MEDIA, AND OTHER DIGITAL RECRUITMENT TECHNIQUES) THAT IS ADAPTIVE TO KNOWN SHIFTS IN DIGITAL TECHNOLOGY. PARTICIPANTS WILL COMPLETE A SURVEY AND HOME-BASED SAMPLING FOR LAB-BASED HIV TESTING AT ENROLLMENT AND ANNUALLY THEREAFTER FOR THREE YEARS AND AN ECOLOGICAL MOMENTARY ASSESSMENT (EMA) FOR SIX WEEKS AFTER ENROLLMENT. CONCORDANT WITH STUDY ENROLLMENT, WE WILL DEVELOP NOVEL METRICS TO QUANTIFY SOCIO-STRUCTURAL FACTORS (STATE-LEVEL POLICY AND SOCIAL CLIMATE INDICATORS) THAT CREATE INTERSECTIONAL OPPRESSION FOR BLM SGMSM, SPECIFICALLY STRUCTURAL RACISM, ANTI-LGBTQ STIGMA, AND RESTRICTIVE HIV-RELATED HEALTHCARE (AIM 1A). WE WILL SUBSEQUENTLY UTILIZE THE NEWLY DEVELOPED METRICS FROM AIM 1A ALONG WITH LOCAL SOCIO-STRUCTURAL FACTORS (LOCAL-LEVEL HIV PREVALENCE AND SOCIOECONOMIC INDICATORS) AND BASELINE AND EMA DATA TO TEST THE INEQUITABLE RISK ENVIRONMENTS HYPOTHESIS TO UNDERSTAND THE ROLE OF STATE AND LOCAL SOCIO- STRUCTURAL RISK FACTORS IN HIV RISK—THIS HYPOTHESIS WILL SPECIFICALLY TEST BOTH THE IMPACT OF SOCIO-STRUCTURAL FACTORS ON DAILY EXPOSURE TO INTERSECTIONAL STIGMA AND THE INTERACTION OF SOCIO-STRUCTURAL RISK WITH INDIVIDUAL BEHAVIORS ON UNDIAGNOSED HIV INFECTION AT BASELINE (AIM 2). THESE DATA WILL ALSO BE USED TO TEST A LONGITUDINAL MODEL OF MECHANISMS THROUGH WHICH STATE AND LOCAL SOCIO-STRUCTURAL FACTORS DIRECTLY AND INDIRECTLY INFLUENCE HIV SEROCONVERSION AND ACCESS TO EMERGING HIV PREVENTION TECHNOLOGIES (E.G., EMERGING PREP MODALITIES) (AIM 3). STUDY FINDINGS WILL BE SYSTEMATICALLY REVIEWED AND TRANSLATED INTO GUIDELINES FOR ENDING THE HIV EPIDEMIC- RELATED PUBLIC HEALTH POLICY AND COMMUNITY-LEVEL INTERVENTIONS TO REDUCE HIV INEQUITIES (AIM 1B). DEVELOPING AND TESTING A SOCIO-STRUCTURAL MODEL OF HIV RISK HAS STRONG POTENTIAL TO MOVE THE FIELD BEYOND INDIVIDUALLY- FOCUSED MODELS OF RISK AND IMPROVE THE NEXT GENERATION OF HIV PREVENTION INTERVENTIONS AIMED AT REDUCING DISPARITIES FOR THIS POPULATION.

COOPERATIVE AGREEMENT FOR A REGIONAL CENTER FOR HEALTH WORKFORCE STUDIES

RCT OF A PARENT-FOCUSED INTERVENTION TO REDUCE HIV RISK IN ADOLESCENT MSM - PROJECT SUMMARY ADOLESCENT MEN WHO HAVE SEX WITH MEN (AMSM) ACCOUNTED FOR 79% OF NEW HIV INFECTIONS AMONG YOUTH AGES 13-19 IN THE UNITED STATES (US) IN 2018. LESS THAN A QUARTER OF AMSM HAVE EVER TAKEN AN HIV TEST. DESPITE THESE STARK DISPARITIES IN HIV INCIDENCE AND TESTING, INTERVENTIONS TO REDUCE SEXUAL RISK AND INCREASE HIV TESTING AMONG AMSM REMAIN EXTREMELY LIMITED. NOTABLY, THE VERY FEW INTERVENTION APPROACHES THAT ARE CURRENTLY BEING EXPLORED FOR AMSM EXCLUDE PARENTS. THE OMISSION OF PARENT-FOCUSED APPROACHES REPRESENTS A GLARING GAP IN NATIONAL EFFORTS TO END THE HIV EPIDEMIC GIVEN PARENTS’ WELL-DOCUMENTED ABILITY TO SHAPE ADOLESCENT SEXUAL HEALTH, INCLUDING FOR AMSM. CONSISTENT WITH NIH PRIORITIES (PA-20-144) THE GOAL OF THE PROPOSED RESEARCH IS TO TEST THE EFFICACY OF A PARENT-FOCUSED INTERVENTION DESIGNED TO REDUCE HIV RISK AND INCREASE HIV TESTING AMONG AMSM. PARENTS AND ADOLESCENTS TALKING ABOUT HEALTHY SEXUALITY (PATHS) IS AN ONLINE INTERVENTION WE CREATED FOR PARENTS OF AMSM THAT WORKS TO INCREASE PARENT COMMUNICATION ABOUT SEXUALITY AND HIV, AS WELL AS OTHER PARENT BEHAVIORS SUPPORTIVE OF SEXUAL RISK REDUCTION. OUR NIH-FUNDED PILOT RCT WITH A NATIONAL SAMPLE OF 61 RACIALLY/ETHNICALLY DIVERSE PARENT-AMSM DYADS REVEALED THAT PATHS INCREASED BOTH PARENT AND CHILD REPORTS OF MULTIPLE PARENT BEHAVIORS SUPPORTIVE OF SEXUAL HEALTH. BUILDING ON THE PROMISING EFFECTS PATHS HAD ON PARENT BEHAVIORS, THE GOAL OF THE PROPOSED STUDY IS TO TEST WHETHER PATHS IMPROVES SEXUAL HEALTH OUTCOMES IN AMSM AGES 14-19. WE WILL CONDUCT AN RCT OF PATHS WITH 350 PARENT-AMSM DYADS RECRUITED ONLINE (50% RACIAL/ETHNIC MINORITY). PARENTS WILL BE RANDOMIZED TO RECEIVE EITHER PATHS OR AN ACTIVE CONTROL, AND THEN ASSESSED EVERY 3 MONTHS OVER A 1-YEAR PERIOD. PRIMARY OUTCOMES WILL BE EVALUATED AT 6 MONTHS POST-INTERVENTION, AND THEN THE CONTROL ARM WILL CROSSOVER AND RECEIVE PATHS, AND DYADS WILL BE FOLLOWED FOR ANOTHER 6 MONTHS. THIS ALLOWS US TO FURTHER TEST THE EFFECTS OF PATHS IN THE CONTROL ARM WHILE SIMULTANEOUSLY MODELING THE LONGER 9- AND 12-MONTH EFFECTS IN THE ORIGINAL INTERVENTION ARM. THE PRIMARY (P) SPECIFIC AIMS ARE TO: (P1) TEST THE EFFICACY OF PATHS IN IMPROVING THE DEGREE TO WHICH AMSM ARE PREPARED FOR INTERCOURSE (OPERATIONALIZED AS: HAVING ACCESS TO CONDOMS, DEMONSTRATING ACCURATE CONDOM SKILLS, EXPRESSING INTENTIONS TO USE CONDOMS, RECEIVING HIV TESTING, UNDERSTANDING WHAT PREP IS, AND EXPRESSING POSITIVE ATTITUDES TOWARD PREP); AND (P2) TEST THE EFFICACY OF PATHS IN REDUCING CONDOMLESS ANAL/VAGINAL INTERCOURSE. SECONDARY (S) AIMS ARE TO: (S1) EXAMINE THE DEGREE TO WHICH INTERVENTION EFFECTS OBSERVED IN P1 AND P2 PERSIST TO 1-YEAR POST INTERVENTION; AND (S2) EXAMINE HOW PARENT BEHAVIORS MEDIATE EFFECTS OF PATHS ON AMSM OUTCOMES. IF PROVEN EFFICACIOUS, PATHS WILL BE AMONG THE FIRST INTERVENTIONS DEMONSTRATED TO REDUCE SEXUAL RISKS AND INCREASE HIV TESTING FOR AMSM – THE POPULATION OF YOUTH AT HIGHEST RISK FOR HIV INFECTION IN THE US. MOREOVER, AS OTHER ADOLESCENT-FOCUSED INTERVENTIONS EMERGE, PATHS’ UNIQUE FOCUS ON PARENTS WILL OFFER A COMPLEMENTARY, ADDITIONAL MEANS FOR REACHING AMSM WHO ARE NOT TOUCHED BY OTHER INTERVENTION OPTIONS.

RCU FOR LIFESTYLE INTERVENTIONS IN OVERWEIGHT AND OBESE PREGNANT WOMEN CONSORTIUM

THE DYNAMICS OF NASAL BACTERIAL ECOLOGY AND S. AUREUS ANTAGONISM

NOVEL PATHOGENIC MECHANISM OF HIV-ASSOCIATED CNS NEUROLOGICAL DISORDERS - ABSTRACT EFFECTIVE TREATMENT OF HIV INFECTION HAS REDUCED THE SEVERITY OF HIV-ASSOCIATED NEUROCOGNITIVE DISORDER (HAND), HOWEVER, THE INCIDENCE OF CNS NEUROLOGICAL DYSFUNCTION (~50% OF HIV PATIENTS) HAS NOT BEEN DIMINISHED BY THE TREATMENT. WITH DRAMATICALLY EXTENDED LIFE EXPECTANCY OF HIV-INFECTED PATIENTS, NEUROLOGICAL DYSFUNCTION REDUCES THE QUALITY OF LIFE BY AFFECTING LEARNING AND EXECUTIVE FUNCTIONS, AND PUTS THESE INDIVIDUALS AT RISK OF DEVELOPING SIGNIFICANT HEALTH PROBLEM. THE TREATMENT OPTIONS FOR THIS CO-MORBIDITY ARE LIMITED BY POOR UNDERSTANDING OF ITS PATHOGENIC MECHANISMS IN VIROLOGICALLY SUPPRESSED PATIENTS. SEVERAL HYPOTHESES HAVE BEEN SUGGESTED, RANGING FROM LOW GRADE CHRONIC NEUROINFLAMMATION CAUSED BY HIV INFECTION, TO NEUROTOXICITY OF HIV-RELATED FACTORS, TO HIV ACCELERATING THE NATURAL DEVELOPMENT OF KNOWN NEURODEGENERATIVE DISEASES, SUCH AS ALZHEIMER’S DISEASE. ALTHOUGH THESE HYPOTHESES ARE CONSISTENT WITH SOME ELEMENTS OF HAND, NONE OF THEM EXPLAINS THE FULL PATHOLOGICAL MANIFESTATION OF THIS DISORDER AND ITS UNIQUE RELATIONSHIP WITH HIV INFECTION. IN THIS APPLICATION, WE PROPOSE TO TEST A NOVEL HYPOTHESIS THAT, IF CONFIRMED, WILL POINT TO THE KEY ELEMENT OF PATHOGENESIS OF CNS NEUROLOGICAL DISORDER CAUSED BY HIV INFECTION AND MAY TRANSLATE TO NOVEL TREATMENT OPPORTUNITIES. WE HYPOTHESIZE THAT THE CENTRAL MECHANISM IN HIV-ASSOCIATED CNS DISORDER IS THE REORGANIZATION OF LIPID RAFTS CAUSED BY HIV NEF. CHANGES IN NEURONAL LIPID RAFTS PROMOTE PROTEIN MISFOLDING/AGGREGATION, EXACERBATE INFLAMMATORY RESPONSES, AND AFFECT NEURONAL COMMUNICATIONS LEADING TO FUNCTIONAL IMPAIRMENT AND EVENTUALLY TO NEURODEGENERATION. DYSFUNCTION OF THE LIPID RAFTS IS ESSENTIAL FOR PATHOGENESIS OF MANY NEURODEGENERATIVE DISEASES, INCLUDING ALZHEIMER’S, POINTING TO A BROAD RELEVANCE OF OUR HYPOTHESIS TO DISEASES OF AGING POPULATION. THIS HYPOTHESIS IS BASED ON OUR PUBLISHED AND PRELIMINARY FINDINGS THAT HIV PROTEIN NEF REORGANIZES LIPID RAFTS IN MACROPHAGES AND NEURONS. WE RECENTLY DEMONSTRATED THAT CHANGES TO LIPID RAFTS INFLICTED BY NEF ARE SIMILAR TO THOSE FOUND IN NEURONS INFECTED BY PRIONS. IMPORTANTLY, RECENT STUDIES HAVE SHOWN THAT NEURONS EXPOSED TO NEF-CONTAINING EXOSOMES, RELEASED BY HIV-INFECTED BRAIN MACROPHAGES, MICROGLIA AND ASTROCYTES, TAKE UP EXOGENOUS NEF, WHICH IS FUNCTIONALLY ACTIVE. NEF PRODUCTION IN VIRAL RESERVOIRS, INCLUDING BRAIN, CONTINUES IN THE PRESENCE OF ANTIRETROVIRAL THERAPY. THE FOLLOWING AIMS WILL BE PURSUED TO TEST THIS INNOVATIVE HYPOTHESIS. AIM 1: TO ESTABLISH THE CONTRIBUTION OF NEF TO HIV-ASSOCIATED CNS NEUROLOGICAL DYSFUNCTION IN MOUSE MODELS; AIM 2: TO DETERMINE MECHANISMS BY WHICH NEF RELEASED FROM HIV-INFECTED CELLS AFFECTS CHOLESTEROL METABOLISM IN NEURONS, CAUSING NEUROLOGICAL DYSFUNCTION; AIM 3: TO TARGET LIPID RAFTS AS A POTENTIAL THERAPEUTIC APPROACH TO TREAT HIV-ASSOCIATED NEUROLOGICAL DYSFUNCTION. THESE INTERCONNECTED BUT INDEPENDENT AIMS WILL PROVIDE AN ACTIONABLE MODEL OF HIV-ASSOCIATED CNS DISORDER.

CONTROLLED INFECTION TRIAL TO TEST EFFICACY OF HOOKWORM VACCINE WITH DIFFERENT TLR AGONISTS

GRK4 AND DEVELOPMENT OF SALT SENSITIVITY

QUANTIFYING THE FITNESS COST OF HIV-1 RESISTANCE TO BROADLY NEUTRALIZING ANTIBODIES

ENICTO CONSORTIUM COORDINATING CENTER - PROJECT SUMMARY ABSTRACT THE GOAL OF THE EXERCISE AND NUTRITION INTERVENTIONS TO IMPROVE CANCER TREATMENT-RELATED OUTCOMES (ENICTO) CONSORTIUM IS TO SUPPORT AND ENHANCE EXERCISE AND/OR MEDICAL NUTRITION INTERVENTION RESEARCH DESIGNED TO EVALUATE INTERVENTIONS THAT MAY IMPROVE CANCER TREATMENT-RELATED OUTCOMES AMONG PATIENTS BEING TREATED WITH CURATIVE OF LIFE-EXTENDING INTENT. THE AIMS OF THE ENICTO COORDINATING CENTER ARE TO FACILITATE THE WORK OF THE ENICTO CONSORTIUM BY: 1) SUPPORTING THE SCIENTIFIC GOALS OF THE ENICTO CONSORTIUM THROUGH COLLECTION, HARMONIZATION AND ANALYSIS OF COMMON DATA ACROSS CONSORTIUM SITES, 2) FACILITATING COMMUNICATION WITHIN THE CONSORTIUM AND BETWEEN THE CONSORTIUM WITH EXTERNAL AUDIENCES, AND 3) COORDINATING ADMINISTRATIVE FUNCTIONS OF THE ENICTO CONSORTIUM. UNDER THE DIRECTION OF THE ENICTO STEERING COMMITTEE, THE ENICTO COORDINATING CENTER WILL WORK WITH CONSORTIUM INVESTIGATORS TO IDENTIFY COMMON DATA ELEMENTS AND PROCEDURES ACROSS CONSORTIUM SITES, HARMONIZE COHORT VARIABLES, AND IDENTIFY OPPORTUNITIES FOR NOVEL DATA COLLECTION TO ENRICH THE ENICTO DATA RESOURCES. THE COORDINATING CENTER WILL ORGANIZE TRAINING SESSIONS FOR CONSORTIUM SITE STAFF TO ENSURE THE QUALITY, CONSISTENCY, AND COMPLETENESS OF THE DATA ACROSS SITES, DEVELOP AND IMPLEMENT A DATA MANAGEMENT PLATFORM FOR DATA COLLECTION AND REPORTING FROM THE CONSORTIUM SITES, AND TRAIN AND SUPPORT CONSORTIUM SITES ON PLATFORM USE. THE COORDINATING CENTER WILL LEAD ANALYSES FOR CROSS-CONSORTIUM PILOT PROJECTS EXAMINING COMMON RESEARCH QUESTIONS, AND MAKE THE HARMONIZED ENICTO DATA AVAILABLE TO QUALIFIED RESEARCHERS BASED ON CONSORTIUM POLICIES AND DATA SHARING AGREEMENTS. THE COORDINATING CENTER WILL PLAN AND COORDINATE THE ENICTO CONSORTIUM ANNUAL MEETING AND MEETINGS OF THE STEERING COMMITTEE, ESTABLISH EMAIL LISTSERVS, DEVELOP AND MAINTAIN A WEBSITE FOR THE ENICTO CONSORTIUM, PLAN AND FACILITATE COMMUNICATION AMONG THE SCIENTIFIC WORKING GROUPS, SUPPORT THE DISTRIBUTION OF RESEARCH MATERIALS SUCH AS STUDY PROTOCOLS AND EDUCATION MATERIALS, AND DISSEMINATE RESEARCH FINDINGS TO THE SCIENTIFIC AND CANCER COMMUNITIES. ADMINISTRATIVE FUNCTIONS OF THE COORDINATING CENTER WILL INCLUDE DEVELOPMENT AND IMPLEMENTATION OF ENICTO OPERATING POLICIES AND PROCEDURES PERTAINING TO DATA SHARING, PUBLICATIONS AND PRESENTATION, EXTERNAL COLLABORATIONS AND ANCILLARY STUDIES UNDER THE GUIDANCE OF THE ENICTO STEERING COMMITTEE, AND AN EVALUATION SYSTEM TO TRACK U01 SITE PERFORMANCE AND PROJECT PROGRESS. THE COORDINATING CENTER WILL PREPARE MEETING AGENDAS, COMPILE MEETING MATERIALS, RECORD MEETING MINUTES AND ACTION ITEMS, AND PROVIDE GENERAL ADMINISTRATIVE SUPPORT AND OVERSIGHT.

DEVELOPMENT OF OLIGODENDRYCYTES IN THE SPINAL CORD

OPTIMAL DOSING OF UNDERSTUDIED DRUGS ADMINISTERED TO PREGNANT INDIVIDUALS PER STANDARD OF CARE (PREGDOSE) - PROJECT SUMMARY/ABSTRACT THE MAJORITY OF DRUGS PRESCRIBED TO PREGNANT INDIVIDUALS LACK DOSING INFORMATION SPECIFIC TO THIS POPULATION. DOSING IS DIFFERENT IN THIS POPULATION DUE TO ANATOMIC AND PHYSIOLOGIC CHANGES DURING PREGNANCY THAT SUBSTANTIALLY AFFECT DRUG EXPOSURE. A LACK OF APPROPRIATE DOSING DATA IN PREGNANT INDIVIDUALS IS AN UNMET PUBLIC HEALTH NEED THAT CAN RESULT IN THERAPEUTIC FAILURE AND MATERNAL AND FETAL MORBIDITY. OUR OBJECTIVE FOR THE DOSING AND SAFETY OF UNDERSTUDIED DRUGS ADMINISTERED TO PREGNANT INDIVIDUALS PER STANDARD OF CARE (PREGDOSE) STUDY IS TO CREATE THE RESEARCH INFRASTRUCTURE TO ADDRESS THESE DOSING KNOWLEDGE GAPS AND DETERMINE OPTIMAL DOSING FOR COMMONLY USED DRUGS IN PREGNANCY. WE WILL ACCOMPLISH THIS GOAL THROUGH AN INTEGRATED APPROACH THAT IS CENTERED ON A PROSPECTIVE, MULTI-CENTER, OPPORTUNISTIC STUDY OF UNDERSTUDIED DRUGS IN PREGNANT INDIVIDUALS. IN AIM 1, WE WILL ENROLL PREGNANT INDIVIDUALS WHO ARE ON A DRUG(S) OF INTEREST PER STANDARD OF CARE. BIOLOGICAL SAMPLES AND MARKERS OF DRUG EFFICACY WILL BE COLLECTED THROUGHOUT PREGNANCY AND IN THE POSTPARTUM PERIOD. POSTPARTUM SAMPLES WILL ALSO INCLUDE CORD BLOOD AND INFANT BLOOD TO BETTER UNDERSTAND FETAL/NEONATAL EXPOSURE. USING AN ALIQUOT OF EACH SAMPLE, IN AIM 2 WE WILL ESTABLISH A BIOREPOSITORY TO AID FUTURE PRECISION- DOSING STUDIES. IN AIM 3 WE WILL USE SOPHISTICATED PHARMACOKINETIC (PK)-PHARMACODYNAMIC (PD) MODELING TO DETERMINE OPTIMAL DOSING. THIS MODELING WILL IDENTIFY KEY DETERMINANTS OF DRUG EXPOSURE-EFFECT TO INFORM A PREGNANCY PRECISION DOSING TOOL. THE PIS AND RESEARCH TEAM HAVE A SUCCESSFUL HISTORY IN MATERNAL PHARMACOLOGY AND POSSESS THE SKILLS, ACCESS TO PATIENTS, AND RESEARCH ENVIRONMENT NEEDED TO COMPLETE THESE PROJECTS. DR. REBECAA CLIFTON IS A BIOSTATISTICIAN, THE PI OF THE MATERNAL-FETAL MEDICINE UNITS (MFMU) DATA COORDINATING CENTER AND WILL OVERSEE ALL STUDY EFFORTS. DR. WATT IS A PEDIATRICIAN, EXPERIENCED TRIALIST AND PHARMACOLOGIST, SERVES ON THE PRGLAC IMPLEMENTATION WORKING GROUP, AND HAS LED SIMILAR OPPORTUNISTIC DOSING STUDIES IN CHILDREN AND LACTATING INDIVIDUALS. DR. TORRI METZ IS A MATERNAL FETAL MEDICINE SPECIALIST WITH EXTENSIVE EXPERIENCE IN OBSTETRIC DRUG TRIALS. IMPORTANTLY, THIS STUDY WILL LEVERAGE THE INFRASTRUCTURE AND RESOURCES OF THE NICHD-FUNDED MFMU NETWORK AND MATERNAL AND PEDIATRIC PRECISION IN THERAPEUTICS (MPRINT) HUB. KEY MPRINT CO-INVESTIGATORS HAVE THE EXPERTISE AND RESOURCES TO DEVELOP THE ASSAYS TO MEASURE DRUG CONCENTRATIONS (MOMPER), SUPPORT THE PK-PD MODELING (QUINNEY, MOMPER, BIES), AND DEVELOP THE MODEL-INFORMED PRECISION DOSING TOOL (QUINNEY, BIES). TO MAXIMIZE SCIENTIFIC EXCHANGE AND ACCELERATE RESEARCH IN THE FIELD, ALL INFORMATION, DATA, PROTOCOLS, RESOURCES, AND METHODS DEVELOPED BY PREGDOSE WILL BE SHARED THROUGH THE MFMU AND MPRINT HUB AND WITH THE RESEARCH AND CLINICAL COMMUNITY AT LARGE.

RESTORING MENTAL HEALTH AFTER COVID-19 THROUGH COMMUNITY-BASED PSYCHOLOGICAL SERVICES IN NEW YORK CITY (RECOUP-NY) - PROJECT SUMMARY/ABSTRACT COVID-19 HAS HAD MAJOR MENTAL HEALTH IMPACTS ACROSS THE UNITED STATES. THE ECONOMIC, LIVELIHOOD, SOCIAL AND OTHER EFFECTS BROUGHT ON BY THE PANDEMIC HAVE AFFECTED MOST OF THE NATIONAL POPULATION, REGARDLESS OF COVID- 19 INFECTION. NEW YORK CITY (NYC) HAS HAD ONE OF THE HIGHEST COVID-19 MORTALITY RATES, AND IT HAS DISPROPORTIONATELY AFFECTED NIH-DESIGNATED U.S. HEALTH DISPARITY POPULATIONS (E.G., BLACK, LATINX). IN HUMANITARIAN CRISIS SUCH AS THIS, THERE IS A NEED FOR DELIVERY OF PSYCHOLOGICAL INTERVENTIONS BY NON-SPECIALISTS WHEN SPECIALISTS ARE UNABLE TO MEET THE INCREASED SERVICE DEMAND. IN THE U.S., TRAINING STAFF AT COMMUNITY- BASED ORGANIZATIONS (CBOS) TO DELIVER PSYCHOLOGICAL SUPPORT HAS BEEN HIGHLIGHTED AS A WAY TO INCREASE AVAILABILITY OF MENTAL HEALTH SERVICES AND INCREASE ACCESS TO MENTAL HEALTH CARE, PARTICULARLY FOR UNDERSERVED POPULATIONS. WE PROPOSE TO EMPLOY A MENTAL HEALTH TASK-SHARING MODEL BY PARTNERING WITH CBOS IN NYC TO TRAIN CBO STAFF WITHOUT PROFESSIONAL MENTAL HEALTH TRAINING TO DELIVER MENTAL HEALTH SERVICES. WE WILL EXAMINE THE IMPACT OF CBO STAFF DELIVERING MENTAL HEALTH SERVICES TO (A) REDUCE THE NEGATIVE MENTAL HEALTH CONSEQUENCES OF THE PANDEMIC, AND (B) IMPROVE PUBLIC HEALTH BEHAVIORS TO REDUCE THE SPREAD OF COVID-19. WE PROPOSE A CLUSTER RANDOMIZED CONTROL TRIAL (CRCT) IN NYC COMPARING SERVICES AS USUAL (SAU ARM) AND DELIVERY OF MENTAL HEALTH SERVICES WITH PROBLEM MANAGEMENT PLUS (PM+) (INTERVENTION ARM) AMONG PARTICIPATING CBOS WITHIN THE THRIVENYC CONSORTIUM. THE TARGET CONDITION WILL BE DEPRESSION. IN AIM 1, WE WILL EVALUATE MENTAL HEALTH OUTCOMES OF COVID-19 VULNERABLE POPULATIONS SERVED BY CBOS INTEGRATING PM+ INTO THEIR OTHER ACTIVITIES COMPARED TO CBOS DELIVERING SAU. IN AIM 2, WE WILL EVALUATE THE DIFFERENCE BETWEEN THE INTERVENTION AND SAU ARMS ON COVID-19 RISK PREVENTION ADHERENCE AMONG POPULATIONS SERVED BY THE CBOS. IN AIM 3, WE WILL EVALUATE IMPLEMENTATION SCIENCE OUTCOMES TO INFORM POLICY RECOMMENDATIONS FOR OF COMMUNITY-BASED DELIVERY OF PSYCHOLOGICAL INTERVENTIONS AND INCLUSION OF MENTAL HEALTH WITHIN THE INFECTIOUS DISEASE RESPONSE MEASURES. SUCCESSFUL COMPLETION OF THESE AIMS WILL CONTRIBUTE TO THE 2020 NIMH STRATEGIC PLAN. SPECIFICALLY, A) EMPLOYING IMPLEMENTATION SCIENCE TO MAXIMIZE THE PUBLIC HEALTH IMPACT OF RESEARCH FOR IMPROVING EFFECTIVENESS AND REACH OF MENTAL HEALTH SERVICES, ESPECIALLY FOR MINORITY GROUPS AND OTHER UNDERSERVED POPULATIONS, B) STRENGTHENING RESEARCH-PRACTICE PARTNERSHIPS TO EXPEDITE ADOPTION, SUSTAINED IMPLEMENTATION, AND CONTINUOUS IMPROVEMENT OF EVIDENCE-BASED MENTAL HEALTH SERVICES, AND C) DEVELOPING INNOVATIVE SERVICE DELIVERY MODELS TO DRAMATICALLY IMPROVE OUTCOMES OF MENTAL HEALTH SERVICES RECEIVED IN DIVERSE COMMUNITIES AND POPULATIONS.

PRAGMATIC EFFICACY TRIAL OF MHEALTH TO IMPROVE HIV OUTCOMES IN THE DC COHORT

DESIGN AND DEVELOPMENT OF HDAC11-SPECIFIC CHEMICAL INHIBITORS FOR DISEASE TREATMENTS - PROJECT SUMMARY THIS RESUBMISSION PROPOSAL AIMS TO ELUCIDATE THE ROLE OF A HISTONE DEACETYLASE, HDAC11, IN DISEASES SUCH AS MULTIPLE SCLEROSIS (MS), AND TO ESTABLISH HDAC11 INHIBITION AS A POTENTIALLY EFFECTIVE NEW TREATMENT STRATEGY FOR DISEASES INCLUDING MS. MS IS A CHRONIC, IMMUNE-MEDIATED DEMYELINATING DISEASE OF THE CENTRAL NERVOUS SYSTEM. LIKE MANY AUTOIMMUNE DISORDERS, IT PRESENTLY HAS NO KNOWN CURE, AND CURRENT DRUGS AVAILABLE FOR MANAGING THIS DISEASE ARE ONLY EFFECTIVE EARLY ON AND ARE ACCOMPANIED BY MANY ADVERSE EFFECTS. THE DISEASE MECHANISM OF MS REMAINS UNCLEAR, AND NO EFFECTIVE TARGETED THERAPY IS AVAILABLE FOR CHRONIC PROGRESSIVE MS. OUR PRELIMINARY STUDIES SHOW THAT DELETION OF HDAC11 AMELIORATES CLINICAL SYMPTOMS IN A MOUSE MODEL OF MS. IN PARALLEL, WE DISCOVERED A NOVEL HDAC11 ENZYMATIC ACTIVITY THAT IS >10,000-FOLD MORE EFFICIENT THAN ITS DEACETYLASE ACTIVITY. THIS NOVEL ACTIVITY ALLOWS US TO BEGIN TO UNCOVER PHYSIOLOGIC SUBSTRATES OF HDAC11, WHICH IN TURN WILL HELP TO UNCOVER THE BIOLOGICAL MECHANISMS OF HDAC11’S ACTIONS. ONE OF THE GOALS OF THIS RESEARCH IS TO INVESTIGATE HOW THIS NEWLY DISCOVERED ENZYMATIC ACTIVITY UNDERLIES THE IMMUNE-REGULATORY FUNCTION OF HDAC11 IN MS. KNOWLEDGE GAINED FROM THESE STUDIES WILL HELP TO FURTHER UNDERSTAND THE DISEASE MECHANISM OF MS AND TO DEVELOP BETTER THERAPEUTICS. BECAUSE THE DISCOVERY OF A NOVEL HDAC11 ACTIVITY HAS ENABLED US TO DEVELOP, FOR THE FIRST TIME, HDAC11-SPECIFIC INHIBITORS, THE CHIEF OBJECTIVE IS TO FURTHER IMPROVE THESE INHIBITORS AND TEST WHETHER THEY CAN BE USED TO TREAT DISEASES SUCH AS MS IN OUR ESTABLISHED MOUSE MODELS. OUR MULTIDISCIPLINARY TEAM HAS EXPERTISE IN ALL ASPECTS NEEDED TO MAKE THIS PROJECT SUCCESSFUL. OVERALL, THE PROPOSED STUDIES IN THIS APPLICATION WILL NOT ONLY YIELD A BETTER UNDERSTANDING OF HDAC11’S FUNCTION IN HEALTH AND DISEASES, BUT MAY ALSO RESULT IN A FIRST PROTOTYPE TARGETED THERAPY FOR THE TREATMENT OF CHRONIC PROGRESSIVE MS, AND POSSIBLY OTHER DISEASES AS WELL.

NUCLEAR PHYSICS CALCULATIONS FROM QCD AND EFT

COOPERATIVE AGREEMENT FOR A REGIONAL CENTER FOR HEALTH WORKFORCE STUDIES

REDUCING STIGMA AMONG HEALTHCARE PROVIDERS TO IMPROVE MENTAL HEALTH SERVICES (RESHAPE)

MWAS+ ? A NOVEL DRUG REPURPOSING STRATEGY FOR ADRD PREVENTION - NEARLY 6 MILLION AMERICANS =65 YEARS SUFFER FROM ALZHEIMER’S DISEASE (AD) OR AD-RELATED DEMENTIAS (ADRD). AD/ADRD POSES SIGNIFICANT EMOTIONAL, PHYSICAL, AND FINANCIAL BURDENS ON PATIENTS, FAMILIES, AND SOCIETIES. THERE IS NO CURE FOR AD/ADRD, AND APART FROM THE JUNE 2021 CONTROVERSIAL “ACCELERATED APPROVAL” OF ADUCANUMAB, NO NEW SYMPTOM-MODIFYING DRUG HAS BEEN APPROVED SINCE 2003, HIGHLIGHTING THE NEED FOR AD/ADRD PREVENTION. CURRENTLY, NO DRUG IS AVAILABLE TO DELAY THE ONSET OF AD/ADRD. THE PROHIBITIVE COST OF DEVELOPING NEW DRUGS OR REPOSITIONING PARTIALLY DEVELOPED DRUGS FOR AD/ADRD TREATMENT WOULD BE EVEN MORE PROHIBITIVE FOR AD/ADRD PREVENTION AS THE LATTER WOULD REQUIRE LARGER SAMPLE SIZE AND LONGER FOLLOW-UP. AN ALTERNATIVE COST-EFFECTIVE AND EFFICIENT APPROACH IS TO REPURPOSE FROM >20,000 FDA-APPROVED DRUGS FOR AD/ADRD PREVENTION. HOWEVER, REPURPOSING OF DRUGS IS OFTEN ACCIDENTAL. A TIMELY AND PURPOSEFUL DISCOVERY OF NEW CLINICAL BENEFITS OF OLD DRUGS REQUIRES A SYSTEMATIC EXAMINATION OF LARGE COMPREHENSIVE CLINICAL DATABASES WITH LONGITUDINAL RECORDS AND LONG FOLLOW-UP, USING INNOVATIVE, SOPHISTICATED MIXED MACHINE LEARNING AND STATISTICAL TOOLS. THIS APPLICATION HAS BEEN PREPARED IN RESPONSE TO THE NIA PAR-20-156 ENTITLED “TRANSLATIONAL BIOINFORMATICS APPROACHES TO ADVANCE DRUG REPOSITIONING AND COMBINATION THERAPY DEVELOPMENT FOR ALZHEIMER’S DISEASE”. WE PROPOSE A 3-STEP MEDICATION-WIDE ASSOCIATION STUDY PLUS (MWAS+) APPROACH. OUR MWAS+ WILL EMPLOY INNOVATIVE EXPLAINABLE DEEP (MACHINE) LEARNING, A POWERFUL ARTIFICIAL INTELLIGENCE TOOL FOR NOISY, NONLINEAR DATA. WE WILL USE VETERANS AFFAIRS (VA) ELECTRONIC HEALTH RECORD (EHR) DATA OF >3 MILLION VETERANS =65 YEARS (54,411 WOMEN; 202,000 AFRICAN AMERICAN), ~600 PRESCRIPTION DRUGS (EACH USED BY =10,000 VETERANS), =10 YEARS OF HISTORY AND ~200,000 AD/ADRD CASES. IN STEP 1 (AIM 1), WE WILL CONDUCT A HYPOTHESIS-FREE EXPLORATORY CASE-CONTROL MWAS (AKIN TO GWAS) TO IDENTIFY DRUGS ASSOCIATED WITH AD/ADRD IN THE VA EHR DATA. DRUGS IDENTIFIED IN AIM 1 WILL BE REVIEWED BY A PANEL OF EXPERTS FOR PLAUSIBLE MECHANISTIC PATHWAYS AND 10 DRUGS WILL BE RECOMMENDED FOR HYPOTHESIS TESTING IN STEP 2 USING VA EHR DATA (AIM 2) AND EXTERNAL VALIDATION IN STEP 3 USING MEDICARE DATA (AIM 3). IN AIMS 2 AND 3, WE WILL CONDUCT OUTCOME-BLINDED COHORT STUDIES USING NEW USER DESIGN. MARGINAL STRUCTURAL MODELS AND OTHER CAUSAL INFERENCE METHODS, INCLUDING DOUBLY-ROBUST INFERENCE PROCEDURES, WILL BE USED TO ESTIMATE TIME- FIXED (“INTENT-TO-TREAT”) AND TIME-VARYING (“AS-TREATED”) EFFECTS OF THOSE DRUGS ON INCIDENT AD/ADRD. THE PROPOSED PROJECT IS HIGHLY SIGNIFICANT BECAUSE IT WILL RIGOROUSLY ACCELERATE THE IDENTIFICATION OF ALREADY APPROVED DRUGS THAT HAVE A HIGH POTENTIAL TO BE REPURPOSED TO DELAY AND PREVENT AD/ADRD, A RAPIDLY GROWING PUBLIC HEALTH CRISIS. THE PROJECT IS INNOVATIVE AS IT COMBINES STATE-OF-THE-ART DEEP LEARNING AND STATISTICAL METHODS TO CONDUCT AN MWAS+ STUDY THAT HAS NEVER BEEN USED BEFORE FOR AD/ADRD PREVENTION. IN ADDITION, THE VA EHR CONTAINS HIGH QUALITY CLINICAL DATA INCLUDING PHARMACY FILL RECORDS AND RICH PHENOTYPIC INFORMATION INCLUDING FITNESS AND FRAILTY. FINDINGS FROM THIS PROJECT WILL INFORM FUTURE CLINICAL TRIALS TO REPURPOSE APPROVED DRUGS FOR AD/ADRD PREVENTION.

A LONGITUDINAL STUDY OF ADVERSITY, STRESS PROCESSES, AND LATINX HEALTH FROM ADOLESCENCE TO YOUNG ADULTHOOD - ABSTRACT THE SHARP RISE IN ANTI-IMMIGRANT POLICY SINCE EARLY 2017, ONGOING COVID-19 PANDEMIC, AND LONGSTANDING EXPERIENCES OF LATINX DISCRIMINATION AND MARGINALIZATION RAISE SERIOUS STRESS-RELATED PUBLIC HEALTH CONCERNS FOR TODAY’S LATINX YOUTH, THE VAST MAJORITY OF WHOM ARE U.S. CITIZENS. CHRONIC AND/OR SEVERE EXPOSURE TO ADVERSITY CAN ELEVATE STRESS PROCESSES IN THE FAMILY (E.G., INCREASED MATERNAL DEPRESSION) AND MANIFEST THROUGH YOUTH’S BEHAVIORAL HEALTH (E.G., UNHEALTHY DIET), AND BIOLOGY (E.G., FLATTER DIURNAL SLOPES OF DAILY CORTISOL OUTPUT). THESE STRESS PROCESSES CAN INCREASE MENTAL HEALTH AND CHRONIC DISEASE RISKS AND LIMIT SOCIAL MOBILITY FOR LATINX YOUTH MAKING THE CONSEQUENTIAL TRANSITION TO ADULTHOOD. WE PROPOSE MAJOR EXPANSIONS TO CAMINOS, AN NICHD- FUNDED STUDY COLLECTING 8 TIME POINTS OF DATA AT 6-MONTH LAGS (2018-2021) FOR A DIVERSE SAMPLE OF 547 LATINX ADOLESCENTS (88% U.S. BORN) AND MOTHERS (80% FOREIGN BORN) IN SUBURBAN ATLANTA. AS IN OTHER NEW SETTLEMENT AREAS, GEORGIA’S LATINX YOUTH AND FAMILIES FACE A LESS WELCOMING IMMIGRANT CONTEXT OF RECEPTION THAN OCCURS IN ESTABLISHED IMMIGRANT AREAS. THE PROPOSED STUDY WILL ADD FIVE TIME POINTS OF ANNUAL DATA, EXTENDING CURRENT MEASURES INTO THE TRANSITION TO ADULTHOOD AND ASSESSING HAIR AND SALIVARY CORTISOL INDICATING CHRONIC AND ACUTE STRESS, WAIST CIRCUMFERENCE, AND SURVEY REPORTS OF CHRONIC DISEASE RISK AND SOCIAL MOBILITY. THE 13 TIME POINTS OF DATA (2018 TO 2026) WILL TRACE THE ONSET OF BEHAVIORS FROM AS EARLY AS AGE 11 AND OCCURRING BEFORE, DURING, AND AFTER THE PANDEMIC AND DURING A CHANGING U.S. IMMIGRANT POLITICAL ENVIRONMENT. WE WILL USE STATE-OF-THE- ART METHODS TO MULTIPLY IMPUTE INTENTIONALLY AND UNINTENTIONALLY MISSING DATA FOR A LATINX COHORT WITH HIGH RETENTION IN THE ONGOING STUDY. GUIDED BY FAMILY STRESS MODELS AND CULTURAL-DEVELOPMENTAL THEORY, CROSS- LAGGED PATH MODELS AND LATENT GROWTH MIXTURE MODELS WILL TEST THE HYPOTHESIS THAT FAMILY, BIOLOGICAL, AND BEHAVIORAL HEALTH STRESS PROCESSES MEDIATE ASSOCIATIONS BETWEEN ADVERSITIES (E.G., RESPONSES TO ANTI- IMMIGRANT ACTIONS, PANDEMIC-RELATED EVENTS, LATINX MARGINALIZATION) AND LATINX YOUTH’S MENTAL HEALTH RISKS (INTERNALIZING AND EXTERNALIZING SYMPTOMS, SUBSTANCE USE), CHRONIC DISEASE RISKS (E.G., ASTHMA, DIABETES), AND SOCIAL MOBILITY (E.G., EDUCATIONAL ATTAINMENT). USING TESTS OF MODERATED MEDIATION, WE WILL IDENTIFY COMMUNITY-, FAMILY-, AND INDIVIDUAL-LEVEL PROTECTIVE FACTORS THAT MITIGATE IMPACTS OF ADVERSITY AND STRESS ON YOUTH OUTCOMES. SEX AS A BIOLOGICAL VARIABLE WILL BE EXAMINED AS A KEY MODIFIER. UNIQUE FROM OTHER NATIONAL AND COHORT STUDIES, THE PROPOSED RESEARCH WILL IDENTIFY HOW ACCUMULATED ADVERSITIES ROOTED IN ANTI-IMMIGRANT EXPERIENCES AND THE PANDEMIC SHAPE LATINX YOUTH’S HEALTH OUTCOMES AND SOCIAL MOBILITY OVER TIME. IN ADDITION, THE PROPOSED STUDY IS UNIQUELY SITUATED IN A NEW IMMIGRANT AREA AND EXAMINES LATINX MARGINALIZATION WITHIN AND OUTSIDE OF THE RESIDENTIAL NEIGHBORHOOD BY USING GEOCODED CENSUS DATA ON MOTHER ACTIVITY SPACES. ELEVATING TRANSLATIONAL IMPACTS, FINDINGS WILL INFORM PROGRAMS FOR LATINX YOUTH WHO MAY STRUGGLE TO RECOVER FROM PANDEMIC AND IMMIGRATION-RELATED ADVERSITIES AS THEY PREPARE FOR ADULTHOOD.

THE IMPACT OF THE 11TH STREET BRIDGE PARK ON THE BUILT ENVIRONMENT AND COMMUNITY HEALTH: WASHINGTON, D.C. - INCREASING POPULATION LEVELS OF DAILY PHYSICAL ACTIVITY HAS ASSUMED CONSIDERABLE PUBLIC HEALTH SIGNIFICANCE IN THE PAST THREE DECADES, AND RECENT EFFORTS HAVE EXPANDED FROM TARGETING INDIVIDUAL BEHAVIOR CHANGE TOWARD ADDRESSING ENVIRONMENTAL RISK CONDITIONS THAT AFFECT EVERYONE WITHIN A COMMUNITY. INDEED, THE BUILT ENVIRONMENT AND URBAN DESIGN ARE NOW RECOGNIZED AS PRIMARY DRIVERS OF ACHIEVING AN ACTIVE AND HEALTHY LIFESTYLE. UNFORTUNATELY, THE DISTRIBUTION OF THESE HEALTH-PROMOTING ENVIRONMENTAL RESOURCES IS NOT UNIFORM, AND PEOPLE LIVING IN LOW-RESOURCE AREAS (URBAN AND RURAL) BEAR A DISPROPORTIONATELY HIGHER BURDEN OF RISK CONDITIONS AND LIFESTYLE-RELATED CHRONIC DISEASES, COMPARED WITH THEIR MORE AFFLUENT COUNTERPARTS. THIS MAY BE ESPECIALLY SO FOR OLDER PEOPLE WHO HAVE LIVED WITH ADVERSE ENVIRONMENTAL RISK CONDITIONS SINCE CHILDHOOD. POLICY, SYSTEMS, AND ENVIRONMENTAL (PSE) STRATEGIES FOR PROMOTING PHYSICAL ACTIVITY AND OTHER HEALTHY BEHAVIORS ARE GAINING MOMENTUM WITHIN THE PUBLIC HEALTH ARENA. THE PSE FRAMEWORK COMPRISES STRATEGIES FOR CHANGE THAT ARE BOTH MULTI-SECTORAL AND MULTI-LEVEL. MOREOVER, SINCE THEY ARE DIRECTED TOWARD THE ENTIRE COMMUNITY, THEY ARE MORE MAINTAINABLE AND CAN ADDRESS DIFFERENCES IN OPPORTUNITIES AND OUTCOMES BETTER THAN INTERVENTIONS TARGETED TO THE INDIVIDUAL. ONE THE OTHER HAND, PSE INTERVENTION STRATEGIES CAN BE VERY EXPENSIVE AND REQUIRE CONSIDERABLY MORE TIME TO ENACT WITHIN COMMUNITIES. THUS, IT BECOMES ADVANTAGEOUS TO IDENTIFY NATURALLY-OCCURRING “INTERVENTIONS” (I.E., NATURAL EXPERIMENTS) FOR WHICH THEIR IMPACT ON POPULATION BEHAVIOR AND HEALTH CAN BE DETERMINED OVER TIME. THE 11TH STREET BRIDGE PARK PROJECT (PLANNED TO BREAK GROUND IN LATE 2025 AND OPEN IN 2027) OFFERS AN ELEGANT STRATEGY FOR ACCOMPLISHING THIS, AS IT WILL CONNECT ONE OF THE MORE AFFLUENT WARDS IN DC (WARD 6) WITH THE LEAST AFFLUENT WARD (WARD 8). WE WILL EXAMINE THE IMPACT OF THIS BRIDGE PARK ON LONGITUDINAL CHANGES IN THE BUILT ENVIRONMENT ITSELF, AS WELL AS IN PHYSICAL ACTIVITY PATTERNS AND DIETARY CHOICES WITHIN THE AREAS DIRECTLY AFFECTED BY IT. SPECIFIC AIMS: 1) TO DETERMINE THE IMPACT OF THE 11TH STREET BRIDGE PARK PROJECT ON THE BUILT ENVIRONMENTS OF WARDS 6 AND 8 THAT ARE WITHIN THE SAMPLING AREA (1-MILE RADIUS) SURROUNDING THE NEW PARK; 2) TO DETERMINE THE INFLUENCE OF THIS PROJECT ON SPACIO-BEHAVIORAL CHARACTERISTICS OF THE PARK ITSELF, AS WELL AS OF THE SAMPLING AREAS OF WARDS 6 AND 8 SURROUNDING THE PARK; AND 3) TO DETERMINE THE IMPACT OF THE 11TH STREET BRIDGE PARK PROJECT ON INDIVIDUAL- AND FAMILY-LEVEL LIFESTYLE BEHAVIOR CHANGES, AS WELL AS ON PERCEPTIONS OF NEIGHBORHOOD SAFETY, SOCIAL CONNECTEDNESS, AND FOOD SECURITY USING AN INTERGENERATIONAL APPROACH.

REGULATORY IMPACT ON VAPE SHOPS AND YOUNG ADULTS' USE OF ENDS

REGULATION OF ANTI-TUMOR IMMUNITY BY HDAC11

DATA ANALYSIS CENTER FOR ELECTROMAGNETIC AND HADRONIC SCATTERING PROCESSES

EFFECT OF HOSPITAL-CARDIOLOGIST INTEGRATION ON CLINICAL PRACTICE, HEALTHCARE QUALITY, AND MEDICARE SPENDING

THE ROLE OF PENILE BACTERIA AND INFLAMMATION IN HIV SUSCEPTIBILITY; RAKAI, UGANDA

EMOTIONAL DISTRESS IN A COMPARATIVE EFFECTIVENESS TRIAL OF DIABETES TREATMENTS

REDUCING BLACK MEN'S DRUG USE AND CO-OCCURRING NEGATIVE MENTAL AND PHYSICAL HEALTH OUTCOMES: INTERSECTIONALITY, SOCIAL-STRUCTURAL STRESSORS, AND PROTECTIVE FACTORS

TRANSLATION OF SOCIAL MEDIA OBESITY TREATMENT INTO TWO COLLEGE CAMPUS COMMUNITIES

IGERT: DYNAMICS OF BEHAVIORAL SHIFTS IN HUMAN EVOLUTION: BRAINS, BODIES AND ECOLOGY

MULTIPLE INSTRUMENTAL CASE STUDIES OF INCLUSIVE STEM-FOCUSED HIGH SCHOOLS: OPPORTUNITY STRUCTURES FOR PREPARATION AND INSPIRATION (OSPRL).

EPIGENETIC REPROGRAMMING IN HIV-ASSOCIATED CARDIO-VASCULAR DISEASE

THALAMIC CONTRIBUTIONS TO THE DEVELOPING EEG

DATA COORDINATING CENTER, MICROBIOME OF THE LUNG AND RESPIRATORY TRACT

PIRE: PROMOTING URBAN SUSTAINABILITY IN THE ARCTIC

SOCIAL-STRUCTURAL STRESSORS, RESILIENCE AND SEXUAL RISK BEHAVIORS AMONG BLACK MEN

DIGITAL MEDIA FOR CANCER CONTROL: RANDOMIZED CONTROLLED TRIAL AND DOSE RESPONSE EFFECTS

SUMMER PROGRAM FOR WOMEN IN MATHEMATICS 9

NRT-AI-FW-HTF: CO-DESIGN OF TRUSTWORTHY AI AND FUTURE WORK SYSTEMS

MENTAL AND SUBSTANCE USE DISORDER PRACTITIONER DATA

HOW SEX, HOST MICROENVIRONMENT, AND IMMUNE RESPONSES SHAPE ACQUISITION OF GENITAL BACTERIA THAT INCREASE HIV RISK - PROJECT SUMMARY RECENTLY, SEVERAL GENITAL ANAEROBIC BACTERIA THAT ARE NOT CLASSICALLY ASSOCIATED WITH SEXUALLY TRANSMITTED INFECTIONS (NON-STI) WERE LINKED TO INCREASED HETEROSEXUAL TRANSMISSION OF HIV, LIKELY BY INDUCING IMMUNE RESPONSES THAT ENHANCES HIV TARGET CELL ACTIVATION AND RECRUITMENT TO THE GENITAL MUCOSA. THIS PROJECT SEEKS TO CLOSE CRITICAL KNOWLEDGE GAPS REGARDING ACQUISITION AND PERSISTENT CARRIAGE OF THIS NEW HIV RISK FACTOR. OUR LONG-TERM GOALS ARE TO ELUCIDATE THE DETERMINANTS OF GENITAL MICROBIOME COMPOSITION AND THE BIOLOGICAL MECHANISMS THAT LINK GENITAL BACTERIA TO HOST SUSCEPTIBILITY TO HIV, AND TO LEVERAGE THIS KNOWLEDGE TO DEVELOP INNOVATIVE SOLUTIONS TO PREVENT HIV. THE OBJECTIVE IS TO UNDERSTAND THE HETEROSEXUAL TRANSMISSION DYNAMICS OF GENITAL BACTERIA ASSOCIATED WITH HIV RISK AND TO DETERMINE THE ABIOTIC AND BIOTIC FACTORS THAT IMPACT ACQUISITION AND PERSISTENCE OF THESE GENITAL BACTERIA IN MEN. OUR CENTRAL HYPOTHESIS IS THAT PERTURBATIONS AFFECT PENILE MICROBIOME COMPOSITION—INCLUDING ACQUISITION, LOSS, OR PERSISTENCE OF GENITAL BACTERIA ASSOCIATED WITH HIV RISK—PREDICTABLY BASED A SET OF ABIOTIC AND BIOTIC FACTORS. THE RATIONALE FOR THIS PROJECT IS THAT, BY UNDERSTANDING THE ABIOTIC AND BIOTIC FACTORS THAT DETERMINE ACQUISITION, LOSS, OR PERSISTENCE OF SPECIFIC GENITAL BACTERIA, WE WILL BE ABLE TO IDENTIFY AND DEVELOP NEW STRATEGIES TO PREVENT OR REDUCE COLONIZATION. AIM 1. ELUCIDATE THE SEXUAL TRANSMISSION OF GENITAL BACTERIA AND THE DETERMINANTS OF THE PENILE MICROBIOME AFTER SEX. WE WILL TEST THIS BY: (I) CHARACTERIZE THE GENITAL BACTERIA STRAINS PRESENT IN ADOLESCENT BOYS BEFORE AND AFTER SEXUAL DEBUT (N = 200) AND (II) DETERMINE THE EFFECT OF PRE-COITAL HOST (PENILE) AND PARTNER (VAGINAL) GENITAL PH, OXYGENATION, MOISTURE, METABOLITES, ANTI-BACTERIA IGA, AND MICROBIOME ON THE ACQUISITION OR PERSISTENCE (1, 8, AND 72 HOUR POST-SEX) OF GENITAL BACTERIA IN THE HOST (N = 106 COUPLES). AIM 2. ELUCIDATE THE DETERMINANTS OF THE PENILE MICROBIOME AFTER ANTIMICROBIAL TREATMENT. WE WILL TEST THIS BY COMPARING PRE- AND POST- TREATMENT (DAY 3, 8, AND 28) PENILE MICROBIOMES IN 1 CONTROL ARM AND 4 TREATMENT ARMS, INCLUDING 3 TOPICAL TREATMENTS: (I) 2% CLINDAMYCIN, (II) 1% H2O2, (III) 0.75% METRONIDAZOLE, AND (IV) ORAL TINIDAZOLE. AIM 3. VALIDATE THE IMPACT OF ABIOTIC AND BIOTIC FACTORS ON THE PENILE MICROBIOME RESPONSE TO PERTURBATION USING AN IN VITRO MODEL. WE WILL ACHIEVE THIS AIM BY ADDING: (I) DONOR VAGINAL MICROBIOME AND (II) TOPICAL ANTIMICROBIALS TO PENILE MICROBIOME IN ORGANOTYPIC FORESKIN MODEL TO ASSESS THE EFFECT OF ABIOTIC FACTORS AND BACTERIAL STRAINS ON MICROBIOME OUTCOME. THE PROPOSED RESEARCH IS INNOVATIVE, IN OUR OPINION, BECAUSE IT REPRESENTS A DEPARTURE FROM THE STATUS QUO BY ELUCIDATING TRANSMISSIBLE DYSBIOSIS, AND DOING SO WITH ABSOLUTE ABUNDANCE METRICS, INNOVATIVE STUDY DESIGNS, AND A NOVEL CO-CULTURE MODEL. THE PROPOSED RESEARCH IS SIGNIFICANT BECAUSE IT IS EXPECTED TO REVEAL HOW SEX AND ANTIMICROBIALS IMPACT PENILE MICROBIOME AND WHAT DRIVES OUTCOME.

AIR POLLUTION, ALZHEIMER'S DISEASE AND RELATED OUTCOMES

EDUCATIONAL FACILITIES CLEARINGHOUSE

HIV PREVALENCE, SEXUAL BEHAVIOR, AND ATTITUDES TOWARD CIRCUMCISION AMONG COLOMBIA

MATERNAL AND CHILD HEALTH PUBLIC HEALTH TRAINING PROGRAM

CD4 DYSFUNCTION AND CEREBRAL TOXOPLASMOSIS

JOINT EFFECT OF MALPRACTICE RISK AND FINANCIAL INCENTIVES ON CARDIAC TESTING

INNATE NKT CELLS IN HIV INFECTION

INFLUENCE OF THE NASAL MICROBIOME ON HOST SUSCEPTIBILITY AND RESPONSE TO RESPIRATORY VIRUSES - PROJECT SUMMARY THE NASAL CAVITY HAS A UNIQUE MICROBIOME, WHICH IS EXPECTED TO SIGNIFICANTLY AFFECT LOCAL IMMUNE RESPONSE AND IN TURN, SUSCEPTIBILITY OF THE HOST TO RESPIRATORY VIRUSES. HOWEVER, WE KNOW LITTLE ABOUT THESE POTENTIAL HOST- MICROBE INTERACTIONS. OUR LONG-TERM GOAL IS TO ELUCIDATE HOW MICROBIOME-IMMUNE INTERACTIONS AND DYNAMICS WITHIN THE NASAL CAVITY AFFECT HOST SUSCEPTIBILITY TO INFECTIOUS AND INFLAMMATORY CONDITIONS. THIS PROJECT’S OBJECTIVE IS TO DETERMINE NATURAL DYNAMICS OF CORRELATIONS BETWEEN NASAL MICROBIOME AND LOCAL IMMUNE ENVIRONMENT AND HOW THIS RELATIONSHIP AFFECTS HOST SUSCEPTIBILITY TO RESPIRATORY VIRAL INFECTIONS. OUR CENTRAL HYPOTHESIS IS THAT DURING HOMEOSTASIS, THE NASAL MICROBIOME IMPACTS LOCAL ANTIVIRAL IMMUNE DEFENSES, INCLUDING EPITHELIAL INTEGRITY, MUCUS PROPERTIES, AND ANTIVIRAL CYTOKINES AND SPECIFIC NASAL MICROBIOME-IMMUNE ENVIRONMENTS DEFINED BY LOW-INFLAMMATION AND HIGH-INTERFERON LEVELS WILL CONFER GREATER NATURAL PROTECTION AGAINST RESPIRATORY VIRAL INFECTIONS. THE RATIONALE FOR THIS PROJECT IS THAT OUR KNOWLEDGE REGARDING THE ADULT NASAL MICROBIOME AND IMMUNE ENVIRONMENT DURING HOMEOSTASIS IS LIMITED. ADDRESSING THIS GAP CAN IMMEDIATELY IMPROVE OUR FUNDAMENTAL UNDERSTANDING OF THE ADULT NASAL CAVITY AND INFORM STRATEGIES THAT PROMOTE NATURALLY OCCURRING PROTECTION AGAINST RESPIRATORY VIRAL INFECTIONS. AIM 1. ELUCIDATE DYNAMICS OF THE HOMEOSTATIC NASAL MICROBIOME AND IMMUNE ENVIRONMENT IN ADULTS. WE WILL ACHIEVE THIS AIM BY STUDYING (I) THE HOMEOSTATIC NASAL MICROBIOME AND INNATE IMMUNE PROFILE IN A CROSS-SECTION OF ADULTS (N = 400) AND (II) ASSESSING SHORT- AND LONG-TERM DYNAMICS OF ADULT NASAL ENVIRONMENT BY SELECTING AND FOLLOWING 118 ADULTS THROUGH MONTHLY AND QUARTERLY DENSE SAMPLING OVER A 12-MONTH PERIOD. AIM 2. DETERMINE HOW THE NASAL MICROBIOME-IMMUNE ENVIRONMENT AFFECTS SUSCEPTIBILITY TO AN INTRA- NASAL VIRUS CHALLENGE. WE WILL ACHIEVE THIS AIM BY STUDYING HOW PRE-VACCINATION NASAL MICROBIOME-IMMUNE ENVIRONMENTS IMPACT POST-VACCINATION VIRAL INFECTION AND REPLICATION AMONG ADULT FLUMIST® RECIPIENTS (N = 200) PER YEAR IN YEARS 1 AND 2. AIM 3. ELUCIDATE INTERACTIONS BETWEEN NASAL MICROBIOME, NASAL IMMUNE ENVIRONMENT, AND HOST SUSCEPTIBILITY TO RESPIRATORY VIRUSES IN VITRO. WE WILL ACHIEVE THIS AIM BY ASSESSING EFFECT OF NASAL MICROBIOME COMPOSITION AND NASAL BACTERIAL ABSOLUTE ABUNDANCE ON: (I) INNATE IMMUNE DEFENSES AND (II) INFLUENZA A, RHINOVIRUS, AND SARS-COV-2 INFECTIVITY USING AN INNOVATIVE IN VITRO NASAL MICROBIOME-RESPIRATORY EPITHELIAL CO-CULTURE MODEL. THE PROPOSED RESEARCH IS INNOVATIVE BECAUSE IT REPRESENTS A DEPARTURE FROM THE STATUS QUO BY ASSESSING HOW THE NASAL MICROBIOME, WHICH IS UBIQUITOUS AND DIVERSE, COULD AFFECT NATURAL IMMUNE ENVIRONMENT. SIGNIFICANT BECAUSE IT IS EXPECTED TO IDENTIFY NASAL MICROBIOME FEATURES AND IMMUNE PROFILES THAT CONFER NATURAL ANTIVIRAL PROTECTION, WHICH COULD INFORM NOVEL STRATEGIES TO REDUCE THE RISK FOR RESPIRATORY VIRAL INFECTIONS.

EMERGING THERAPEUTIC CANDIDATES FOR RARE MATERNALLY INHERITED MITOCHONDRIAL DISEASES WITH SHARED ETIOLOGIES - PROJECT SUMMARY/ABSTRACT THIS UG3/UH3 PROPOSAL IS IN RESPONSE TO RFA-TR-20-031-BASKET CLINICAL TRIALS OF DRUGS TARGETING SHARED MOLECULAR ETIOLOGIES IN MULTIPLE RARE DISEASES. THE PROPOSED STUDIES FOCUS ON TWO ULTRA-RARE MATERNALLY INHERITED MITOCHONDRIAL DISEASES MELAS (MITOCHONDRIAL ENCEPHALOPATHY, LACTIC ACIDOSIS, STROKE-LIKE EPISODES) AND LHON-PLUS (LEBER’S HEREDITARY OPTIC NEUROPATHY-PLUS). BOTH DISEASES ARE AMONG THOSE STUDIED BY THE RARE DISEASES CLINICAL RESEARCH NETWORK. PATIENTS DO NOT HAVE ACCESS TO EFFECTIVE THERAPEUTIC INTERVENTION, RESULTING IN SIGNIFICANT DISABILITY, MORBIDITY, AND PREMATURE DEATH. THE DEVASTATION WROUGHT BY THESE DISEASES UNDERSCORES THE URGENCY TO ADDRESS THIS UNMET MEDICAL NEED AND DEVELOP NOVEL THERAPEUTIC CANDIDATES. HOWEVER, THEIR ULTRA-RARE PREVALENCE MAKES IT CHALLENGING TO RECRUIT AN ACCRUED NUMBER OF MELAS AND LHON- PLUS PATIENTS TO CLINICAL TRIALS. THUS, THE PROPOSED BASKET CLINICAL TRIAL DESIGN WILL COMBINE THESE TWO ULTRA-RARE POPULATIONS TO PROVIDE PROOF-OF-CONCEPT OF ITS FEASIBILITY FOR DIVERGENT PATIENT POPULATIONS. MELAS AND LHON-PLUS PATIENTS EXHIBIT DIVERGENT AND OVERLAPPING CLINICAL NEUROLOGICAL AND NON-NEUROLOGICAL SYMPTOMS. THEY ARE CAUSED BY A MATERNALLY INHERITED PATHOGENIC VARIANT THAT RESULTS IN A DEFECTIVE OXIDATIVE PHOSPHORYLATION PATHWAY RESPONSIBLE FOR MITOCHONDRIAL ATP SYNTHESIS. BOTH DISEASES SHARE THE MOLECULAR ETIOLOGY OF COMPLEX I DEFICIENCY, CAUSING ATP DEFICIENCY AND CHRONIC ENERGY DEFICIT. WE DESIGNED A NOVEL TWO-PRONGED PHARMACO-EPIGENOMIC STRATEGY TO INCREASE ATP OUTPUT IN MELAS AND LHON-PLUS PATIENTS. OUR PRE-CLINICAL STUDIES USING EX-VIVO PATIENT-DERIVED FIBROBLASTS DEMONSTRATE THE FEASIBILITY OF OUR LEAD COMPOUND TO PROMOTE MITOCHONDRIAL RECOVERY IN MELAS AND LHON-PLUS PATIENT’S FIBROBLASTS. THE PROPOSED MULTI-PI STUDIES COMBINES THE CROSS-DISCIPLINARY STRENGTHS OF THE GEORGE WASHINGTON UNIVERSITY SCHOOL OF MEDICINE AND HEALTH SCIENCES AND CHILDREN’S NATIONAL MEDICAL CENTER, A REFERRING SITE FOR THE NORTH AMERICAN MITOCHONDRIAL DISEASE CONSORTIUM. THIS PARTNERSHIP IS FUNDED BY AN NIH CLINICAL AND TRANSLATIONAL SCIENCE AWARD UL1 PROGRAM PROVIDING A ROBUST INFRASTRUCTURE FOR THE PROPOSED STUDIES. AIM 1 (UG3 PHASE) FOCUSES ON TRANSLATIONAL MELAS AND LHON-PLUS STUDIES AND SUBMISSION OF AN IND PROTOCOL TO THE FDA. AIM 2 (UH3 PHASE)FOCUSES ON A BASKET CLINICAL TRIAL WITH MELAS AND LHON-PLUS TO: 1) PROVIDE PROOF-OF-CONCEPT THAT THE BASKET DESIGN CAN BE APPLIED TO DIVERGENT ULTRA-RARE DISEASES; 2) ADVANCE THE DATASET FOR SAFETY AND PHARMACOKINETICS/PHARMACODYNAMICS OF OUR LEAD COMPOUND FOR A LARGER NUMBER OF PATIENTS THAN IN A CONVENTIONAL CLINICAL TRIAL SETTING; AND 3) GATHER OUTCOMES AND PRACTICAL INFORMATION FOR OPTIMIZING THE DESIGN OF FUTURE BASKET CLINICAL TRIAL. OUR INNOVATIVE DESIGN LIES IN APPLYING THE CONCEPT OF BASKET CLINICAL TRIAL NOT ONLY TO MULTIPLE DISEASES WITH A COMMON MOLECULAR TARGET, BUT ALSO TO GROUPS WITH SIMILAR EX-VIVO FIBROBLASTS RESPONSE TO BUTYRATE ACROSS THESE DISEASES TO IMPROVE OUR ABILITY TO EVALUATE OUR THERAPEUTIC DRUG IN ULTRA-RARE DISEASE POPULATIONS.

SCALABLE PLATFORM FOR OPTIMIZING HUMAN CARDIAC TISSUE ENGINEERING VIA OPTICAL PACING AND ON-DEMAND OXYGENATION

D2 RECEPTOR VARIATION AND RENAL DYSFUNCTION - SALT-SENSITIVE (SS) INDIVIDUALS ON HIGH NA+ INTAKE NOT ONLY DEVELOP HYPERTENSION BUT ALSO KIDNEY INJURY/ CHRONIC KIDNEY DISEASE (CKD) AND CARDIOVASCULAR DISEASE (CVD). A REDUCTION IN NA+ INTAKE MAY PREVENT AND TREAT HYPERTENSION, CVD, AND CKD. HOWEVER, LOW NA+ INTAKE MAY NOT ALWAYS BE BENEFICIAL IN THE TREATMENT OF HYPERTENSION OR CVD. A LOW NA+ INTAKE IS ASSOCIATED WITH INCREASED RISK OF HYPERTENSION (I.E., INVERSE SALT SENSITIVITY (ISS), CVD, AND DEATH. HYPERTENSION AND DIABETES ARE THE MAJOR CAUSES OF RENAL INJURY, ACCOUNTING FOR UP TO 75% OF END-STAGE RENAL DISEASE. HOWEVER, HYPERTENSION MAY CAUSE CKD ONLY IN THE GENETICALLY SUSCEPTIBLE. IN 13 OF 16 STUDIES IN THE GEO DATASET OF CKD PATIENTS, DOPAMINE TYPE 2 RECEPTOR (D2R) GENE (DRD2) EXPRESSION IS LOWER IN THOSE WITH CKD THAN THOSE WITHOUT CKD. A DECREASE IN THE EXPRESSION OR FUNCTION OF D2R, PER SE, OR CAUSED BY DRD2 VARIANTS, INCREASES RENAL INFLAMMATION, RENAL FIBROSIS, AND ISS. THE MECHANISMS/GENETICS OF ISS ARE NOT WELL UNDERSTOOD. MICE WITH GLOBAL GERMLINE DELETION OF DRD2 (DRD2-/-) HAVE SS HYPERTENSION AND ISS. HOWEVER, MICE WITH RENAL PROXIMAL TUBULE (RPT)-SPECIFIC CONDITIONAL DELETION OF DRD2 (DRD2CPT) HAVE INCREASED BLOOD PRESSURE (BP) ONLY WHEN NA+ INTAKE IS DECREASED, A CASE OF ISS. SPRAGUE- DAWLEY RATS HAVE ISS, RELATED TO AN INCREASE IN THE ACTIVITY OF THE ANGIOTENSIN TYPE 1 RECEPTOR (AT1R) AND A1-ADRENOCEPTORS. ABOUT 15% OF HYPERTENSIVE SUBJECTS HAVE ISS AND SOME ASSOCIATED WITH DRD2 RS6276/RS6277. RENAL-SELECTIVE EXPRESSION OF DRD2 VARIANT RS6277 IN MICE SHOULD INCREASE BP AND IMPAIR INHIBITION OF RENAL NA+ TRANSPORT AND EXCRETION. WE WILL TEST THE OVERALL HYPOTHESIS THAT DRD2/DRD2 IS IMPORTANT IN PREVENTING ISS BY MITIGATING OVERLY ACTIVE RENIN-ANGIOTENSIN AND SYMPATHETIC NERVOUS SYSTEMS AND THE INCREASE IN RPT NA+ TRANSPORT ON A LOW NA+ DIET. SPECIFIC AIM 1 WILL TEST THE HYPOTHESIS THAT IN DRD2-/- OR DRD2CPT MICE, BP INCREASES WHEN NA+ INTAKE IS “LOW”, A CASE OF ISS. THE INCREASE IN BP IN DRD2-/- OR DRD2CPT MICE FED A LOW NA+ DIET IS CAUSED BY IMPAIRED D2R INHIBITION OF RPT NA+ TRANSPORT AND AN INCREASE IN RPT NA+ TRANSPORT CAUSED BY ACTIVATION OF BOTH THE RENIN-ANGIOTEN-SIN AND SYMPATHETIC NERVOUS SYSTEMS. IN THE LONG-TERM, RENAL FUNCTION IS DECREASED BECAUSE OF UNMITIGATED RENAL FIBROSIS. SPECIFIC AIM 2 WILL TEST THE HYPOTHESIS THAT DRD2 VARIANTS, RS6276/RS6277, DECREASE D2R EXPRESSION THAT IS DEPENDENT ON THE EFFECTS OF THE TRANSCRIPTION FACTORS NR4A2 AND MIR4301. THESE STUDIES ARE SIGNIFICANT AND IMPORTANT BECAUSE THEY MAY LEAD TO THE IDENTIFICATION OF THE HUMAN POPULATION THAT WOULD BE ADVERSELY AFFECTED BY THE CURRENT RECOMMENDATION TO DECREASE THE NA+ INTAKE IN EVERYONE.

ENHANCING AND MAKING BIOMARKER KNOWLEDGE FAIR USING CONTEXTUAL CFDE DATA - THE COMMON FUND (CF) RESEARCH INITIATIVE HAS GENERATED A WEALTH OF DATA THAT CAN PROVIDE VITAL CONTEXT, ORIGIN, AND, IN SOME INSTANCES, QUANTITATIVE INFERENCES FOR BIOMARKERS. HOWEVER, THE SYSTEMATIC HARMONIZATION AND ORGANIZATION OF BIOMARKER DATA, AS WELL AS THEIR CONNECTIONS TO CF DATA, REMAIN IN AN EARLY STAGE AND IS CURRENTLY THE FOCUS OF THE YEAR-LONG COMMON FUND DATA ECOSYSTEM (CFDE) BIOMARKER-PARTNERSHIP PROJECT THAT AIMS TO DEVELOP A WORKING BIOMARKER DATA MODEL. THE PROPOSED BIOMARKERKB PROJECT AIMS TO REFINE AND POPULATE THE BIOMARKER DATA MODEL THROUGH A CLOSE AND DYNAMIC EXTERNAL PARTNERSHIP WITH THE NCI-SUPPORTED EARLY DETECTION RESEARCH NETWORK (EDRN) WITH BUILT-IN COMMUNITY INPUT MECHANISMS. THE INITIAL FOCUS IS ON REFINING OUR CURRENT BIOMARKER DATA MODEL USING EDRN'S CANCER BIOMARKER DATA AND KNOWLEDGE. INITIALLY FOCUSING ON CANCER WILL ALLOW US TO LIMIT OUR SCOPE WHILE RETAINING THE ABILITY TO EVALUATE A VARIETY OF DATA TYPES AND THEREFORE ENSURE EXTENSIBILITY OF THE MODEL AS NEW DATA TYPES AND TECHNOLOGIES EMERGE. THE MINIMAL VIABLE PRODUCT (MVP) WILL INCLUDE PERSISTENT BIOMARKER IDENTIFIERS, LINKED DATA, CONNECTIONS TO RECOGNIZED STANDARDS AND ONTOLOGIES, DOWNLOADS/APIS, AND DATA ACCESS THROUGH INTERFACES FOR BIOMARKER EXPLORATIONS. THIS DATA MODEL WILL SERVE AS THE CORNERSTONE FOR AI-READY DATASETS, MACHINE LEARNING-BASED BIOMARKER PREDICTION MODELS, AND BIOMARKER KNOWLEDGE GRAPHS. THE SCIENTIFIC USE CASE THE PROJECT PROPOSES TO SUPPORT IS THE ABILITY TO EXPLORE MOLECULAR BIOMARKER-RELATED KNOWLEDGE FOR MOST PREVALENT CANCERS AT A SYSTEMS LEVEL, CATEGORIZED BY BIOLOGICAL FUNCTIONS THROUGH MAPPING TO KEY ONTOLOGIES, PATHWAYS, BIOMOLECULAR DATA (GLYCANS, PROTEINS, GENES, METABOLITES) AND ELECTRONIC HEALTH RECORD (EHR) TERMS AND TESTS. EXAMPLE BIOMARKERS (INCLUDING NON-MOLECULAR ONES THAT ARE OF INTEREST TO DATA COORDINATING CENTERS (DCCS)) FOR OTHER DISEASES WILL ALSO BE CONSIDERED TO ENSURE THE COMPREHENSIVENESS AND ROBUSTNESS OF THE DATA MODEL. THIS PROJECT PROMISES TO ENRICH OUR UNDERSTANDING OF THE TRANSLATIONAL HEALTH RECORD AND INTERVENTION SPACE, REVOLUTIONIZING THE WAY WE APPROACH DIVERSE DISEASES, CLINICAL ASSAYS, MOLECULAR MECHANISMS, AND DISEASE CLASSIFICATIONS. THE POTENTIAL BENEFITS EXTEND TO OUR PARTNERS IN THE EDRN AND THE BROADER CFDE COMMUNITY, UNDERSCORING THE REAL-WORLD SIGNIFICANCE OF BIOMARKERS ACROSS THE MEDICAL AND RESEARCH LANDSCAPE.

PERIPHERAL AND TISSUE-RESIDENT GAMM/DELTA T CELLS IN HIV LATENCY

2/2 CORD-CHD: CLAMP OR DELAY AMONG NEONATES WITH CONGENITAL HEART DISEASE - PROJECT SUMMARY/ABSTRACT CLAMPING AND CUTTING THE UMBILICAL CORD IS THE MOST COMMON INTERVENTION IN HUMANS, OCCURRING IN 140 MILLION ANNUAL BIRTHS. TO MAXIMIZE EXPEDIENCY (MANAGE 3RD STAGE OF LABOR, INITIATE NEONATAL RESUSCITATION), EARLY CORD CLAMPING (ECC) IS PERFORMED WITHIN ~30 SEC OF DELIVERY. RECENTLY, EVIDENCE HAS EMERGED ON THE HEALTH BENEFITS OF DELAYED CORD CLAMPING (DCC, WAITING ~1-2 MIN BEFORE CLAMPING). AMONG TERM NEONATES, MULTIPLE RANDOMIZED CONTROLLED TRIALS (RCTS) HAVE SHOWN THAT DCC TRANSFERS BLOOD FROM PLACENTAS TO NEWBORNS, RESULTING IN LESS IRON- DEFICIENCY ANEMIA AND IMPROVED NEURODEVELOPMENTAL (NEUROMOTOR) OUTCOMES THROUGH 4 YEARS, THAN WITH ECC. DESPITE ADVANTAGES FOR HEALTHY NEWBORNS, IN VIEW OF THEIR EXCLUSION FROM PREVIOUS RCTS, THE BEST APPROACH TO CORD CLAMPING IN HIGHER-RISK PREGNANCIES, NOTABLY THOSE COMPLICATED BY A FETAL DIAGNOSIS OF CRITICAL CONGENITAL HEART DISEASE (CCHD), REMAINS UNCERTAIN. ALTHOUGH ONE MIGHT ASSUME THAT THE BENEFITS OF DCC IN LOW-RISK NEW- BORN POPULATIONS WOULD TRANSLATE SIMPLY TO CCHD NEONATES, UNIQUE ANATOMIC AND PHYSIOLOGIC DIFFERENCES IN NEONATES WITH CCHD SUGGEST THAT RISKS OF DCC IN THIS SUBGROUP MAY DIFFER FROM RISKS IN NEONATES WITHOUT CCHD. THUS, A TREATMENT DILEMMA EXISTS ON THE OPTIMAL CORD CLAMPING PRACTICE AT BIRTH AMONG CCHD NEONATES. THE PROPOSED STUDY, ENTITLED CORD-CHD (CLAMP OR DELAY AMONG NEONATES WITH CONGENITAL HEART DISEASE) TRIAL WILL BE THE FIRST RCT TO DETERMINE THE EFFECTIVENESS OF DCC VS. ECC ON POSTNATAL AND NEURODEVELOPMENTAL OUTCOMES OF CCHD NEONATES. OUR PRELIMINARY DATA DEMONSTRATE THAT, AMONG CCHD NEONATES, DCC RESULTS IN LOWER GLOBAL RANK SCORES (GRS), INDICATIVE OF BETTER HEALTH OUTCOMES, THAN ECC. GRS IS A VALIDATED COMPOSITE MEASURE, BASED UPON THE WORST OUTCOME POST-CARDIAC SURGERY OR CATHETERIZATION AND REFLECTS THE NEED FOR COM- PLEX INTENSIVE CARE. GIVEN THE ABSENCE OF HIGH-QUALITY DATA, MATERNAL OUTCOMES WILL ALSO BE DETERMINED. WE WILL LEVERAGE A NETWORK OF SITES WITH REQUISITE INFRASTRUCTURES, ESTABLISHED GUIDELINES WITH HIGH ADHERENCE RATES AND TREATMENT FIDELITY, AND TRACK RECORDS OF COLLABORATION. AIM 1 IS TO TEST THE HYPOTHESIS THAT, AMONG CCHD NEONATES, DCC RESULTS IN LOWER GRS (BETTER OUTCOMES) POST-CARDIAC SURGERY OR CATHETERIZATION, BASED ON A HIGHER WIN-ODDS (WIN-RATIO ADAPTED TO INCLUDE TIES), THAN WITH ECC. AIM 2 IS TO TEST THE HYPOTHESIS THAT, AMONG NEONATES WITH CCHD, DCC WILL RESULT IN BETTER NEUROMOTOR OUTCOMES AT 22-26MOS POSTNATAL, BASED ON A JOINT TEST OF A BIVARIATE OUTCOME (DEVELOPMENTAL ASSESSMENT OF YOUNG CHILDREN SECOND EDITION MOTOR SCORE AND THE HAMMERSMITH NEONATE NEUROLOGICAL EXAM) THAN WITH ECC. AS A SECONDARY OBJECTIVE, WE WILL TEST THE HYPOTHESIS THAT AMONG CCHD NEONATES IMPROVED NEUROMOTOR PROFILES (GENERAL MOVEMENT ASSESSMENT) AT 3-4MOS MEDIATE IMPROVED NEUROMOTOR OUTCOMES AT 22-26MOS. AIM 3 IS TO PRECISELY ESTIMATE THE DIFFERENCE IN THE RISK OF MATERNAL POSTPAR- TUM HEMORRHAGE BETWEEN DCC AND ECC TO EVALUATE SAFETY AMONG MOTHERS WHO GIVE BIRTH TO CCHD NEONATES. THIS TRIAL WILL ADVANCE THE CARE OF CCHD NEONATES AND PROVIDE THE EVIDENCE CALLED FOR BY NATIONAL AND INTERNA- TIONAL ORGANIZATIONS, CREATING A GLOBAL IMPACT ON UMBILICAL CORD MANAGEMENT AMONG A VULNERABLE POPULATION.

BIOMARKERS OF OPISTHORCHIS VIVERRINI-INDUCED CHOLANGIOCARCINOMA

GW CRRE CENTER FOR INNOVATIVE TRAINING FOR VOCATIONAL REHABILITATION PERSONNEL

LINKING COMMUNITY AND FAMILY CHARACTERISTICS TO ADOLESCENT ADJUSTMENT

GENE-ENVIRONMENT INTERPLAY AND CHILDHOOD OBESITY: AN ADOPTION STUDY.

ADVANCED NURSING EDUCATION WORKFORCE

CYBERCORPS SCHOLARSHIP FOR SERVICE (RENEWAL): PARTNERSHIP IN SECURING CYBERSPACE THROUGH EDUCATION AND SERVICE (PISCES) -THE NEED TO DEVELOP HIGH-EXPERTISE GRADUATES FOR THE US GOVERNMENT'S CYBERSECURITY WORKFORCE IS CRITICAL TO THE NATION?S SECURITY AND PROSPERITY. THE GEORGE WASHINGTON UNIVERSITY (GW) IS A CENTER OF ACADEMIC EXCELLENCE IN CYBER RESEARCH (CAE-R), DESIGNATED BY THE NATIONAL CENTERS OF ACADEMIC EXCELLENCE IN CYBERSECURITY (NCAE-C) PROGRAM WITH OVER TWENTY YEARS OF EXPERIENCE TRAINING CYBERCORPS STUDENTS FOR GOVERNMENT EMPLOYMENT. THIS RENEWAL PROJECT, ENTITLED THE GW PISCES PROGRAM, AIMS TO RECRUIT AND PLACE HIGHLY TRAINED CYBERSECURITY PROFESSIONALS INTO THE PUBLIC SERVICE. THE PROJECT WILL SUPPORT SCHOLARSHIPS FOR STUDENTS AS WELL AS EXPAND OPPORTUNITIES FOR CYBERSECURITY STUDENTS BEYOND THOSE DIRECTLY SUPPORTED BY SCHOLARSHIPS. THE SCHOLARS WILL BE EQUIPPED WITH KNOWLEDGE OF CYBERSECURITY MECHANISMS, TOOLS, POLICIES, AND AVAILABLE RESOURCES BEFORE ENTERING THE FEDERAL WORKFORCE. THIS PROJECT WILL BE BUILT ON THE SUCCESSFUL AND SOLID FOUNDATION ESTABLISHED BY PISCES OVER THE PAST TWO DECADES. THE PROJECT WILL TRAIN FOUR COHORTS OF STUDENTS FOR EMPLOYMENT IN THE CYBERSECURITY MISSION OF THE FEDERAL GOVERNMENT. THE KEY ENABLER IS AN INTERDISCIPLINARY APPROACH TO CYBERSECURITY EDUCATION, WHICH WILL PROVIDE STUDENTS WITH HANDS-ON EXPERIENCES, PERSONAL CONNECTIONS, AND AN UNDERSTANDING OF THE CYBERSECURITY LANDSCAPE IN THE FEDERAL GOVERNMENT. THE PROJECT?S GOALS INCLUDE: (1) ENHANCING INTERDISCIPLINARY EDUCATION BY COLLABORATING WITH INITIATIVES FOCUSED ON TRUSTWORTHY ARTIFICIAL INTELLIGENCE (AI) AND QUANTUM COMPUTING; (2) INCREASING RESEARCH OPPORTUNITIES AVAILABLE TO SFS STUDENTS THROUGH PARTNERSHIPS WITH THE CYBERSECURITY LABS AND RESEARCH GROUPS ON THE GW CAMPUS; (3) MAKING PORTIONS OF THE EXCLUSIVE SFS SEMINAR COURSE AVAILABLE TO BROADER RANGE OF STUDENTS TO RAISE AWARENESS OF CYBERSECURITY CAREERS IN GOVERNMENT THROUGH INVITED TALKS AND RECRUITING EVENTS; (4) BROADENING AND DIVERSIFYING THE POOL OF PROSPECTIVE STUDENTS BY PROMOTING A NEW BRIDGE-TO-CYBER PROGRAM TO ATTRACT STUDENTS FROM NON-TECHNICAL BACKGROUNDS TO PURSUE DEGREES IN CYBERSECURITY. THIS PROJECT IS SUPPORTED BY THE CYBERCORPS? SCHOLARSHIP FOR SERVICE (SFS) PROGRAM, WHICH FUNDS PROPOSALS ESTABLISHING OR CONTINUING SCHOLARSHIP PROGRAMS IN CYBERSECURITY AND ALIGNS WITH THE U.S. NATIONAL CYBER STRATEGY TO DEVELOP A SUPERIOR CYBERSECURITY WORKFORCE. FOLLOWING GRADUATION, SCHOLARSHIP RECIPIENTS ARE REQUIRED TO WORK IN CYBERSECURITY FOR A FEDERAL, STATE, LOCAL, OR TRIBAL GOVERNMENT ORGANIZATION FOR THE SAME DURATION AS THEIR SCHOLARSHIP SUPPORT. 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.

NEUROPHYSIOLOGY OF PARASYMPATHETIC CARDIAC NEURONS

ENGLISH LANGUAGE ACQUISITION: NATIONAL PROFESSIONAL DEVELOPMENT PROGRAM

INHIBITION OF MEP PATHWAY ISOPRENOID BIOSYNTHESIS

LIPID RAFT THERAPY ? A NOVEL THERAPEUTIC APPROACH FOR HIV-ASSOCIATED CARDIOMETABOLIC CO-MORBIDITIES - ABSTRACT HIV INFECTION IS ACCOMPANIED BY A NUMBER OF CO-MORBIDITIES, WITH CARDIO-METABOLIC COMPLICATIONS BEING AMONG THE MOST PROMINENT. CURRENT ANTIRETROVIRAL THERAPY (ART) CONTROLS THE HIV LOAD AND REVERSES IMMUNODEFICIENCY, BUT DOES NOT ELIMINATE HIV-ASSOCIATED CO-MORBIDITIES. THE MECHANISMS RESPONSIBLE FOR THE PERSISTENCE OF CARDIO- METABOLIC CO-MORBIDITIES IN ART-TREATED HIV-INFECTED SUBJECTS WITH AN UNDETECTABLE VIRUS LOAD REMAIN UNKNOWN, PREVENTING THE DEVELOPMENT OF THERAPEUTIC TREATMENTS. OUR STUDIES IDENTIFIED HIV PROTEIN NEF AS THE MAIN CONTRIBUTOR TO VIRAL EFFECTS ON CHOLESTEROL METABOLISM AND POTENTIAL CARDIAC PHENOTYPES. OTHER RECENT REPORTS FROM SEVERAL GROUPS DEMONSTRATED THAT HIV-INFECTED CELLS RELEASE EXTRACELLULAR VESICLES (EVS) CONTAINING NEF, WHICH WERE FOUND IN THE PLASMA OF ~50% OF ART-TREATED HIV-INFECTED INDIVIDUALS WITH UNDETECTABLE VIRAL LOAD. WE SHOWED THAT NEF-CONTAINING EVS, BUT NOT EVS PRODUCED BY CELLS INFECTED WITH NEF-DEFICIENT HIV, TRIGGERED PERTURBATIONS OF CELLULAR CHOLESTEROL METABOLISM IN UNINFECTED MACROPHAGES, INCREASED ABUNDANCE AND CHANGED THE PROPERTIES OF LIPID RAFTS IN THESE CELLS, AND LED TO POTENTIATION OF INFLAMMATORY RESPONSES. THESE FINDINGS LED US TO A HYPOTHESIS THAT CHANGES TO LIPID RAFTS INDUCED BY NEF EVS MAY UNDERLIE THE MECHANISM OF CARDIO- METABOLIC CO-MORBIDITIES OF HIV DISEASE, AND THEREFORE THESE CO-MORBIDITIES CAN BE TREATED BY AGENTS BLOCKING OR REVERSING THE NEF-INDUCED CHANGES OF LIPID RAFTS. WE NAMED THIS TREATMENT APPROACH “LIPID RAFT THERAPY”. IN THE PROPOSED PROJECT WE WILL TEST THIS HYPOTHESIS BY PURSUING THE FOLLOWING SPECIFIC AIMS. IN AIM 1, WE WILL CHARACTERIZE THE EFFECTS OF NEF-CONTAINING EVS ON THE COMPOSITION AND STRUCTURE OF THE LIPID RAFTS AND WILL RELATE THESE CHANGES TO FUNCTIONAL PROPERTIES. WE WILL ALSO DETERMINE WHETHER TREATMENTS BLOCKING THE EFFECT OF NEF EVS ON LIPID RAFTS CAN REVERSE THE NEF-INDUCED FUNCTIONAL EFFECTS. IN AIM 2, WE WILL INVESTIGATE THE ASSOCIATION BETWEEN NEF EVS AND CARDIO-METABOLIC CO-MORBIDITIES AND WILL TEST LIPID RAFT-TARGETING TREATMENT APPROACHES IN VIVO. WE WILL USE APOE-/- MICE TRANSGENIC FOR HIV OR INFECTED WITH MURINE HIV (ECOHIV) TO MODEL HIV-ASSOCIATED ATHEROSCLEROSIS AND METABOLIC IMPAIRMENT. IN AIM 3, WE WILL DETERMINE WHETHER LEVELS OF EXNEF IN PLASMA OF PEOPLE LIVING WITH HIV (PLWH) CORRELATE WITH MARKERS OF CARDIO-METABOLIC CO-MORBIDITIES, WHETHER BLOOD MONOCYTES OF PLWH EXHIBIT LIPID RAFTS CHANGES, AND WHETHER THESE CHANGES CAN BE REVERSED EX VIVO BY THE LIPID RAFT THERAPY TESTED IN AIMS 1 AND 2. TOGETHER, THESE STUDIES WILL DESCRIBE A NEW MECHANISM OF HIV-ASSOCIATED CO-MORBIDITIES AND WILL INVESTIGATE NEW THERAPEUTIC TREATMENTS TARGETING THIS MECHANISM, THUS PRODUCING BOTH A BASIC SCIENCE AND A TRANSLATIONAL IMPACT ON THE FIELD.

NIAKHAR SOCIAL NETWORKS AND HEALTH PROJECT

LIPID RAFTS, DOPAMINE 1 RECEPTOR, AND HYPERTENSION

AD SUPPLEMENT TO HYPOTH NEURON ACTIVATION TO BLUNT MYOCAR REMODELING DURING CHRONIC SLEEP APNEA

HEALTH CAREERS OPPORTUNITY PROGRAM

ENGINEERED ENSEMBLE NANOIMMUNOTHERAPIES FOR CANCER

PHOTOVOLTAIC MATERIAL AND DEVICE RESEARCH AND DEVELOPMENT

TOTAL WAR: MULTI-AGENT NETWORK THEORY OF CONNECTIVE ACTION IN A CROSS-DOMAIN COUPLED WORLD

REGULATION OF RESISTANCE TO CDK4/6 INHIBITOR IN BREAST CANCER - PROJECT SUMMARY CYCLIN-DEPENDENT KINASE CDK4/6 INHIBITOR (CDK4/6I) IN COMBINATION WITH AROMATASE INHIBITORS IS THE FIRST-LINE TREATMENT FOR ER+ ADVANCED OR METASTATIC BREAST CANCER. DESPITE CDK4/6 INHIBITORS SIGNIFICANTLY IMPROVE OVERALL SURVIVAL OF SUCH PATIENTS, NOT ALL PATIENTS RESPOND TO THESE DRUGS AND MOST PATIENTS WHOSE TUMORS INITIALLY RESPOND TO CDK4/6I EVENTUALLY DEVELOP ACQUIRED RESISTANCE. ALTHOUGH MANY EFFORTS HAVE BEEN INVESTED INTO THE STUDYING MECHANISM OF RESISTANCE, CDK4/6I RESISTANCE REMAINS A BIG CHALLENGE FOR HR+ BREAST CANCER. THUS, IT IS URGENT TO DEVELOP NEW APPROACHES TO OVERCOME RESISTANCE IN CDK4/6I RESISTANT BREAST CANCER (CRBC). O-LINKED-N-ACETYLGLUCOSAMINYLATION (O-GLCNACYLATION) IS ONE TYPE OF GLYCOSYLATION THAT OCCURS WHEN A MONOSACCHARIDE, O-GLCNAC, IS ADDED ONTO SERINE OR THREONINE RESIDUES OF PROTEINS BY O-GLCNAC TRANSFERASE (OGT). O-GLCNACYLATION IS INVOLVED IN A RANGE OF CELLULAR ACTIVITIES AND ABERRANT O-GLCNACYLATION HAS BEEN IMPLICATED IN A HOST OF DISEASES INCLUDING CANCER. HOWEVER, THE ROLE OF O-GLCNACYLATION IN CANCER DRUG RESISTANCE REMAINS LARGELY UNKNOWN. THROUGH AN INNOVATIVE QUANTITATIVE HIGH THROUGHPUT COMBINATION SCREEN (QHTCS) AND FOLLOW-UP EXTENSIVE PRELIMINARY STUDIES USING CELLULAR AND MOLECULAR APPROACHES, WE IDENTIFIED A NOVEL OGT-MEDIATED MECHANISM REGULATING THE RESISTANCE TO CDK4/6I IN ER+ BREAST CANCER. THE MAJOR OBJECTIVE OF THIS PROPOSAL IS TO DETERMINE THE ROLE OF OGT-MEDIATED PATHWAY IN THE REGULATION OF CDK4/6I RESISTANCE IN CRBC CELLS. SPECIFICALLY, WE WILL (1) INVESTIGATE THE MOLECULAR MECHANISM OF HOW OGT-MEDIATED PATHWAY REGULATES CDK4/6I RESISTANCE IN CRBC CELLS, (2) EVALUATE THE EFFECTS OF NEWLY IDENTIFIED DRUG COMBINATIONAL TREATMENTS ON PALBOCICLIB RESISTANCE USING RESISTANT PDX AND SYNGENEIC MODELS, (3) CONDUCT CLINICAL STUDY TO FURTHER EVALUATE THE CORRELATION BETWEEN OGT-MEDIATED PATHWAY AND CDK4/6I RESISTANCE IN TUMORS FROM PATIENTS. THE COMPLETION OF PROPOSED STUDIES WILL NOT ONLY ELUCIDATE A NOVEL MECHANISM REGULATING CDK4/6I RESISTANCE IN ER+ BREAST CANCER, BUT ALSO PROVIDE AN INNOVATIVE THERAPEUTIC STRATEGY TO TREAT CRBC PATIENTS.

RESEARCH AND ENGAGEMENT FOR ACTION ON CLIMATE AND HEALTH (REACH) CENTER - PROJECT SUMMARY - OVERALL THE MISSION OF THE RESEARCH AND ENGAGEMENT FOR ACTION ON CLIMATE AND HEALTH (REACH) CENTER IS TO BRIDGE BIG DATA TO CLIMATE SOLUTIONS THAT ADVANCE HEALTH AND ENVIRONMENTAL JUSTICE. SPECIFICALLY, THE CENTER LEVERAGES THE POWER OF NOVEL GEOSPATIAL DATASETS AND RESEARCH CO-GENERATION WITH GOVERNMENTAL AND NON- GOVERNMENTAL PARTNERS TO RESEARCH HEALTH AND EQUITY IMPACTS OF CLIMATE CHANGE MITIGATION AND ADAPTATION ACTIONS FROM LOCAL TO GLOBAL SCALES. THE CENTER FORMS A NEW MULTI-INSTITUTIONAL PARTNERSHIP THAT LEVERAGES WORLD- CLASS STRENGTHS IN PUBLIC HEALTH, MEDICINE, AND PUBLIC POLICY AT GEORGE WASHINGTON UNIVERSITY; EARTH AND ATMOSPHERIC SCIENCES AT GEORGE MASON UNIVERSITY AND HOWARD UNIVERSITY; ENVIRONMENTAL JUSTICE AT HOWARD UNIVERSITY; AND RESEARCH TRANSLATION AT ENVIRONMENTAL DEFENSE FUND. THE CENTER’S GROUND-BREAKING PARTNERSHIP CULTIVATES A DIVERSE, MULTI-DISCIPLINARY, COLLABORATIVE RESEARCH ENTERPRISE THAT GENERATES NEW KNOWLEDGE AND ACCELERATES RESEARCH TRANSLATION INTO HEALTH-PROTECTIVE AND EQUITABLE CLIMATE CHANGE MITIGATION AND ADAPTATION. OUR IDEAL LOCATION IN THE NATIONAL CAPITAL REGION, HOSTED AT THE ONLY SCHOOL OF PUBLIC HEALTH IN WASHINGTON, DC, GIVES US UNIQUE OPPORTUNITIES TO COLLABORATE WITH THE LOCAL AND FEDERAL GOVERNMENT AND A PLETHORA OF CIVIL SOCIETY ORGANIZATIONS ENGAGED IN CLIMATE AND HEALTH POLICY DEVELOPMENT. THE REACH CENTER WILL GENERATE NEW KNOWLEDGE ALONG THE SPECTRUM OF DISCOVERY TO APPLIED RESEARCH, PARTICULARLY LEVERAGING THE STRENGTHS OF GEOSPATIAL DATASETS TO ADDRESS RESEARCH QUESTIONS THAT CAN GUIDE MITIGATION AND ADAPTATION ACTIONS AT A RANGE OF ADMINISTRATIVE SCALES. THE CENTER WILL CATALYZE COLLABORATIONS BETWEEN INVESTIGATORS AND GOVERNMENTAL AND NON-GOVERNMENTAL STAKEHOLDERS TO UNDERSTAND THE COMPLEX INTERACTIONS BETWEEN CLIMATE AND HEALTH AND DESIGN APPROACHES FOR PROTECTING PUBLIC HEALTH UNDER FUTURE CLIMATE CHANGE. THE CENTER WILL ACHIEVE ITS MISSION THROUGH ADMINISTRATIVE, DEVELOPMENTAL, COMMUNITY ENGAGEMENT, AND EXPOSURE ASSESSMENT CORES. THE DEVELOPMENTAL CORE CENTER WILL DEVELOP NEW RESEARCH INFRASTRUCTURE THAT FOSTERS RESEARCH EXPLORING CLIMATE SOLUTIONS THAT ADVANCE HEALTH AND EQUITY THROUGH PILOT AWARDS, STUDENT FELLOWSHIPS, EDUCATIONAL AND NETWORKING OPPORTUNITIES, AND INTERACTION BETWEEN INVESTIGATORS AND GOVERNMENTAL AND NON- GOVERNMENTAL PARTNERS. THE COMMUNITY ENGAGEMENT CORE WILL PROVIDE A BRIDGE BETWEEN ACADEMIC RESEARCH AND A COMMUNITY OF POTENTIAL USERS OF THE FINDINGS TO DRIVE HEALTH-PROTECTIVE AND EQUITABLE CLIMATE SOLUTIONS FORWARD. THE EXPOSURE ASSESSMENT CORE WILL LEAD THE CENTER’S EFFORTS TO MAKE GEOSPATIAL CLIMATE AND ENVIRONMENTAL DATA MORE ACCESSIBLE, INTEROPERABLE, AND INTERPRETABLE FOR CLIMATE AND HEALTH RESEARCH CONDUCTED BY RESEARCHERS FROM VARIOUS DISCIPLINES.

DEMONSTRATION OF THE IN-TIME LEARNING-BASED SAFETY MANAGEMENT FOR SCALABLE HETEROGENEOUS AAM OPERATIONS

THE GEORGE WASHINGTON UNIVERSITY CAPITAL/DOE ALLIANCE CENTER (CDAC) – A CENTER OF EXCELLENCE FOR HIGH PRESSURE SCIENCE AND TECHNOLOGY NEW AWARD PROVIDES INCREMENTAL FUNDING TO FULLY FUND BUDGET PERIOD 1 OF THE PROJECT PERIOD

BRAIN ENDOPLASMIC RETICULUM STRESS IN NON-ALCOHOLIC FATTY LIVER DISEASE

DATA ANALYSIS CENTER FOR ELECTROMAGNETIC AND HADRONIC SCATTERING PROCESSES

INTEGRATING SOCIAL DETERMINANTS OF HEALTH INTO RISK ADJUSTMENT MODELS: AN OPPORTUNITY TO IMPROVE CARE COORDINATION STRATEGIES FOR MEDICAID BENEFICIARIES

REGULATION OF ER-BETA SIGNALING IN CARCINOGENESIS

FOREBRAIN-HYPOTHALAMIC MECHANISMS IN OBESITY-INDUCED HYPERTENSION

EXPANDING EFFORTS AND STRATEGIES TO PROTECT AND IMPROVE PUBLIC HEALTH GLOBALLY

CLONAL HEMATOPOIESIS IN MONOCYTES CONTRIBUTES TO HIV-ASSOCIATED NEUROINFLAMMATION - SUMMARY EXTRAVASATION OF INFLAMMATORY MONOCYTES ACROSS THE BLOOD-BRAIN BARRIER (BBB) IN RESPONSE TO HUMAN IMMUNODEFICIENCY VIRUS TYPE-1 (HIV) IS A CRITICAL EVENT THAT LEADS TO CHRONIC NEUROINFLAMMATION, NEUROLOGIC INJURY, AND SUBSEQUENT LOSS OF COGNITIVE ABILITIES IN A SIGNIFICANTLY LARGE NUMBER OF INFECTED INDIVIDUALS. HOWEVER, GIVEN THE HETEROGENEITY OF MONOCYTES THAT EXISTS IN HIV-INFECTED INDIVIDUALS RECEIVING ANTI-RETROVIRAL THERAPY (ART), IT REMAINS UNKNOWN AS TO WHETHER THE NEURO-MODULATORY ACTIONS OF MONOCYTES ARE LIMITED TO SELECT SUBSET OF MONOCYTES. DIRECTLY RELEVANT TO THE GOALS OF RFA-21-250, OUR SUPPORTING DATA REVEALS THAT THE ART-TREATED HIV- INFECTED INDIVIDUALS HARBOR HIGHER NUMBERS OF INFLAMMATORY MONOCYTES (CD14LOWCD16HI) IN THEIR CIRCULATION. THESE CELLS ALSO EXHIBIT CHARACTERISTIC FEATURES OF CLONAL HEMATOPOIESIS (CH), SUCH AS LOSS OF DNA METHYLTRANSFERASE 3A (DNMT3A) AND TET METHYLCYTOSINE DIOXYGENASE 2 (TET2) WITH CONCURRENT INCREASE IN THE EXPRESSION OF JANUS KINASE-2 (JAK2 ; THESE THREE GENE PRODUCTS, AND FEW OTHERS, ARE OFTEN TERMED AS CH DRIVERS). INTERESTINGLY, SUBSEQUENT EXPERIMENTS IN VARIOUS MODELS SUGGESTED THAT THIS MONOCYTE SUBSET (1) TRANSLOCATE TO THE CENTRAL NERVOUS SYSTEM (CNS) IN RESPONSE TO ART, IN PLATELET-DEPENDENT MANNER, (2) IS NEURO-MODULATORY IN ACTION, AND (3) CAN BE EXPANDED FOLLOWING EXPOSURE OF MONOCYTES TO ACTIVATED PLATELETS AND ART. BASED ON THESE FINDINGS, WE POSIT THAT THE PRIMING OF MONOCYTES BY ACTIVATED PLATELETS POTENTIATES ART-MEDIATED CLONAL HEMATOPOIESIS IN MONOCYTES, LEADING TO HIV-ASSOCIATED NEUROLOGIC INJURY. IN THIS MODEL, WE PROPOSE THAT THE COMPOSITE EFFECT OF ACTIVATED PLATELETS AND ART RESULTS INTO CLONAL EXPANSION OF INFLAMMATORY (CD14LOWCD16HI) MONOCYTE SUBSET WITH CH, AND SUBSEQUENT DEMETHYLATION/INDUCTION OF PSGL-1 GENE IN THEM. FUNCTIONALLY, THESE EVENTS FACILITATE THE TRANSMIGRATION OF SUCH MONOCYTES INTO THE PERIVASCULAR SPACES WITHIN THE CNS, WHERE THESE CELLS DIFFERENTIATE INTO MACROPHAGE PHENOTYPE, WHILE RETAINING CH PROFILE, AND CONTRIBUTE TO THE NEURONAL DYSFUNCTION. THIS MODEL THEN, IN FULL ACCORDANCE WITH THE AVAILABLE LITERATURE, ACCOUNTS FOR HOW NEUROLOGIC MANIFESTATIONS ARE INITIATED AND MAINTAINED DUE TO IMMUNE-CNS INTERACTION IN ART-TREATED HIV- INFECTED INDIVIDUALS.

COLLABORATIVELY ACHIEVING HEALTH EQUITY: CAPACITY BUILDING TO ADVANCE CANCER CONTROL SYSTEMS-LEVEL CHANGE - COMPREHENSIVE CANCER CONTROL (CCC) BRINGS TOGETHER MULTI-SECTORAL PARTNERS TO COLLECTIVELY ADDRESS CANCER BURDEN BY LEVERAGING RESOURCES TO IMPLEMENT EVIDENCE-BASED INTERVENTIONS (EBI) ACROSS THE CANCER CONTINUUM. APPLYING FOR COMPONENT A OF CDC-RFA-DP-23-0017: PROVISION OF TRAINING AND TECHNICAL ASSISTANCE TO ENHANCE COMPREHENSIVE CANCER CONTROL OUTCOMES, THE GEORGE WASHINGTON UNIVERSITY CANCER CENTER (GWCC) SEEKS TO BUILD UPON ITS DEMONSTRATED TRACK RECORD AS A TRAINING AND TECHNICAL ASSISTANCE (TTA) PROVIDER. SINCE 2013, GWCC HAS REACHED 7,774 LEARNERS THROUGH 10 ENDURING ONLINE TRAININGS, GAINED 3,453 ACTIVE NEWSLETTER SUBSCRIBERS, ENGAGED 81 TTA STEERING COMMITTEE MEMBERS AND DEVELOPED 74 UNIQUE HEALTH AWARENESS CAMPAIGNS, AND AUTHORED OVER 80 GWCC RESOURCES THAT CONTINUE TO BE ACTIVELY MAINTAINED AND PROMOTED. THIS PROPOSAL BUILDS ON EXISTING DISSEMINATION CHANNELS, PARTNERSHIPS AND TTA PRODUCTS TO ENHANCE CAPACITY OF CDC-FUNDED CCC PROGRAMS AND COALITIONS TO ADDRESS THE HEALTH EQUITY THROUGH POLICY, SYSTEM, AND ENVIRONMENTAL CHANGE. GWCC’S APPROACH CENTERS NCCCP RECIPIENT NEEDS WITH INPUT FROM NATIONAL COLLABORATORS. LEVERAGING EXISTING INFRASTRUCTURE, GWCC WILL FACILITATE MULTIMODAL AND INTERACTIVE PEER-TO-PEER LEARNING THROUGH DIVERSE CHANNELS TO ACHIEVE THE FOLLOWING OUTCOMES: REDUCED DUPLICATION OF EFFORTS; IMPROVED USE OF RESOURCES; ENHANCED REACH OF TTA; DELIVERY OF HIGH-QUALITY TTA; PROMOTION OF CCC SUCCESSES; AND INCREASED IMPLEMENTATION OF EBIS AND PSE STRATEGIES BY CCC PROGRAMS AND COALITIONS. THESE ACTIVITIES WILL INCREASE CAPACITY AND IMPACT OF CCC PROGRAMS AND COALITIONS, LEADING TO REDUCED CANCER DISPARITIES. SPECIFIC STRATEGIES AND ACTIVITIES INCLUDE: STRATEGY A1: DEVELOP TRAINING AND TECHNICAL ASSISTANCE PLAN - RESTRUCTURE GWCC’S TTA STEERING COMMITTEE IN COLLABORATION WITH TTA PROVIDERS TO IDENTIFY NCCCP RECIPIENT NEEDS AND OPTIMIZE RESOURCE INVENTORIES ON THE TECHNICAL ASSISTANCE PORTAL (TAP) AND THE CCCNP WEBSITES, BOTH MANAGED BY GWCC. STRATEGY A2: IMPLEMENT TTA PLAN THROUGH PARTNERSHIPS AND/OR PARTNERSHIP NETWORKS. - MAINTAIN STRONG ENGAGEMENT IN CCCNP AND WITH NATIONAL NETWORKS TO COLLECTIVELY ADVANCE CCC WITH OTHER TTA PROVIDERS. STRATEGY A3: DELIVER MULTIMODAL TTA TO FACILITATE NCCCP RECIPIENT INFORMATION SHARING - MAINTAIN EFFECTIVE COMMUNICATION CHANNELS TO DISSEMINATE TTA TO NCCCP RECIPIENT AND COALITIONS INCLUDING HIGHLY UTILIZED MONTHLY SOCIAL MEDIA CAMPAIGNS AND NEWSLETTERS - INCREASE USE OF PSE CHANGE APPROACHES AND ACCELERATE EBI IMPLEMENTATION AMONG NCCCP RECIPIENTS THROUGH TWO COMMUNITIES OF PRACTICE THAT LEVERAGE GWCC PSE AND IMPLEMENTATION SCIENCE TRAININGS TO SUPPORT PEER-TO-PEER LEARNING. - BUILD CAPACITY TO ADVANCE NCCCP PRIORITIES BY MAINTAINING, PROMOTING AND OPTIMIZING THE EXISTING GWCC ONLINE ACADEMY WHICH INCLUDES 10 ASYNCHRONOUS DIDACTIC TRAININGS TO INCREASE KNOWLEDGE AND CONFIDENCE AMONG NCCCP RECIPIENTS AND COALITION MEMBERS. - IMPROVE CCC COALITION FUNCTIONING AND EFFECTIVENESS BY ENHANCING AND BUILDING UPON A VARIETY OF EXISTING USER-TESTED RESOURCES INCLUDING THE COMP CANCER 101 WIKI, TAILORED RESOURCE REMINDERS AND VISUAL MENUS, AND REPRESENTATION AND ENGAGEMENT TOOLS TO HELP NCCCP RECIPIENTS ASSESS AND IMPROVE THEIR COALITIONS’ DIVERSITY AND INCLUSION PRACTICES STRATEGY A4: MONITOR AND EVALUATE TTA EFFORTS AND DISSEMINATE FINDINGS - CONTINUE TO DISSEMINATE PUBLIC-FACING ANNUAL REPORTS DETAILING IMPACT OF TTA.

UNDERSTANDING THE EFFECTS OF MOTOR LEARNING IN WILD-TYPE AND MECP2-DEFICIENT MICE - PROJECT SUMMARY OBSERVERS OF CHILDREN OR YOUNG ANIMALS WILL NOTICE HOW MUCH LEARNING ABOUT THE WORLD DEPENDS ON BEING ABLE TO MOVE WITHIN IT. INDEED, STUDIES IN HUMANS AND OTHER PRIMATES HAVE SHOWN THAT THE MOTOR CORTEX (M1) IS INVOLVED IN WORKING MEMORY, EMPATHY, AND LANGUAGE. COULD MOTOR DYSFUNCTION CONTRIBUTE TO THE VARIOUS COGNITIVE AND AFFECTIVE DEFICITS THAT OCCUR IN NEURODEVELOPMENTAL DISORDERS (NDD)? CONVERSELY, COULD IMPROVING MOTOR FUNCTION IMPROVE OTHER ASPECTS OF NDD PHENOTYPES? RECENT WORK FROM MY LAB PROVIDES EVIDENCE THAT THIS MAY BE THE CASE. WE HAVE BEEN STUDYING RETT SYNDROME (RTT), WHICH IS CAUSED BY LOSS-OF-FUNCTION MUTATIONS IN THE X- LINKED GENE METHYL CPG-BINDING PROTEIN 2 (MECP2) AND IS A LEADING MONOGENETIC CAUSE OF NDD, AFFECTING 1 IN 10,000 LIVE FEMALE BIRTHS. THE PHENOTYPE IS STRIKING FOR ITS POSTNATAL ONSET: AFFECTED GIRLS APPEAR TO DEVELOP NORMALLY AND REACH THE APPROPRIATE MILESTONES FOR THE FIRST YEAR OR TWO OF LIFE BEFORE THEY REGRESS, LOSING MOST ACQUIRED SKILLS AND DEVELOPING MOTOR, COGNITIVE, AND SOCIAL ABNORMALITIES. BOTH MALE AND FEMALE MECP2- DEFICIENT MICE REPLICATE THIS NATURAL HISTORY, AND THE DELAYED ONSET STRONGLY SUGGESTS THAT ALTHOUGH MECP2 IS EXPRESSED FROM EARLY DEVELOPMENT, IT HAS ADDITIONAL, AS-YET UNCLEAR FUNCTIONS IN MAINTAINING MATURE NEURONS AND SYNAPTIC CONNECTIONS. WE THEREFORE SET OUT TO ASK TWO QUESTIONS: 1) HOW DOES MECP2 DEFICIENCY AFFECT THE PROCESS OF LEARNING AT THE MOTOR CIRCUIT LEVEL, AND 2) WOULD MOTOR LEARNING EXERT BENEFICIAL EFFECTS BEYOND THE PARTICULAR SKILL LEARNED? WE USED CALCIUM TWO-PHOTON IMAGING TO SIMULTANEOUSLY RECORD EXCITATORY ACTIVITY IN LAYERS 2/3 AND 5A WHILE 8-WEEK OLD WILD TYPE AND NULL MALE MICE LEARNED TO ADAPT TO CHANGING SPEEDS ON A COMPUTERIZED RUNNING WHEEL OVER TWO WEEKS OF TRAINING. WE FOUND THAT A SUBGROUP OF M1 NEURONS IN LAYERS 2/3 AND 5A STRENGTHEN THEIR FUNCTIONAL CONNECTIVITY WHILE THE REST OF THE POPULATION DECREASES FUNCTIONAL CONNECTIVITY, LIKELY TO MAINTAIN FLEXIBILITY FOR LEARNING NEW SKILLS. LOSS OF MECP2 ATTENUATES BUT DOES NOT ABOLISH THIS REORGANIZATION: ALTHOUGH CROSS-LAYER CONNECTIVITY WAS MUCH LOWER IN THE NULL MICE, AND THE FUNCTIONAL CONNECTIONS BETWEEN NEURONAL PAIRS IN THE NULL M1 CIRCUIT LAST HALF AS LONG AS THOSE IN WT, THE NULL M1 CIRCUIT RETAINS ENOUGH PLASTICITY TO SUPPORT MOTOR SKILL LEARNING. MOREOVER, TRAINED NULL MICE SHOWED LESS ANXIETY-LIKE BEHAVIOR AND LIVED ~20% LONGER THAN UNTRAINED MICE (MANUSCRIPT UNDER RE-REVIEW). THIS IS ALL THE MORE REMARKABLE GIVEN THAT THE ENTIRE BRAIN IS DISRUPTED BY LOSS OF MECP2. THIS WORK LAID THE FOUNDATION FOR THE CURRENT PROPOSAL, WHICH SEEKS TO UNDERSTAND THE CONTRIBUTIONS OF CORTICAL INPUTS AND INHIBITORY NEURONS TO L2/3 PLASTICITY DURING LEARNING, DETERMINE THE EFFECTS OF MOTOR LEARNING ON M1 IN FEMALE MECP2 HETEROZYGOUS MICE, AND SHED LIGHT ON HOW 'NORMAL' THE M1 CIRCUIT ACTUALLY IS IN PRESYMPTOMATIC RTT MICE.

PHYSICAL FITNESS AS AN OBJECTIVE BIOMARKER FOR AD/ADRD RISK MODIFICATION

CARDIAC OPTOGENETICS: A CELL DELIVERY APPROACH

NOVEL MECHANISMS THAT RESTORE CARDIAC PARASYMPATHETIC ACTIVITY LIMITS ARRHYTHMIAS AND CARDIAC DYSFUNCTION AFTER MYOCARDIAL INFARCTION

VTA MICROCIRCUIT DYNAMICS DURING CHRONIC STRESS

NON-CODING RNA AND CKD PROGRESSION

BOOSTING ANTITUMOR IMMUNITY BY BLOCKING BOTH TUMOR AND ADIPOSE DDR1

A NOVEL 3D BIOPRINTED SMART VASCULARIZED NANO TISSUE

GENDERED SOCIAL CONTEXT OF ADOLESCENT HIV RISK BEHAVIOR: FAMILY, PEER GROUP, AND

THE ROLE OF AND-1 IN NUCLEOTIDE EXCISION REPAIR - PROJECT SUMMARY NUCLEOTIDE EXCISION REPAIR (NER) IS THE MAJOR PATHWAY TO REMOVE BULKY DNA LESIONS INDUCED BY UV IRRADIATION, ENVIRONMENTAL MUTAGENS, AND CHEMOTHERAPEUTIC AGENTS. DEFICIENCY OF GENES INVOLVED IN NER HAS BEEN LINKED TO XERODERMA PIGMENTOSUM (XP) AND SKIN CANCER. THERE ARE TWO MECHANISMS TO DETECT DNA DAMAGE BY NER, ONE IS GLOBAL GENOME NER(GG-NER) AND ANOTHER IS TRANSCRIPTION-COUPLED NER(TC-NER). GG-NER OCCURS ANYWHERE IN THE GENOME, WHEREAS TC-NER IS RESPONSIBLE FOR THE ACCELERATED REPAIR OF LESIONS IN THE TRANSCRIBED STRAND OF ACTIVE GENES. THE BOTH PATHWAYS ARE DIVIDED INTO EARLY AND LATE STEPS. THE EARLY STEP IS THE SEQUENTIAL ACTIONS, IN WHICH XP PROTEINS RECOGNIZE, UNWIND, AND INCISE THE DNA LESION. THE LATTER STEP IS IDENTICAL IN BOTH MECHANISMS AND IS CHARACTERIZED BY GAP-FILLING REPAIR SYNTHESIS, IN WHICH DNA REPLICATION PROTEINS FILL IN THE ~30 NUCLEOTIDE GAP, FOLLOWED BY LIGATION. COMPARED TO THE WELL-CHARACTERIZED EARLY STEP, THE MOLECULAR MECHANISM REGULATING THE ACTIVATION OF GAP-FILLING DNA SYNTHESIS AT LATE STEP REMAINS LARGELY UNKNOWN. EVEN LESS IS KNOWN ABOUT THE PHYSIOLOGICAL IMPACT OF SUCH A REGULATORY PATHWAY. AND-1 IS AN ACIDIC NUCLEOPLASMIC DNA-BINDING PROTEIN AND ITS YEAST ORTHOLOG, CTF4, WAS ORIGINALLY IDENTIFIED AS A CRITICAL GENE FOR CHROMOSOME STABILITY. INTERESTINGLY, YEAST CELLS WITH DEPLETION OF CTF4 GENE ARE HYPERSENSITIVE TO UV LIGHTS, SUGGESTING A ROLE OF AND-1 IN UV-INDUCED DNA DAMAGE RESPONSE. HOWEVER, HOW AND-1 REGULATES NER REMAINS LARGELY UNKNOWN. IN THIS STUDY, WE NOW HAVE EXTENSIVE PRELIMINARY DATA DEMONSTRATING THAT AND-1 IS CRITICAL FOR NER BY REGULATING GAP-FILLING DNA SYNTHESIS. OUR HYPOTHESIS IS THAT AND-1 REGULATES DNA POLYMERASE ACTIVITY AT UV-LESION SITES TO ACTIVATE GAP-FILLING DNA SYNTHESIS AT THE LATE STAGE OF NER. TO TEST THIS HYPOTHESIS, WE PLAN TO PURSUE THREE SPECIFIC AIMS. AIM 1: DETERMINE THE MECHANISM BY WHICH AND-1 REGULATES DNA POLYMERASE ACTIVITY IN NER. AIM 2: DETERMINE THE UNIQUE MECHANISM BY WHICH AND-1 IS RECRUITED TO UV-LESION SITES. AIM 3: DETERMINE THE ROLE OF AND-1 IN NER AND SKIN TUMORIGENESIS USING AND-1 DEFICIENT MOUSE MODELS. THE COMPLETION OF PROPOSED STUDIES WILL NOT ONLY ADVANCE THE FIELD BY UNCOVERING A NOVEL AND-1-MEDIATED PATHWAY TO REGULATE NER, BUT ALSO PROVIDE US WITH THE IN VIVO EVIDENCE TO ELUCIDATE A NOVEL ROLE OF AND-1 IN NER AND SKIN TUMOR.

ROLE OF TETHERIN IN HIV-ASSOCIATED THROMSOSIS

SOCIETAL STRESSORS, ADAPTIVE FACTORS, AND DEVELOPMENTAL TIMING: INFLUENCES ON LATINX MENTAL HEALTH FROM EARLY CHILDHOOD THROUGH YOUNG ADULTHOOD - ABSTRACT IN 2021, THE US SURGEON GENERAL ISSUED AN ADVISORY WARNING OF A YOUTH MENTAL HEALTH CRISIS, EXACERBATED BY THE COVID-19 PANDEMIC. LATINX YOUTH, A GROUP MARGINALIZED BY RACE, ETHNICITY, CLASS, AND CULTURE, HAVE EXCEEDINGLY HIGH RATES OF INTERNALIZING SYMPTOMS SUCH AS DEPRESSION AND ANXIETY. ECOSOCIAL THEORY POSITS THAT HISTORICAL, SOCIETAL, AND ECOLOGICAL CONDITIONS OVER THE LIFE COURSE HAVE CRITICAL IMPACTS ON LATER MENTAL HEALTH. THIS RESEARCH WILL EXAMINE HOW DISTAL AND PROXIMAL SOCIETAL STRESSORS INFLUENCE MENTAL HEALTH TRAJECTORIES FOR A DIVERSE SAMPLE OF US LATINX YOUTH FOLLOWED FROM EARLY CHILDHOOD INTO YOUNG ADULTHOOD. DISTAL SOCIETAL STRESSORS, SUCH AS THE PANDEMIC, ANTI-IMMIGRANT RHETORIC, AND NEIGHBORHOOD ETHNIC MARGINALIZATION, MAY INCREASE LATINX YOUTH’S INTERNALIZING SYMPTOMS DIRECTLY AND INDIRECTLY THROUGH PROXIMAL SOCIETAL STRESSORS, SUCH AS FAMILIES’ COVID-RELATED ECONOMIC, HEALTH, AND SOCIAL PROBLEMS AND INDIVIDUALS’ PERCEPTIONS OF IMMIGRANT THREATS AND ETHNIC DISCRIMINATION. THESE KINDS OF SOCIETAL STRESSORS ALSO MAY HAVE DIRECT AND INDIRECT EFFECTS ON INCREASED INTERNALIZING SYMPTOMS THROUGH FAMILY STRESS PROCESSES, INCLUDING MATERNAL DEPRESSION AND HARSH PARENTING. THE NATURE OF YOUTH’S EXPOSURE TO THESE STRESSORS (FOR HOW LONG, WHEN IN HISTORY AND DEVELOPMENT) AND THE PRESENCE OF PROTECTIVE ADAPTIVE FACTORS (E.G., PARENTS’ CULTURAL SOCIALIZATION; YOUTH SELF-REGULATION) CAN MODERATE STRESSOR IMPACTS ON INTERNALIZING SYMPTOMS. THIS RESEARCH WILL LEVERAGE ADVANCES IN INTEGRATED DATA ANALYSIS (IDA) TO POOL DATA FROM FIVE LONGITUDINAL LATINX COHORT STUDIES TO OBTAIN A SINGLE, AGGREGATED DATA SET WITH 2,515 LATINX MOTHER-YOUTH DYADS FOLLOWING YOUTH FROM AGE 2 TO 22 (2010-26). IDA INCREASES STATISTICAL POWER, SAMPLE HETEROGENEITY AND GENERALIZABILITY, AND MEASUREMENT BREADTH AND DEPTH IN WAYS NOT POSSIBLE WITH A SINGLE DATA SET. THE APPLICATION WILL SUPPORT 1) COLLECTING CROSS-SECTIONAL DATA FOR 500 LATINX INDIVIDUALS TO ESTABLISH STANDARD MEASUREMENT SCALING ACROSS THE FIVE STUDIES; 2) INTEGRATING DATA ACROSS ALL FIVE STUDIES; AND 3) EXTRACTING DATA FROM TWITTER AND THE US CENSUS TO ASSESS ANTI-IMMIGRANT RHETORIC AND NEIGHBORHOOD FACTORS, RESPECTIVELY. ANALYSES WILL UTILIZE A GENERAL LATENT VARIABLE MODELING FRAMEWORK THAT INCLUDES MULTILEVEL MODELING, STRUCTURAL EQUATION MODELING, ITEM RESPONSE MODELING, AND FINITE MIXTURE MODELING. WE HYPOTHESIZE A CASCADE OF EFFECTS FROM DISTAL SOCIETAL STRESSORS TO INCREASED INTERNALIZING SYMPTOMS THROUGH GREATER PROXIMAL SOCIETAL STRESSORS AND INCREASED FAMILY STRESS PROCESSES. WE EXPECT THAT PATHWAYS LINKING SOCIETAL STRESSORS TO YOUTH’S INTERNALIZING SYMPTOMS WILL VARY DEPENDING UPON THE PRESENCE OF ADAPTIVE FACTORS, THE DEVELOPMENTAL TIMING AND CUMULATIVE EFFECTS OF YOUTH EXPERIENCES, AND SOCIODEMOGRAPHIC CHARACTERISTICS (E.G., YOUTH BIOLOGICAL SEX, FAMILY NATIONAL ORIGIN). THIS STUDY OFFERS AN UNPARALLELED OPPORTUNITY TO UNDERSTAND LATINX MENTAL HEALTH IN RELATIONSHIP TO MULTI-LEVEL STRESSORS, ADAPTIVE FACTORS, AND SENSITIVE PERIODS OF DEVELOPMENT. AS LATINX YOUTH COMPRISE MORE THAN ONE-IN-FOUR US YOUTH, FINDINGS FROM THIS RESEARCH WILL HELP GUIDE NEW PREVENTIVE INTERVENTIONS AND REFINE EXISTING ONES FOR A LARGE AND GROWING SEGMENT OF THE US POPULATION.

REGULATION OF REPETITIVE ELEMENTS IN CANCER BY P53 AND EPIGENETIC MECHANISMS - DESPITE FOCUSED RESEARCH EFFORTS, THE FIVE YEAR SURVIVAL FOR OVARIAN CANCER (OC) HAS REMAINED UNCHANGED FOR DECADES AND NOVEL THERAPIES ARE URGENTLY NEEDED FOR THIS DEADLY DISEASE. THERAPIES THAT ACTIVATE THE IMMUNE SYSTEM TO KILL CANCER CELLS, INCLUDING ANTI-PD-1 CHECKPOINT BLOCKADE THERAPY, HAVE SHOWN VIGOROUS AND DURABLE RESPONSES, BUT THE MAJORITY OF PATIENTS, INCLUDING THOSE WITH OC, FAIL TO RESPOND. THE UNDERLYING MECHANISM REMAINS UNCLEAR. REPETITIVE ELEMENTS (RES) COMPRISE THE MAJORITY (45%) OF THE HUMAN GENOME. IN MOST SOMATIC TISSUES, RES ARE SILENCED BY DNA METHYLATION AND OTHER EPIGENETIC MODIFICATIONS TO PREVENT THEIR TRANSCRIPTION. WE DEMONSTRATED THAT TREATING OC CELLS WITH DNA METHYLATION INHIBITORS (DNMTIS) AND HISTONE DEACETYLASE INHIBITORS (HDACIS) INCREASES IMMUNE SIGNALING FROM TUMORS THROUGH DEMETHYLATION OF RES AND PRODUCTION OF RE DOUBLE-STRANDED RNA TO ACTIVATE THE INTERFERON RESPONSE. THIS SIGNALING RECRUITS CD8+ T CELLS TO SENSITIZE TUMORS TO ANTI-PD-1 IMMUNOTHERAPY. RES TRANSLATE PROTEINS THAT CAN BE TARGETED AS TUMOR-ASSOCIATED ANTIGENS. THUS RE ACTIVATION BOTH PROMOTES INTERFERON SIGNALING TO REVERSE THE IMMUNE- SUPPRESSIVE TUMOR MICROENVIRONMENT AND PRESENTS POTENTIAL TUMOR-SPECIFIC ANTIGENS AS T CELL TARGETS. THE PREMISE OF THIS PROPOSAL IS THAT P53 AND EPIGENETIC MECHANISMS REGULATE RES IN CANCER AND THUS MUTANT TP53 WILL AFFECT IMMUNE SIGNALING AND RESPONSE TO EPIGENETIC AND IMMUNE THERAPY. APPROXIMATELY HALF OF ALL CANCERS HAVE MUTATIONS IN TP53, THE GENE ENCODING THE P53 PROTEIN, 90% OF WHICH ARE “HOTSPOT” MUTATIONS LOCATED IN THE DNA BINDING DOMAIN. THESE MISSENSE MUTATIONS ENCODE FUNCTIONAL PROTEINS WITH REDUCED TRANSCRIPTIONAL ACTIVITY AT CANONICAL CELL CYCLE TARGET GENES THAT MAY ALSO EXHIBIT ONCOGENIC GAIN OF FUNCTION TRANSCRIPTIONAL ACTIVITY AT NEW TARGETS. HIGH GRADE SEROUS OC MAKES UP ABOUT 70% OF ALL CASES AND IS CHARACTERIZED BY NEARLY 100% MUTANT TP53. WHILE THE CRITICAL ROLE OF P53 IN CELL CYCLE REGULATION AND APOPTOSIS IS KNOWN, P53 REGULATION OF RES IN CANCER REMAINS POORLY DEFINED. APPROXIMATELY 30% OF P53 BINDING SITES ARE FOUND IN RES AND OUR PRELIMINARY DATA SHOW THAT P53 BINDS DIRECTLY TO RES. FURTHER, WE SHOW THAT P53 HOTSPOT MUTANT CELL LINES TREATED WITH DNMTI/HDACI EXHIBIT SIGNIFICANTLY INCREASED CHROMATIN ACCESSIBILITY AT RES AND TRANSCRIPTION OF RES COMPARED TO TP53 WILD TYPE CELL LINES. WE HYPOTHESIZE THAT MUTANT P53 ABERRANTLY ACTIVATES RES, AMPLIFYING THE RE-INDUCED IMMUNE RESPONSE. WE WILL TEST THIS HYPOTHESIS VIA THE FOLLOWING AIMS: IN AIM 1, WE WILL DETERMINE HOW WILD TYPE AND MUTANT TP53 REGULATE RES TO AFFECT THE DNMTI/HDACI-INDUCED INTERFERON RESPONSE. IN AIM 2, WE WILL DETERMINE HOW P53 STATUS AFFECTS THE DNMTI/HDACI-INDUCED T CELL RESPONSE AND SENSITIZATION TO IMMUNE THERAPY IN A MOUSE MODEL OF OC AND A CLINICAL TRIAL OF OC PATIENTS TREATED WITH IMMUNOTHERAPY. IN AIM 3, WE WILL EVALUATE RES AS TUMOR ANTIGENS IN DIFFERENT P53 BACKGROUNDS. RESULTS OF THIS INNOVATIVE WORK WILL ANSWER NOVEL BASIC SCIENCE QUESTIONS ABOUT RES AND P53 AND OPEN NEW DIRECTIONS FOR EPIGENETIC AND IMMUNE THERAPY IN OC.

ADVANCING 3D OPTICAL BODY SURFACE SCAN TECHNOLOGY TO ASSESS PHYSIOLOGICAL AND PSYCHOLOGICAL EFFECTS IN HIGHLY OBESE POPULATION - PROJECT SUMMARY CURRENT TECHNIQUES FOR MEASURING THE PHYSIOLOGICAL OR PSYCHOLOGICAL EFFECTS OF OBESITY, AND IN PARTICULAR BARIATRIC SURGERY, EITHER LACK SENSITIVITY, ARE INVASIVE, OR REQUIRE EXPENSIVE SPECIALIZED DEVICES. FOR MEASURING THE PHYSIOLOGICAL EFFECTS, BMI IS COMMONLY USED TO DIAGNOSE OBESITY DESPITE THE KNOWN SHORTCOMINGS AS A MARKER FOR METABOLIC SYNDROME. BIOMARKERS SUCH AS ANTHROPOMETRIC MEASUREMENTS (E.G., WAIST-TO-HIP RATIO) AND VISCERAL ADIPOSE TISSUE (VAT) HAVE BEEN SHOWN TO BE SUPERIOR TO BMI IN PREDICTING HEALTH RISKS ASSOCIATED WITH OBESITY, BUT THESE MEASURES LACK SENSITIVITY, SPECIFICITY, OR ARE EXPENSIVE. ANOTHER KEY MORBIDITY ASSOCIATED WITH OBESITY IS NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) AND NON-ALCOHOLIC STEATOHEPATITIS (NASH). THE GOLD STANDARD TO THE DIAGNOSIS AND ASSESSMENT OF THESE CONDITIONS IS HISTOLOGIC EVALUATION OF LIVER BIOPSIES. FIBROSCAN TRANSIENT ELASTOGRAPHY IS A NONINVASIVE TEST WHICH CAN ALSO ASSESS FIBROSIS, BUT HIGH BMI AND SEVERE STEATOSIS CAN DECREASE ITS ACCURACY. THESE APPROACHES ARE EITHER INVASIVE, EXPENSIVE, OR RELATIVELY INACCURATE. MEASURES OF SELF-BODY PERCEPTION ARE COMMONLY USED TO ASSESS PSYCHOLOGICAL ASPECTS OF OBESITY, AS BODY IMAGE IS AN IMPORTANT MOTIVATOR FOR DIET, PHYSICAL ACTIVITY, AND WEIGHT LOSS INTENTION. BODY IMAGE PERCEPTION IS COMMONLY ASSESSED USING SELF-REPORTS AND CARTOON-LIKE LINE DRAWINGS WHICH ARE NON-SUBJECT SPECIFIC AND INSENSITIVE. BASED ON OUR PRELIMINARY WORK (R21HL124443) THAT DEVELOPED OPTICAL BODY SCANNING TECHNOLOGY TO CAPTURE 3D BODY SHAPES USING INEXPENSIVE HARDWARE, WE PROPOSE TO USE THE TECHNOLOGY TO STUDY THE PHYSIOLOGICAL AND PSYCHOLOGICAL EFFECTS ON SUBJECTS WITH SEVERE OBESITY: · DEVELOP PREDICTION ALGORITHM FOR HEPATIC STEATOSIS, FIBROSIS, ADIPOSITY, AND BLOOD BIOMARKERS USING OPTICAL SCANS. THE OPTICAL SCAN AND BIOPSY DATA WILL BE USED AS THE TRAINING AND VALIDATION SET TO DEVELOP A MACHINE LEARNING ALGORITHM TO CHEAPLY AND NON-INVASIVELY PREDICT THE BIOMARKERS FROM 3D BODY SURFACE DATA. · DEVELOP THE USE OF OPTICAL SCANS FOR MEASURING THE PHYSIOLOGICAL EFFECTS OF OBESITY. WE WILL CONDUCT A CROSS SECTIONAL AND LONGITUDINAL STUDY TO FURTHER ASSESS THE USE OF OPTICAL SURFACE SCANS TO DETERMINE HEALTH INDICATORS ASSOCIATED WITH OBESITY (USING DATA FROM SURFACE SCAN, DXA AND SERUM BIOMARKERS) FOR ONE YEAR FOLLOWING SURGERY. WE WILL ESTABLISH A DATABASE OF SUCH DATA ALONG WITH SOFTWARE FOR DATA MINING THE DATABASE. · DEVELOP THE USE OF OPTICAL SCANS FOR MEASURING THE PSYCHOLOGICAL EFFECTS OF OBESITY. WE WILL COLLECT 3D SURFACE GEOMETRY OF EACH SUBJECT USING OPTICAL SCANS AND MORPH THESE TO PRODUCE SUBJECT-SPECIFIC IMAGES OF LARGER OR SMALLER BODY SHAPE. WE WILL USE THESE IMAGES TO STUDY PERCEPTION RELATED TO OBESITY AND IN PARTICULAR PATIENTS UNDERGOING POST-OPERATIVE BODY CHANGES

COMBINATION VACCINES TO INTERRUPT MALARIA TRANSMISSION

BRAIN ANGIOTENSIN II AS A MEDIATOR OF FEAR MEMORY AND CARDIOVASCULAR DYSFUNCTION

IMPLEMENTING A SCALABLE SMOKE-FREE HOME INTERVENTION IN ARMENIA AND GEORGIA - SUMMARY/ABSTRACT AMONG THE DISPARITIES FACED BY POPULATIONS IN LOW- AND MIDDLE-INCOME COUNTRIES (LMICS) ARE THOSE RELATED TO TOBACCO USE AND SECONDHAND SMOKE EXPOSURE (SHSE). TWO COUNTRIES PARTICULARLY IMPACTED BY TOBACCO USE AND SHSE ARE ARMENIA (AM) AND GEORGIA (GE), WHICH REPRESENT THE 11TH AND 6TH HIGHEST SMOKING RATES IN MEN GLOBALLY (51.5% AND 55.5%, RESPECTIVELY). HOWEVER, SMOKING PREVALENCE IS MUCH LOWER AMONG WOMEN (1.8% AND 7.8%). NOTABLY, A PRIMARY SOURCE OF SHSE AMONG CHILDREN AND MOST NONSMOKING ADULTS IN MANY LMICS, INCLUDING AM AND GE, IS THE HOME. SMOKE-FREE HOMES (SFHS) CAN REDUCE SHSE, PROMOTE CESSATION, AND POSSIBLY DISRUPT INITIATION; HOWEVER, 61.4% OF HOUSEHOLDS IN AM AND GE ALLOW SMOKING IN THE HOME. THUS, PROMOTING SFHS MAY BE AN INNOVATIVE AND RELATIVELY UNTAPPED STRATEGY FOR CHRONIC DISEASE PREVENTION IN THESE COUNTRIES – AND IN OTHER LMICS WITH HIGH SMOKING RATES. RESEARCH FOCUSED ON IMPLEMENTING EVIDENCE-BASED INTERVENTIONS (EBIS) OFFERS UNIQUE OPPORTUNITIES TO ADDRESS THE PRESSING NEEDS IN LMICS AND TO EXAMINE KEY BARRIERS IN THE ADOPTION, SCALE-UP, AND SUSTAINMENT OF EBIS IN LOW-RESOURCE SETTINGS. THIS PROPOSAL BUILDS ON ONGOING COLLABORATIONS AMONG MPIS BERG AND KEGLER, THE GE NATIONAL CENTER FOR DISEASE CONTROL (NCDC), THE AM NATIONAL INSTITUTE OF HEALTH (NIH), AND THE AMERICAN UNIVERSITY OF ARMENIA (AUA), DATING BACK TO 2013. THESE COLLABORATIONS HAVE ESTABLISHED: 1) A STRONG COMMUNITY-BASED INFRASTRUCTURE FOR IMPLEMENTING PUBLIC HEALTH PROGRAMS USING LOCAL COALITIONS IN 14 COMMUNITIES, DEVELOPED IN OUR CURRENT FOGARTY-FUNDED R01; AND 2) A THEORY-BASED SFHS INTERVENTION, DESIGNED TO BE BRIEF AND ADAPTABLE AND SHOWN TO BE EFFECTIVE, GENERALIZABLE, SCALABLE, AND COST-EFFECTIVE AMONG LOW-INCOME HOUSEHOLDS IN THE US. THE CURRENT PROPOSAL WILL STRATEGICALLY CAPITALIZE ON OUR STRONG PARTNERSHIPS WITH NATIONAL PUBLIC HEALTH AGENCIES, LOCAL COMMUNITY MOBILIZATION INFRASTRUCTURE, AND SFH EBI TO ADDRESS OUR SPECIFIC AIMS. AIM 1: WE WILL ADAPT OUR SFH INTERVENTION TO BE CULTURALLY APPROPRIATE FOR THE AM AND GE POPULATIONS, USING A COMMUNITY-ENGAGED APPROACH AND ROBUST ADAPTATION FRAMEWORKS AND METHODS, AND DEVELOP IN-COUNTRY CAPACITY FOR INTERVENTION DISSEMINATION (VIA LOCAL COALITIONS) AND DELIVERY (VIA NATIONAL QUITLINES). AIM 2: WE WILL EXAMINE THE EFFECTIVENESS OF THE ADAPTED INTERVENTION (VS. CONTROL) ON SFH ADOPTION (PRIMARY OUTCOME) AMONG HOUSEHOLDS IN AM AND GE, USING A TYPE 1 HYBRID EFFECTIVENESS-IMPLEMENTATION RCT (N=550 PARTICIPANTS; 275/COUNTRY), WITH FOLLOW-UP ASSESSMENTS AT 3 AND 6 MONTHS. AIM 3: WE WILL ASSESS INTERVENTION REACH, ADOPTION, IMPLEMENTATION, AND MAINTENANCE POTENTIAL, AS WELL AS RELATED CONTEXTUAL INFLUENCES, USING A MIXED-METHODS PROCESS EVALUATION GUIDED BY RE-AIM. OUR TEAM (INCLUDING NATIONAL PUBLIC HEALTH AGENCIES) WILL USE THESE FINDINGS TO DEVELOP A SUSTAINABILITY AND DISSEMINATION PLAN (E.G., INTERVENTION PACKAGING FOR SCALE-UP). THIS WORK WILL PROVIDE A ROBUST MODEL FOR ADAPTING AND IMPLEMENTING THIS EBI FOR AM AND GE, WHICH COULD THEN BE USED FOR THIS INTERVENTION IN OTHER COUNTRIES AND/OR FOR OTHER BEHAVIORAL TARGETS AND EBIS IN AM, GE, AND ELSEWHERE. THIS WORK WILL ADVANCE OUR LONG-TERM GOALS OF BUILDING THE KNOWLEDGE BASE INFORMING STRATEGIES TO REDUCE TOBACCO-RELATED DISPARITIES GLOBALLY AND THE IMPLEMENTATION AND SCALE-OUT OF EBIS IN LMICS.

PHASE 1 TRIAL OF NA-APR-1 AND NA-GST-1 HOOKWORM VACCINES IN BRAZILIAN ADULTS

TARGETING FANCONI ANEMIA PATHWAY TO OVERCOME PLATINUM DRUG RESISTANCE IN OVARIAN CANCER - PROJECT SUMMARY OVARIAN CANCER (OC) IS THE FIFTH LEADING CAUSE OF CANCER-RELATED DEATH AMONG WOMEN AND THE DEADLIEST GYNECOLOGICAL CANCER IN THE UNITED STATES. THE CURRENT STANDARD TREATMENT FOR OVARIAN CANCER CONSISTS OF SURGERY FOLLOWED BY PLATINUM DRUG-BASED CHEMOTHERAPY. PLATINUM DRUGS COULD INDUCE DNA INTERSTRAND CROSSLINK (ICL), WHICH RESULTS IN REPLICATION FORK STALLING AND THUS DECREASE CELL VIABILITY. ALTHOUGH MOST OF PATIENTS INITIALLY RESPOND TO PLATINUN DRUG-BASED CHEMOTHERAPY AND ACHIEVE REMISSION, UP TO 80% OF PATIENTS BECOME REFRACTORY TO PLATINUM DRUGS OVER TIME AND ULTIMATELY SUCCUMB TO THE DISEASE DUE TO THE RESISTANCE TO PLATINUM-BASED THERAPY. THUS, IT IS URGENT TO DEVELOP NOVEL APPROACHES TO OVERCOME PLATINUM DRUG RESISTANCE OF OVARIAN CANCER (PROC). FANCONI ANEMIA (FA) PATHWAY IS CRITICAL TO REPAIR ICLS AND ELEVATED ACTIVITY OF FA SIGNALING IS ONE OF MAJOR MECHANISMS LEADING TO PLATINUM-RESISTANCE IN OVARIAN CANCER. THE ROLE OF FA PATHWAY IN REPAIR OF ICL HAS BEEN WELL STUDIED LAST DECADE, HOWEVER, HOW THE REGULATORY SWITCH FROM A STALLED REPLICATION FORK CAUSED BY PLATINUM DRUGS TO INITIATION OF FA SIGNALING AND HOW FA IS ACTIVATED IN PROC CELLS ARE POORLY UNDERSTOOD. TO ELUCIDATE THE MECHANISM REGULATING INITIATION OF FA SIGNALING, WE HAVE CONDUCTED THE SIGNIFICANT AMOUNT OF PRELIMINARY STUDIES TO DEMONSTRATE THAT AND-1 IS CRITICAL FOR ACTIVATION OF FA SIGNALING AND FA- MEDIATED PLATINUM DRUG RESISTANCE IN OVARIAN CANCER. THE MAJOR OBJECTIVE OF THIS PROPOSAL IS TO DETERMINE THE MECHANISM OF HOW AND-1-FANCM AXIS REGULATES FA SIGNALING AND PLATINUM RESISTANCE IN PROC. HERE, WE PROPOSE THREE SPECIFIC AIMS. AIM 1: DETERMINE HOW AND-1 PROMOTES THE SWITCH FROM STALLED REPLICATION FORKS TO INITIATION OF FA SIGNALING AT ICLS. AIM 2: DETERMINE THE ROLE OF AND-1 IN THE REGULATION OF PLATINUM DRUG RESISTANCE IN PROC CELLS. AIM 3: EVALUATE THE EFFECTS OF AND-1 INHIBITION ON PLATINUM DRUG RESISTANCE USING ORTHOTOPIC PROC PDX AND SYNGENEIC MODELS. THE COMPLETION OF PROPOSED STUDIES WILL NOT ONLY ELUCIDATE A NOVEL MECHANISM REGULATING PLATINUM RESISTANCE IN PROC, BUT ALSO PROVIDE AN INNOVATIVE THERAPEUTIC STRATEGY AS WELL AS A NEW POTENTIAL DRUG FOR TREATMENT OF PROC PATIENTS.

LOW ENERGY DEFIBRILLATION

DC CITY-WIDE PATIENT NAVIGATION RESEARCH PROGRAM

ARRHYTHMOGENIC REMODELING IN HUMAN HEART FAILURE

CROSSTALK BETWEEN BRCA1 AND TRANSCRIPTION IN BREAST CANCER

METABOLIC DYSREGULATION AND CANCER RISK PROGRAM: COORDINATING CENTER - PROJECT SUMMARY THE GOAL OF THE METABOLIC DYSREGULATION AND CANCER RISK CONSORTIUM (MDCRC) IS TO IDENTIFY TANGIBLE MECHANISTIC/ETIOLOGIC PATHWAYS THAT LINK OBESITY-RELATED METABOLIC DYSREGULATION WITH CANCER RISK TO INFORM CANCER PREVENTION STRATEGIES. THE CONSORTIUM PROPOSES TO ACCOMPLISH THIS THROUGH DEVELOPING COMMON MEASURES FOR OBESITY-RELATED METABOLIC DYSREGULATION FOR DIFFERENT CANCER TYPES, UNDERSTANDING HOW OBESITY- RELATED METABOLIC DYSREGULATION AFFECTS CANCER INITIATION AND DEVELOPMENT, CHARACTERIZING SIGNAL CROSS-TALK BETWEEN KEY BIOLOGIC PROCESSES THAT IMPACT OBESITY-ASSOCIATED METABOLIC DYSREGULATION AND CANCER RISK, AND DETERMINING THE UTILITY OF EMERGING APPROACHES FOR THE DISCOVERY OF NOVEL OBESITY-ASSOCIATED METABOLIC TARGETS IN CANCER RISK AND PREVENTION. THE BIOSTATISTICS CENTER (CENTER) IN THE MILKEN INSTITUTE SCHOOL OF PUBLIC HEALTH (SPH) OF THE GEORGE WASHINGTON UNIVERSITY (GW), THE PARTICIPATING INSTITUTION, PROPOSES TO SERVE AS THE MDCRC COORDINATING CENTER (CC). THE MDCRC CC WILL INTEGRATE THIS EXPERTISE AND EXPERIENCE, DRAWING UPON OUR SUCCESSFUL HISTORY OF COORDINATING CENTER LEADERSHIP IN COLLABORATIVE RESEARCH CONSORTIA, CAPACITY FOR INNOVATION, AND THE EXTENSIVE SCIENTIFIC EXPERTISE IN OBESITY AND CANCER PREVENTION, NUTRITION, EXERCISE, METABOLISM, BODY COMPOSITION, AND BIOINFORMATICS/COMPUTATIONAL BIOLOGY TO FORM A CC THAT IS ROOTED IN SCIENTIFIC RIGOR AND IS FLEXIBLE AND RESPONSIVE TO THE DIVERSE CHALLENGES AND SCIENTIFIC OPPORTUNITIES OF THE MDCRC. THE SPECIFIC AIMS OF THE MDCRC INCLUDE TO 1) PROVIDE SCIENTIFIC LEADERSHIP AND PROJECT MANAGEMENT FOR COLLABORATIVE CROSS-CONSORTIUM ACTIVITIES, INCLUDING PROVIDING GUIDANCE ON THE SELECTION OF COMMON MEASURES AND DEVELOPMENT OF CONSISTENT PROTOCOLS AND MANUALS OF OPERATIONS, MAINTAIN PRIVATE AND PUBLIC WEBSITES, ESTABLISHING TOPICAL WORK GROUPS, AND SPEARHEAD OUTREACH ACTIVITIES; 2) FACILITATE DATA HARMONIZATION, DATA SHARING AND RESULTS DISSEMINATION ACROSS THE MDCRC SITES AND WITH NCI, INCLUDING IDENTIFICATION OF OPPORTUNITIES FOR NOVEL DATA COLLECTION TO ENRICH THE MDCRC DATA RESOURCES, DEVELOPING A COMMON DATA MANAGEMENT PLATFORM, AND TRAINING FOR SITE STAFF; AND 3) ESTABLISH A SELF-EVALUATION CORE TO PROMOTE TIMELY SELF- EVALUATION, ALONG WITH EFFECTIVE SELF-CORRECTING ACTIONS, WORKING WITH NCI AND THE CONSORTIUM INVESTIGATORS TO ESTABLISH CRITERIA AND OUTPUTS RELATED TO THE “SUCCESS” OF INDIVIDUAL INVESTIGATORS, STUDY TEAMS, AND CONSORTIUM SITES.

HEALTH EQUITY LEADERSHIP DEVELOPMENT INITIATIVE

GERIATRIC EDUCATION CENTERS

DEVELOPING PATHOGEN RECOGNITION RECEPTOR AGONISTS AS LATENCY REVERSING AGENTS

TRANSDUCTION OF SCHISTOSOMA MANSONI BY PSEUDOTYPED RETROVIRUS

EFFECT OF THE HOUSING AND URBAN DEVELOPMENT?S SMOKEFREE PUBLIC HOUSING RULE ON AIR QUALITY AND HEALTH IN THE DISTRICT OF COLUMBIA

COMPTON SCATTERING STUDIES AT HIGS

EFFECTS OF A NON-NUTRITIVE SWEETENER REDUCTION INTERVENTION IN PREGNANCY AND LACTATION ON MATERNAL AND INFANT OUTCOMES (THE SWEETPEA TRIAL) - ABSTRACT INCREASING EVIDENCE DEMONSTRATES THAT SUBOPTIMAL CONDITIONS IN THE WOMB, INCLUDING POOR MATERNAL NUTRITION, CONTRIBUTES TO OBESITY AND CARDIOMETABOLIC DISEASE RISK. ONE POTENTIAL CONTRIBUTOR TO POOR MATERNAL NUTRITION IS CHRONIC CONSUMPTION OF NON-NUTRITIVE SWEETENERS (NNS). STUDIES INDICATE THAT APPROXIMATELY 30% OF PREGNANT WOMEN AND 44% OF LACTATING WOMEN IN THE UNITED STATES REGULARLY CONSUME NNS. HOWEVER, A GROWING BODY OF EVIDENCE DEMONSTRATES THAT NNS CONSUMPTION IS PARADOXICALLY ASSOCIATED WITH OBESITY AND METABOLIC RISK FACTORS. WHILE EFFECTS OF NNS CONSUMPTION DURING PREGNANCY AND LACTATION ON MATERNAL AND INFANT METABOLIC HEALTH ARE NOT WELL UNDERSTOOD, THE AVAILABLE EVIDENCE SUGGESTS CAUSE FOR CONCERN. FOR EXAMPLE, NNS CONSUMPTION DURING PREGNANCY INCREASES MATERNAL BLOOD SUGAR AND INDUCES FETAL HYPOGLYCEMIA AND GROWTH RESTRICTION IN MICE – BOTH OF WHICH ARE RISK FACTORS FOR OFFSPRING OBESITY. FURTHER, THREE PROSPECTIVE COHORT STUDIES IN HUMANS HAVE REPORTED AN ASSOCIATION BETWEEN MATERNAL NNS CONSUMPTION AND CHILDHOOD WEIGHT OR ADIPOSITY, ALTHOUGH ANOTHER FOUND NO RELATIONSHIP. OUR OWN PILOT DATA INDICATE THAT NNS CONSUMPTION DURING PREGNANCY INCREASES INFANT FAT MASS AND DISRUPTS THE INFANT GUT MICROBIOME AT 1 MONTH OF AGE. HOWEVER, THE LIMITED, CONTRADICTORY, AND OBSERVATIONAL NATURE OF THE HUMAN EVIDENCE COLLECTED TO DATE HAS MADE IT DIFFICULT TO ESTABLISH GUIDELINES AROUND NNS CONSUMPTION DURING PREGNANCY. WE THEREFORE PROPOSE THE FIRST RANDOMIZED CONTROLLED TRIAL (RCT) TO EXAMINE THE EFFECTS OF NNS DURING PREGNANCY AND LACTATION. WE WILL RECRUIT 324 PREGNANT WOMEN WHO FREQUENTLY CONSUME NNS (≥7 SERVINGS/WEEK) AND EXAMINE THE EFFECTS OF NNS RESTRICTION ON MATERNAL AND INFANT METABOLIC OUTCOMES. PREGNANT WOMEN WILL BE RANDOMLY ASSIGNED TO ONE OF THREE GROUPS: 1) NO NNS RESTRICTION (CONTROL); 2) NNS RESTRICTION DURING LACTATION ONLY; AND 3) NNS RESTRICTION DURING PREGNANCY AND LACTATION. THE INTERVENTION WILL CONSIST OF MONTHLY CONSULTATIONS WITH A DIETITIAN TO PROVIDE COUNSELING ON REPLACEMENT OF NNS CONSUMPTION WITH UNSWEETENED FOOD AND BEVERAGE ALTERNATIVES AND HOME DELIVERY OF SUCH ALTERNATIVES. ADHERENCE WILL BE ASSESSED VIA 24-HOUR DIETARY RECALLS AND BY OBJECTIVELY MEASURING NNS CONCENTRATIONS IN URINE AND BREAST MILK. OUR PRIMARY AIMS WILL BE TO DETERMINE THE EFFECTS OF NNS-RESTRICTION ON: 1) INFANT BODY COMPOSITION AT 1 AND 6 MONTHS OF AGE; 2) MATERNAL GLUCOSE TOLERANCE AT 24-28 WEEKS’ GESTATION; AND, 3) INFANT GUT MICROBIOME AND FECAL METABOLITES AT 1 AND 6 MONTHS OF AGE. WE HYPOTHESIZE THAT NNS RESTRICTION AMONG PREGNANT WOMEN WHO HABITUALLY CONSUME NNS DURING PREGNANCY AND/OR LACTATION WILL REDUCE INFANT FAT MASS (COMPARED TO A NO NNS RESTRICTION (USUAL NNS INTAKE) CONTROL GROUP), VIA IMPROVEMENTS TO MATERNAL GLYCEMIA AND THE INFANT GUT MICROBIOME AND METABOLOME, WITH THE GREATEST BENEFIT IN THE PREGNANCY AND LACTATION GROUP. THIS RESEARCH COULD SHAPE RECOMMENDATIONS AROUND NNS CONSUMPTION DURING PREGNANCY AND LACTATION, THEREBY POTENTIALLY REDUCING THE GLOBAL BURDEN OF OBESITY AND CARDIOMETABOLIC DISEASE.

CHRONIC NICOTINE EFFECTS ON RECEPTOR SUBTYPES

NRSA FOR PRIMARY MEDICAL CARE

EVALUATING COMPANION DIAGNOSTICS TO THE ANAL PAP TEST TO IMPROVE PREDICTION OF AIN2+ IN HIV-INFECTED MSM

AMBULATORY SENSOR ARRAYS FOR REAL-LIFE MONITORING OF PEDIATRIC PATIENTS WITH ASTHMA

MTA1 IN ONCOGENESIS

PISCES-S-2014: PARTNERSHIP IN SECURING CYBERSPACE THROUGH EDUCATION AND SERVICE

EFRI CEE: HUMAN CARDIAC OPTO-EPIGENETICS WITH HDAC INHIBITORS

ADIPOCYTE PD-L1 IN THE BREAST TUMOR MICROENVIRONMENT - ABSTRACT PROGRAMMED DEATH-LIGAND 1 (PD-L1) AND ITS RECEPTOR, PROGRAMMED CELL DEATH PROTEIN 1 (PD-1), MODULATE ANTI-TUMOR IMMUNITY AND ARE MAJOR TARGETS OF CURRENT CHECKPOINT BLOCKADE IMMUNOTHERAPIES. HOWEVER, CLINICAL TRIALS OF ΑPD-L1/ΑPD-1 ANTIBODIES IN BREAST CANCER TO DATE HAVE DEMONSTRATED ONLY LIMITED EFFICACY. THE IMPORTANCE OF A BREAST-SPECIFIC TUMOR MICROENVIRONMENT (TME) IN REGULATING ANTI-TUMOR IMMUNITY IS VASTLY UNDER- EXPLORED. GIVEN THE ABUNDANCE OF ADIPOCYTES IN BREAST TISSUE, THE WELL-DOCUMENTED ASSOCIATION BETWEEN ADIPOSITY AND BREAST CANCER-RELATED MORTALITY, AND THE EMERGING OBESITY PARADOX IN ANTICANCER IMMUNOTHERAPY, IT IS IMPERATIVE TO INVESTIGATE THE MOLECULAR UNDERPINNINGS OF THE COMPLEX ADIPOSE-IMMUNE-TUMOR NETWORK WITHIN THE ADIPOCYTE-RICH BREAST TME. WE RECENTLY IDENTIFIED A PREVIOUSLY UNAPPRECIATED, FUNCTIONALLY SIGNIFICANT SOURCE OF PD-L1 IN WHITE ADIPOCYTES. ADIPOCYTE PD-L1 IS MARKEDLY INDUCED DURING ADIPOGENESIS AND OBESITY-RELATED CHRONIC INFLAMMATION. USING AN ADIPOCYTE-SPECIFIC KNOCKOUT MOUSE MODEL, WE DEMONSTRATE AN IMPORTANT ROLE OF ADIPOCYTE PD-L1 IN PROMOTION OF TUMOR GROWTH AND ATTENUATION OF ANTI-TUMOR IMMUNITY. FURTHERMORE, OUR PRELIMINARY DATA INDICATE PHYSICAL AND FUNCTIONAL INTERACTIONS BETWEEN PD-L1 AND LIPID METABOLISM-RELATED PROTEINS AND PATHWAYS IN ADIPOCYTES, WHICH SUGGESTS AN ADIPOCYTE-INTRINSIC FUNCTION OF PD-L1. BASED ON OUR PRELIMINARY DATA, WE HYPOTHESIZE THAT ADIPOCYTE PD-L1 IMPEDES ANTI-TUMOR LYMPHOCYTES AND/OR ABETS TUMOR CELLS THROUGH A LIPID METABOLISM-RELATED MECHANISM. WE FURTHER PROPOSE THAT THIS ACTION OF ADIPOCYTE PD-L1 IS PARTICULARLY IMPORTANT AT THE TUMOR MARGIN OF IMMUNE-EXCLUDED TUMORS, WHERE ADIPOCYTES ARE IN PROXIMITY WITH BOTH TUMOR AND IMMUNE CELLS. WE WILL COMBINE OUR ESTABLISHED TOOLS AND EXPERTISE IN CANCER BIOLOGY, TUMOR IMMUNOLOGY, AND TRANSCRIPTIONAL REGULATION TO VALIDATE THIS NOVEL HYPOTHESIS THROUGH THE FOLLOWING AIMS: (1) DELINEATE HOW ADIPOCYTE PD-L1 MEDIATES ADIPOSE-IMMUNE-TUMOR CROSSTALK, (2) DETERMINE HOW ADIPOCYTE PD-L1 EXPRESSION IS REGULATED, AND (3) DETERMINE HOW ADIPOCYTE PD-L1 IMPACTS IMMUNOTHERAPY IN OBESE VS NON-OBESE HOSTS. OUR STUDIES ON ADIPOCYTE PD-L1 SIGNALING IN LIPID METABOLISM WILL PROVIDE NEW MOLECULAR EXPLANATIONS FOR PD-L1 ACTION IN TUMOR IMMUNOLOGY, A CLEAR DEPARTURE FROM THE PREVAILING PARADIGM REGARDING TUMOR/IMMUNE PD-L1 ACTIONS. THIS PROPOSED WORK REPRESENTS A CONCEPTUAL ADVANCE TOWARD UNDERSTANDING THE SPATIAL LANDSCAPE OF THE BREAST TME IN IMMUNE REGULATION AND TUMORIGENESIS – A CLINICALLY RELEVANT YET MECHANISTICALLY UNDER-EXPLORED PROBLEM. OUR RESULTS COULD LAY A SOLID FOUNDATION FOR DEVELOPING NEW TOOLS THAT PREDICT AND ENHANCE THERAPEUTIC RESPONSE TO APD-1/APD-L1 IMMUNOTHERAPY FOR BREAST CANCER PATIENTS, ESPECIALLY THOSE WITH OBESITY.

A NOVEL REGULATOR OF ANTITUMOR IMMUNITY AND IMMUNOTHERAPY - ABSTRACT TUMOR ANTIGEN-TRIGGERED T CELL RECEPTOR (TCR) SIGNALING IN THE CYTOPLASM AND TRANSCRIPTIONAL/EPIGENETIC CONTROL IN THE NUCLEUS ARE CENTRAL TO CD8+ T CELL-DEPENDENT ANTITUMOR IMMUNITY. HOWEVER, STRONG AND PERSISTENT ANTIGEN STIMULATION LEADS TO IMMUNE EXHAUSTION. COMPARED TO TUMOR DRAINAGE LYMPH NODES, THE TUMOR MICROENVIRONMENT (TME) CONTAINS HIGHER AMOUNTS OF TUMOR ANTIGENS AND THEIR PROLONGED PRESENTATION TO TUMOR- INFILTRATING CD8+ T CELLS CAN EXACERBATE T CELL EXHAUSTION AND IMMUNE EVASION. EXCEPT FOR CO-INHIBITORY RECEPTORS, IT IS LARGELY UNKNOWN HOW T CELLS ADAPT TO THE ANTIGEN-RICH MILIEU OF TME. BETTER UNDERSTANDING OF THE MECHANISMS UNDERLYING TME-UNIQUE REGULATION OF T CELL FUNCTIONS COULD INFORM NOVEL THERAPIES AIMED AT REINVIGORATING THE ANTITUMOR POTENTIAL OF EXHAUSTED CD8+ T CELLS. THE OVERARCHING SCIENTIFIC OBJECTIVE OF OUR PROPOSED WORK IS TO DETERMINE HOW NEGATIVE ELONGATION FACTOR (NELF), KNOWN FOR ITS FUNCTION IN RNA POLYMERASE II (POL II) PAUSING, REGULATES CD8+ T CELL ACTIVITIES IN A TME- UNIQUE MANNER. OUR PRELIMINARY WORK SUGGESTS THAT NELF IS BOTH NECESSARY AND RATE-LIMITING IN PROMOTING THE ANTITUMOR ACTIVITY OF CD8+ T CELLS. OF NOTE, THIS NELF FUNCTION IS UNIQUE TO CD8+ T CELLS WITHIN THE TME, BUT NOT IN TUMOR DRAINAGE LYMPH NODES. FURTHERMORE, OUR PUBLISHED AND UNPUBLISHED DATA POINT TO POTENTIAL DUAL ACTIONS OF DISTINCT SUBCELLULAR POOLS OF NELF: WHILE NUCLEAR NELF PARTICIPATES IN TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS, CYTOPLASMIC NELF ATTENUATES TCR SIGNALING. WE HYPOTHESIZE THAT THE COMBINED ACTIONS OF NELF LIKELY CONTRIBUTE TO STRONGER T CELL MEMORY AND LESS T CELL EXHAUSTION. BUILT UPON RIGOROUS SCIENTIFIC PREMISES AND MULTIDISCIPLINARY EXPERTISE, WE WILL VALIDATE THIS NOVEL HYPOTHESIS BY DECIPHERING THE TME-UNIQUE FUNCTION OF NELF (AIM 1), INTERROGATING ITS DUAL MOLECULAR ACTIONS IN THE NUCLEUS AND CYTOPLASM (AIM 2), AND EXPLORING THE UTILITY OF NELF OVEREXPRESSION IN BOOSTING EFFICACY OF ANTICANCER IMMUNOTHERAPIES (AIM 3). THE CONCEPT THAT NELF HAS A TME-UNIQUE FUNCTION IN ANTITUMOR IMMUNITY IS NOVEL. FURTHERMORE, THE PROPOSED DUAL ACTIONS OF NELF CLEARLY DEVIATE FROM THE POL II PAUSING-EXCLUSIVE PARADIGM OF NELF BIOLOGY. THE PROPOSED WORK IN THIS MULTI-PI R01 PROPOSAL PROMISES TO SHED LIGHT ON A PREVIOUSLY UNAPPRECIATED REGULATOR OF TME-UNIQUE FUNCTIONS OF TUMOR-INFILTRATING T CELLS, WITH POTENTIAL FOR A SUSTAINED IMPACT ON THE UNDERSTANDING OF ANTITUMOR IMMUNITY. FROM A TRANSLATIONAL PERSPECTIVE, DISCOVERIES FROM THIS PROJECT COULD INFORM MORE EFFECTIVE APPROACHES TO BOOST T CELL MEMORY AND OVERCOME T CELL EXHAUSTION, THUS HELPING ADDRESS A SIGNIFICANT BARRIER AND UNMET CLINICAL NEED IN ANTICANCER IMMUNOTHERAPIES.

TNFR2 SEX DIFFERENCES AND EAE - ABSTRACT THE SUSCEPTIBILITY TO MULTIPLE SCLEROSIS (MS) IS BELIEVED TO BE DUE IN PART TO NEUROINFLAMMATION AND DISEASE BURDEN LINKED TO NEURODEGENERATION. IT IS WELL ESTABLISHED THAT FEMALES HAVE A MORE ROBUST IMMUNE RESPONSE THAN MALES HOWEVER, NEURODEGENERATION AND DISEASE PROGRESSION ARE MORE SEVER IN MALES. THUS, IN THE CONTEXT OF MS, THIS RAISES AN INTRIGUING QUESTION. DO FEMALES, BY VIRTUE OF HAVING A MORE ROBUST INFLAMMATORY RESPONSES, HAVE ENDOGENOUS PROTECTION/REPAIR MECHANISMS TO PROTECT THE CENTRAL NERVOUS SYSTEM (CNS) FROM INFLAMMATION INDUCED PATHOLOGY, THAT MALES DO NOT HAVE OR THAT ARE NOT AS EFFECTIVE IN MALES? THIS PROPOSAL IS BASED UPON EXTENSIVE PRELIMINARY AND PUBLISHED DATA DEMONSTRATING THAT TMTNF/TNFR2 SIGNALING IN FEMALES, BUT NOT MALES, SIGNIFICANTLY IMPROVES MOTOR FUNCTION AND REDUCES NEUROPATHOLOGY IN EAE BY ACTIVATING ENDOGENOUS REPAIR PROGRAMS IN NEURONS AND OLIGODENDROCYTES. BASED UPON THESE AND OTHER RESULTS, OUR FIRST EXPERIMENTAL GOAL IS TO INTERROGATE SEX DIFFERENCES IN TMTNF/TNFR2 INDUCED IMPROVEMENTS IN MOTOR FUNCTION AND NEUROPATHOLOGY. FURTHER, WE HAVE VERY NOVEL PHARMACOLOGICAL AND GENETIC DATA THAT LIGATION OF TNFR2 ON BOTH NEURONS AND OLIGODENDROCYTES INDUCE REGENERATIVE RESPONSES, THROUGH IRE1-DEPENDENT MECHANISMS. BASED UPON THESE AND ADDITIONAL DATA OUR SECOND EXPERIMENTAL GOAL IS TO INVESTIGATE THE INTERSECTION BETWEEN TNFR2/IRE1 SIGNALING AND TO DETERMINE IF THE THERAPEUTIC EFFECTS OF TNFR2 ACTIVATION ARE DEPENDENT UPON IRE1 ACTIVATION. THESE GOALS WILL BE TESTED IN THE FOLLOWING AIMS: SPECIFIC AIM 1: INVESTIGATE THE SEX-SPECIFIC EFFECTS OF TMTNF/TNFR2 SIGNALING IN THE IMPROVEMENT OF MOTOR FUNCTION AND NEUROPATHOLOGY. A) WE WILL INVESTIGATE THE ROLE OF SEX HORMONES IN TMTNF/TNFR2 SIGNALING IN THE IMPROVEMENT OF MOTOR FUNCTION AND NEUROPATHOLOGY IN MALE AND FEMALE MICE. B) WE WILL INVESTIGATE THE ROLE OF SEX CHROMOSOMES IN TMTNF/TNFR2 SIGNALING IN THE IMPROVEMENT OF MOTOR FUNCTION AND NEUROPATHOLOGY IN MALE AND FEMALE MICE. SPECIFIC AIM 2: INVESTIGATE TNFR2 INDUCED ENDOGENOUS REPAIR MECHANISMS IN MALE AND FEMALE MICE. A) WE WILL INTERROGATE TNFR2 INDUCED ENDOGENOUS REPAIR MECHANISMS OLIGODENDROCYTES AND DETERMINE IF THEY ARE REQUIRED FOR MOTOR RECOVERY IN FEMALES. B) WE WILL INTERROGATE TNFR2 INDUCED ENDOGENOUS REPAIR MECHANISMS NEURONS AND DETERMINE IF THEY ARE REQUIRED FOR MOTOR RECOVERY IN FEMALES, IN VIVO AND IN VITRO.

EFFECTS OF STATE PREEMPTION OF LOCAL TOBACCO CONTROL LEGISLATION ON DISPARITIES IN TOBACCO USE, EXPOSURE AND RETAIL - PROJECT SUMMARY A KEY HEALTHY PEOPLE 2030 TOBACCO-USE OBJECTIVE IS TO ELIMINATE STATE PREEMPTION OF LOCAL TOBACCO CONTROL. HOWEVER, LITTLE PUBLISHED RESEARCH HAS RIGOROUSLY QUANTIFIED THE IMPACTS OF STATE PREEMPTION OF LOCAL TOBACCO CONTROL, PARTICULARLY: 1) ACROSS STATES AND OVER TIME; 2) ACROSS A BROAD RANGE OF TOBACCO CONTROL EFFORTS (E.G., RESTRICTIONS ON ADVERTISING, YOUTH ACCESS); 3) ACROSS A RANGE OF KEY OUTCOMES (E.G., YOUTH AND ADULT TOBACCO USE, SECONDHAND SMOKE EXPOSURE [SHSE], TOBACCO RETAIL); AND 4) WITH REGARD TO POTENTIAL DISPROPORTIONATE IMPACTS AMONG CERTAIN SUBGROUPS THAT FACE TOBACCO-RELATED DISPARITIES (E.G., RACIAL/ETHNIC MINORITIES, LOWER SOCIOECONOMIC STATUS [SES], THOSE IN RURAL SETTINGS). AS INITIAL EVIDENCE PROVIDING A BASIS FOR THIS PROPOSAL, OUR RWJF-FUNDED RESEARCH CONCLUDED THAT STATE SMOKE-FREE AIR PREEMPTION WAS ASSOCIATED WITH AN INCREASE IN ADULT SMOKING PREVALENCE AND AFFECT COUNTIES DIFFERENTLY. THIS PROPOSAL WILL BUILD ON THIS WORK AND ADVANCE THE LITERATURE BY FILLING THE AFOREMENTIONED GAPS IN THE EXISTING RESEARCH. THE LONG-TERM GOAL OF THIS RESEARCH IS TO INFORM POLICIES TO REDUCE TOBACCO USE AND RELATED HEALTH DISPARITIES, AS WELL AS TO INFORM POLICY EFFORTS MORE BROADLY, PARTICULARLY AS PUBLIC HEALTH ISSUES, LIKE FIREARM SAFETY, NUTRITION POLICIES, AND COVID-19 MITIGATION MEASURES, ARE INCREASINGLY SUBJECT TO STATE PREEMPTION. OUR OBJECTIVE IS TO ADVANCE OUR UNDERSTANDING OF WHETHER—AND TO WHAT EXTENT—ENACTMENT OR REPEAL OF STATE PREEMPTION ON LOCAL TOBACCO CONTROL IS ASSOCIATED WITH DISPARITIES IN TOBACCO USE, SHSE, AND RETAIL (SALES, RETAILER DENSITY). OUR CENTRAL HYPOTHESIS IS THAT STATE PREEMPTION RESULTS IN DISPROPORTIONATELY HIGH TOBACCO USE, SHSE, AND RETAIL IN COMMUNITIES WITH GREATER RACIAL/ETHNIC MINORITIES, OF LOWER SES, AND/OR IN RURAL SETTINGS. OUR RATIONALE IS THAT, BY PREEMPTING LOCAL TOBACCO CONTROL, STATE GOVERNMENTS DEPRIVE LOCALITIES OF A CRUCIAL TOOL FOR REDUCING THE BURDEN OF TOBACCO IN THEIR COMMUNITIES, POTENTIALLY WIDENING DISPARITIES. WE WILL ANALYZE NATIONAL DATA FROM 1999 TO 2021 TO EXAMINE THE IMPACTS OF ENACTMENT OR REPEAL OF STATE PREEMPTION OF 5 STATE TOBACCO PREEMPTION (I.E., SMOKE-FREE POLICY, ADVERTISING, LICENSURE, YOUTH ACCESS, AND TAXATION). OUR SPECIFIC AIMS ARE TO EXAMINE STATE PREEMPTION ON TOBACCO CONTROL IN RELATION TO CHANGES IN: 1) INDIVIDUAL-LEVEL TOBACCO USE (INCLUDING E-CIGS) IN ADOLESCENTS AND ADULTS AND NONSMOKERS' SHSE, AND POTENTIAL DISPROPORTIONATE IMPACTS AMONG CERTAIN SUBGROUPS OF INDIVIDUALS; AND 2) SALES OF TOBACCO PRODUCTS AND TOBACCO RETAIL DENSITY OVER TIME, AND POTENTIAL DISPROPORTIONATE IMPACTS AMONG COMMUNITIES REPRESENTING THOSE FACING TOBACCO-RELATED DISPARITIES. WE WILL EMPLOY MULTILEVEL MODELS AND CROSSWALK/MERGE (STATE/LOCAL LAWS, OUTCOMES, SOCIODEMOGRAPHICS) DATA FROM VARIOUS SOURCES AT DIFFERENT GEOGRAPHIC LEVELS. THIS STUDY WILL HAVE HIGH IMPACT, AS IT WILL: 1) ADD TO THE EVIDENCE BASE REGARDING STATE PREEMPTION IMPACT ON POPULATION OUTCOMES AND MECHANISMS OF IMPACT; 2) INFORM EFFORTS TO REDUCE TOBACCO USE AND RELATED DISPARITIES; AND 3) ENGAGE KEY TOBACCO CONTROL AND POLICY EXPERTS IN RESEARCH DISSEMINATION.

ENGLISH LANGUAGE ACQUISITION: NATIONAL PROFESSIONAL DEVELOPMENT PROGRAM

UNDERSTANDING LACTATE CATABOLISM BY BACH1 IN TRIPLE NEGATIVE BREAST CANCER - PROJECT SUMMARY PRIMARY METABOLIC PATHWAYS IN CANCER ARE USEFUL TARGETS FOR THERAPEUTIC INTERVENTION. HOWEVER, INTRATUMORAL HETEROGENEITY IN CANCER METABOLISM IS A MAJOR CHALLENGE FOR ANTI-CANCER THERAPY. REDUCING METABOLIC VARIANCE BY REPROGRAMMING CANCER METABOLISM IS ESSENTIAL TO ENHANCE EFFICACY OF INHIBITORS TARGETING METABOLISM. OUR LONG-TERM GOAL IS TO OVERCOME METABOLIC HETEROGENEITY THROUGH REPROGRAMMING METABOLIC NETWORKS TO INCREASE THE NUMBER OF CANCER CELLS VULNERABLE TO METABOLIC INHIBITORS. TO REACH THIS GOAL, OUR NOVEL STRATEGY IS TO REDUCE METABOLIC VARIANCE AMONG CANCER CELLS BY TARGETING BACH1, A MASTER REGULATOR OF METABOLISM-RELATED TRANSCRIPTION IN TRIPLE NEGATIVE BREAST CANCER (TNBC), TO OBTAIN MAXIMAL RESPONSE OF DRUGS TARGETING METABOLIC PATHWAYS. OUR PREVIOUS MOLECULAR AND METABOLOMIC PROFILING OF BREAST TUMORS REVEALED THAT BACH1 SUPPRESSES MITOCHONDRIAL METABOLISM. THUS, BACH1 DEPLETION MADE TNBC CELLS MORE SENSITIVE TO MITOCHONDRIAL INHIBITORS. THESE FINDINGS LED TO THE NOVEL CONCEPT THAT BACH1 DEPLETION INCREASES THE PROPORTION OF CANCER CELLS WITH HIGHER DEPENDENCY ON MITOCHONDRIAL RESPIRATION AND RESTRICTED TUMOR METABOLIC PLASTICITY. OUR PRELIMINARY STUDIES INDICATE THAT BACH1 ALSO SUPPRESSES LACTATE CATABOLISM, WHICH IS A PRIMARY PATHWAY FOR LACTATE OXIDATION IN MITOCHONDRIA OF CANCER CELLS. IN SUPPORT OF THIS FINDING, RECENT CLINICAL STUDIES SHOWED THAT LACTATE CATABOLISM DEPENDS ON LACTATE TRANSPORTER (MCT1). IN TNBC CELLS, BACH1 REPRESSES TRANSCRIPTION OF GENES THAT ENCODE ENZYMES INVOLVED IN LACTATE CATABOLISM, INCLUDING LACTATE TRANSPORTER (MCT1), LACTATE DEHYDROGENASE B (LDHB), AND MITOCHONDRIAL PYRUVATE CARRIERS. SPECIFICALLY, BACH1 DEPLETION SENSITIZED CANCER CELLS TO BLOCKADE OF MCT1 OR LDHB. BASED ON OUR PRELIMINARY DATA, WE HYPOTHESIZE THAT BACH1 IS THE KEY DETERMINANT OF WHETHER CANCER CELLS PRODUCE LACTATE OR CONSUME LACTATE. THE PRIMARY OBJECTIVE OF THIS PROPOSED STUDY IS TO LINK BACH1 CONTRIBUTION TO LACTATE CATABOLIC VARIANCE, AND TO BETTER UNDERSTAND REGULATION OF LACTATE OXIDATION IN TNBC. USING MULTIPLE INNOVATIVE APPROACHES, INCLUDING IN VITRO AND IN VIVO BREAST TUMOR MODELS AND A COMBINATION OF TRANSCRIPTOMICS AND METABOLOMICS, WE WILL INTERROGATE BACH1 REGULATION OF LACTATE CATABOLISM AND DEFINE THE UNDERLYING MOLECULAR REGULATORY MECHANISM IN BREAST CANCER CELLS. FURTHERMORE, USING PATIENT-DERIVED XENOGRAFT AND SYNGENEIC MOUSE MODELS, WE WILL INVESTIGATE WHETHER BACH1 INHIBITION (THROUGH THE REPURPOSED NON-TOXIC FDA-APPROVED DRUG, PANHEMATIN) INCREASES BREAST TUMOR VULNERABILITY TO DRUGS TARGETING THE LACTATE TRANSPORTER MCT1. BY COMBINING CELL BIOLOGY AND IN VIVO ASSAYS, THIS STUDY WILL PROVIDE COMPREHENSIVE INSIGHTS INTO HOW CANCER CELLS USE LACTATE AS A SUBSTRATE, WHETHER METABOLIC VARIANCES ARE REDUCED BY TARGETING BACH1, AND HOW TO ACHIEVE BETTER THERAPEUTIC STRATEGIES USING LACTATE CATABOLISM INHIBITORS.

BASIC/CORE AHEC PROGRAM