Georgetown University

GH19-1950 TRANSLATING DATA AND EVIDENCE INTO IMPACT (TIDE)

SUPPORT ESWATINI TO ACHIEVE SUSTAINED EPIDEMIC CONTROL

HIGHER EDUCATION SCHOLARSHIPS AND TRAINING FOR DEVELOPMENT , COOPERATIVE AGREEMENT

CANCER CENTER SUPPORT GRANT

GEORGETOWN-HOWARD UNIVERSITIES CENTER FOR CLINICAL AND TRANSLATIONAL SCIENCE (GHUCCTS)

AWARD CORP AGMT. TO GEORGETOWN UNIIVERSITY IN THE AMOUNT OF $5,212,794.00 IN SUPPORT OF GH/ FAM PROJECT

WASHINGTON METROPOLITAN WOMEN'S INTERAGENCY HIV STUDY

RESEARCH ON HLA TYPING TO SUPPORT MILITARY CONTINGENCY

FERTILITY AWARENESS FOR COMMUNITY TRANSFORMATION (FACT)

GH/PRH/RTU, PASSAGES

SURVIVING THE HIV EPIDEMIC (S/HE) IN METROPOLITAN WASHINGTON DC - ADVANCING KNOWLEDGE THROUGH COHORT STUDIES

GEORGETOWN UNIVERSITY IS HEREBY AWARDED $20.5 MILLION TO ADMINISTER THE FY 2021 ENGLISH LANGUAGE FELLOWS AND SPECIALISTS PROGRAM.

DESPITE EVIDENCE OF PROGRESS IN MEXICO, CENTRAL AMERICA AND THE CARIBBEAN, MUCH OF THIS REGION S POPULATION STILL LIVES IN POVERTY, NATURAL RESOURCES

GEORGETOWN-HOWARD UNIVERSITIES CENTER FOR CLINICAL AND TRANSLATIONAL SCIENCE (GHU

RESEARCH ON HLA TYPING TO SUPPORT MILITARY CONTINGENCY

GEORGETOWN UNIV. IS AWARDED A FEDERAL AWARD TO SUPPORT THE FY2022 ENGLISH LANGUAGE FELLOW, SPECIALIST, AND VIRTUAL EDUCATOR PROGRAM, INCLUDING RECRUITMENT AND PLACEMENT OF APPROXIMATELY 500 PROFESSIONALS.

GEORGETOWN UNIVERSITY IS HEREBY AWARDED $15.8 MILLION TO SUPPORT THE FY23 ENGLISH LANGUAGE FELLOW SPECIALIST AND VIRTUAL EDUCATOR PROGRAM.

SUSTAINING CAPACITY OF LOCAL ORGANIZATIONS TO REACH AND END HIV/AIDS PANDEMIC (SCORE)

CARES ACT IMPACT AT GEORGETOWN UNIVERSITY

GEORGETOWN UNIVERSITY IS HEREBY AWARDED $17,625,000 TO SUPPORT THE FY 2024 ENGLISH LANGUAGE FELLOW, SPECIALIST, AND VIRTUAL EDUCATOR PROGRAM.

OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION

PREP GAITHERSBURG

GEORGETOWN UNIVERSITY IS HEREBY AWARDED $15,900,000 TO SUPPORT FY 2020 ENGLISH LANGUAGE FELLOW AND SPECIALIST PROGRAM.

NATIONAL TECHNICAL ASSISTANCE CENTER FOR CHILD & ADOLESCENT MENTAL HEALTH

FY 2018 ENGLISH LANGUAGE FELLOW AND SPECIALIST PROGRAM

GEORGETOWN UNIVERSITY IS HEREBY AWARDED A COOPERATIVE AGREEMENT IN THE AMOUNT $10.000.000 TO SUPPORT THE EL PROGRAM.

GEORGETOWN-HOWARD UNIVERSITIES CENTER FOR CLINICAL AND TRANSLATIONAL SCIENCE (GHU

CARE ACT IMPACT ON GEORGETOWN UNIVERSITY

DISCOVERY AND VALIDATION OF PERIPHERAL BIOMARKERS OF TRAUMATIC BRAIN INJURY

ENGLISH LANGUAGE FELLOW AND SPECIALIST PROGRAM

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 BOULDER 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 NOT INTEND TO SUBAWARD FUNDS.

NATIONAL TRAINING AND TECHNICAL ASSISTANCE

FY 2016 ENGLISH LANGUAGE FELLOW AND SPECIALIST PROGRAM

CONSIDERING THE HIGH SPONTANEOUS INCIDENCE OF GASTROINTESTINAL (GI) CANCER AND HIGHER INCIDENCE OF PREMALIGNANT COLONIC POLYPS AN EVEN MODEST INCREASE BY SPACE RADIATION EXPOSURE COULD HAVE A SIGNIFICANT EFFECT ON ASTRONAUTS HEALTH RISK ESTIMATES DURING AND AFTER LONG-DURATION MANNED SPACE FLIGHTS. HOWEVER THERE IS SUBSTANTIAL UNCERTAINTY FOR GI CANCER RISK ESTIMATION FROM SPACE RADIATION DUE TO THE LACK OF IN VIVO HUMAN DATA. THIS PROPOSAL ADDRESSES THE CATEGORY IN THE CURRENT SOLICITATION INVOLVING `NEW APPROACHES TOWARDS `MECHANISTIC UNDERSTANDING OF GI CANCER RISK USING `NEW BIOLOGICAL MODELS FOR `STUDIES OF RADIATION QUALITY AND DOSE-RATE EFFECTS IN RELATION TO `INDIVIDUAL RADIATION SENSITIVITY . THE OVERARCHING GOAL OF THE CURRENT PROPOSAL IS TO SPECIFICALLY INVESTIGATE CELLULAR AND MOLECULAR HYPOTHESIS DRIVEN MECHANISMS IN RELEVANT MOUSE MODELS THAT WILL CONTRIBUTE TO CARCINOGENIC RISK ESTIMATES OF GI CANCER AFTER EXPOSURE TO SPACE RADIATION BEAMS PRIORITIZED IN THE CURRENT SOLICITATION. WE HAVE CHOSEN HIGH PRIORITY HZE BEAMS. SINCE MAXIMAL EFFECTS HAVE ALREADY BEEN SEEN WITH 28SI IONS THIS WILL BE A PRIORITY AND WE WILL EXTEND TO LOWER Z AT SIMILAR ENERGY USING 16O AND 4HE IONS. HAVING FOUND MODEST EFFECTS IN SOME STUDIES WITH PROTONS AND CONSIDERING THE IMPORTANCE OF ASSESSING THE EFFECTS OF MIXED BEAMS WE WILL TAKE ADVANTAGE OF THE AVAILABILITY OF THE SEQUENTIAL FIELD PROTON/56FE (0.2/150 KEV/M) BEAM TO START TO REPRESENT THE MIXED PARTICLE RADIATION IN SPACE. WE WILL CONSULT WITH NASA ON BEAM PRIORITIZATION AND CONSIDER THE GCR SIMULATOR AS THE STUDY PROGRESSES. SPECIFICALLY THIS PROPOSAL SEEKS TO DETERMINE INCIDENCE AND GRADE AS WELL AS IDENTIFY MOLECULAR PERTURBATIONS AND TARGET CELLS ASSOCIATED WITH INTESTINAL AND GASTRIC (STOMACH) TUMORS THROUGH MONITORING OF CHANGES IN THE TUMOR NUMBER HISTOLOGY GENE EXPRESSION METABOLOME AND IN THE GENOME OF THE PROPOSED MODEL SYSTEM AFTER EXPOSURE TO THESE SPACE-RADIATION BEAMS. WE ARE PROPOSING FOUR COMPLEMENTARY AIMS (AND PROJECTS) THAT WILL HAVE A COMMON OBJECTIVE TO DEVELOP A MORE RELIABLE GI CANCER RISK PREDICTION MODEL. 1] QUANTITATIVELY ASSESS GI TUMORIGENESIS IN MOUSE MODELS OF GI CANCER AND COLLECT SAMPLES FOR QUALITATIVE ANALYSIS (PROJECT 1) 2] DISSECTION OF THE SIGNALING EVENTS AND CONSEQUENCES IN GASTROINTESTINAL CELLS OF THE PERSISTENT EFFECTS OF SPACE RADIATION (PROJECT 2) 3] CHARACTERIZATION OF RADIATION-INDUCED NEOPLASTIC EVENTS IN NORMAL DIPLOID HUMAN COLONOCYTES (PROJECT 3) 4] DEVELOPMENT OF SYSTEMS BIOLOGY (PROJECT 4A) AND MATHEMATICAL MODELING (PROJECT 4B) APPROACHES FOR GI CANCER RISK ASSESSMENT.

FY2015 ENGLISH LANGUAGE (EL) FELLOW AND SPECIALIST PROGRAM

FY2014 ENGLISH LANGUAGE (EL) FELLOW AND SPECIALIST PROGRAM

ENGLISH LANGUAGE FELLOWS AND SPECIALIST PROGRAM

RESEARCH ON HLA TYPING TO SUPPORT MILITARY CONTINGENCY

ENGLISH LANGUAGE FELLOW PROGRAM

LEADERSHIP EXCHANGE AND CIVIL SOCIETY DEVELOPMENT PROGRAM FOR UNIVERSITY STUDENTS FROM THE MIDDLE EAST AND NORTH AFRICA.

RESEARCH ON HLA TYPING TO SUPPORT MILITARY CONTINGENCY

RESEARCH ON HLA TYPING TO SUPPORT MILITARY CONTINGENCY

COMPARATIVE MODELING: INFORMING BREAST CANCER CONTROL PRACTICE AND POLICY

ENGLISH LANGUAGE FELLOW PROGRAM

RESEARCH ON HLA TYPING TO SUPPORT MILITARY CONTINGENCY

2012-2013 ENGLISH LANGUAGE FELLOW PROGRAM

RESEARCH ON HLA TYPING TO SUPPORT MILITARY CONTINGENCY

RESEARCH ON HLA TYPING TO SUPPORT MILITARY CONTINGENCY

STROKE DISPARITIES PROGRAM

NATIONAL CENTER OF EXCELLENCE FOR INFANT AND CHILDHOOD MENTAL HEALTH CONSULTATION

TRAINING GRANT IN TUMOR BIOLOGY

BUILDING LOCAL ORGANIZATIONS AND STRUCTURES TO OVERCOME HIV/TB/GBVAND MAINTAIN EPIDEMIC CONTROL - ESWATINI’S ACHIEVEMENT IN 2020 OF THE UNAIDS 95-95-95 FAST-TRACK TARGETS FOR HIV EPIDEMIC CONTROL (HEC) IS REMARKABLE, BUT INEQUALITIES IN HIV RISK AND RESPONSE REMAIN. WHILE BOTH FACILITY-BASED HEALTH PROGRAMS AND COMMUNITY-BASED SERVICES HAVE BEEN INSTRUMENTAL IN TACKLING HIV AND TB, SUSTAINING HIV AND TB CONTROL REQUIRES A STRONGER FOCUS ON COMPREHENSIVE, PERSON-CENTERED COMMUNITY-BASED SERVICES, TARGETING THE SUBPOPULATIONS MOST AT RISK OF HIV, TB AND GBV, BUILDING ON EXISTING SUCCESSES AND LOCAL STRUCTURES. GEORGETOWN UNIVERSITY (GU), THROUGH ITS CENTER FOR GLOBAL HEALTH PRACTICE AND IMPACT, AND ITS PARTNERS, PACT INC, SWAZILAND NETWORK OF YOUNG POSITIVES (SNYP+), COMPASSIONATE SWAZILAND, CABRINI MINISTRIES AND THE MINISTRY OF HEALTH (MOH) RURAL HEALTH MOTIVATOR (RHM) PROGRAM, SUBMIT THIS APPLICATION IN RESPONSE TO CDC-RFA-GH22-2222 “COMPREHENSIVE COMMUNITY-BASED PROGRAMMING TO MAINTAIN HIV EPIDEMIC CONTROL IN ESWATINI UNDER THE PRESIDENT’S EMERGENCY PLAN FOR AIDS RELIEF”(PEPFAR).THROUGH THE PROJECT ENTITLED BLOSSOM – BUILDING LOCAL ORGANIZATIONS AND STRUCTURES TO OVERCOME HIV/TB/GBV AND MAINTAIN EPIDEMIC CONTROL, WE WILL SUPPORT ESWATINI IN MAINTAINING HEC AND ACHIEVING TB EPIDEMIC CONTROL IN MANZINI AND LUBOMBO REGIONS, BY: 1) ESTABLISHING OR EXTENDING RESILIENT, DIFFERENTIATED AND SUSTAINABLE COMMUNITY-BASED SERVICES FOR PREVENTION, DIAGNOSIS, TREATMENT AND CARE OF HIV AND TB, ESPECIALLY FOR THE MOST VULNERABLE AND HARD-TO-REACH POPULATIONS ACROSS THE CASCADE, IN WAYS THAT BOTH SERVE THEIR NEEDS, 2) BUILDING AN INTERFACE BETWEEN HEALTH FACILITIES AND THE COMMUNITY TO ENSURE SEAMLESS SERVICE ACCESS AND DELIVERY, 3) BUILDING THE CAPACITY OF COMMUNITY- AND FAITH-BASED ORGANIZATIONS TO IMPLEMENT AND MONITOR PROGRAMS THAT CAN BE USED TO ADDRESS EMERGING PUBLIC HEALTH THREATS, AND 4) SUPPORTING THE COMMUNITY SYSTEMS STRENGTHENING INITIATIVES OF THE MINISTRY OF HEALTH, PARTICULARLY WITH THE GOVERNMENT COMMUNITY HEALTH VOLUNTEER PROGRAM (RURAL HEALTH MOTIVATORS [RHM] PROGRAM) TO DELIVER INTEGRATED SERVICES INCLUDING HIV & TB. BLOSSOM WILL BUILD ON THE SUCCESSES OF THE SCORE PROGRAM TO CONSOLIDATE GAINS & OVERCOME REMAINING GAPS TO ACHIEVE SUSTAINED HIV & TB EPIDEMIC CONTROL AND REDUCE GBV THROUGHOUT LUBOMBO AND MANZINI REGIONS. BLOSSOM WILL ENHANCE PROGRAMMATIC REACH & DEPTH BY LEVERAGING GU’S EXPERIENCE DELIVERING COMPREHENSIVE, HIGH-QUALITY, FACILITY-BASED HIV SERVICES, DATA SCIENCE FOR PRECISION SERVICE DELIVERY LINKED TO QUALITY IMPROVEMENT, AND HUMAN-CENTERED DESIGN EXPERTISE; ALONG WITH PACT’S EXPERTISE IN DELIVERING COMMUNITY-BASED SERVICES TO ORPHANS & VULNERABLE CHILDREN, ADOLESCENT GIRLS AND YOUNG WOMEN, IMPLEMENTING DETERMINED, RESILIENT, EMPOWERED, AIDS-FREE, MENTORED AND SAFE (DREAMS) INTERVENTIONS, AND BUILDING ORGANIZATIONAL CAPACITY. LEVERAGING GU’S DEMONSTRATED CAPACITY TO ENGAGE WITH THE GOVERNMENT AND THE MOH, WE WILL SUPPORT COMMUNITY HEALTH SYSTEMS STRENGTHENING THROUGH THE RHM PROGRAM AND LOCAL COMMUNITY-BASED ORGANIZATIONS. OUR APPROACH WILL BE BOLSTERED BY SIX CROSS-CUTTING PRINCIPLES: 1) PERSON-CENTERED SERVICES INFORMED BY HUMAN-CENTERED DESIGN; 2) EVIDENCE-INFORMED PRECISION PROGRAMMING; 3) COMMUNITY-FACILITY INTEGRATED CARE NETWORK; 4) CONTINUAL QUALITY IMPROVEMENT INTEGRATED WITH COMMUNITY-LED MONITORING; 5) CAPACITY- AND RESILIENCE-BUILDING OF LOCAL ORGANIZATIONS; 6) DESIGN ANCHORED WITHIN MOH STRATEGIES. OUR ESTABLISHED PRESENCE AND EXISTING RELATIONSHIPS IN FACILITIES AND COMMUNITIES WILL ENABLE RAPID STARTUP, AND OUR COMPLEMENTARY TECHNICAL AND ORGANIZATIONAL COMPETENCIES WILL BE APPLIED TO ENSURE A SEAMLESS SERVICE CONTINUUM BETWEEN HEALTH FACILITIES AND THE COMMUNITY, USING EXPERT FACILITY-TO-COMMUNITY TEAMS, ESTABLISHING BI-DIRECTIONAL REFERRAL SYSTEMS, AND IMPROVING COVERAGE AND USE OF ELECTRONIC RECORD-KEEPING IN THE COMMUNITY. OUR COMPREHENSIVE, PERSON-CENTERED, COMMUNITY-BASED SERVICES LINK

MOLECULAR EPIDEMIOLOGY AND MECHANISMS FOR BREAST CARCINOGENESIS: ALCOHOL DRINKING AS A PARADIGM

COMPARATIVE MODELING: INFORMING BREAST CANCER CONTROL PRACTICE & POLICY

GEORGETOWN-HOWARD UNIVERSITIES CENTER FOR CLINICAL AND TRANSLATIONAL SCIENCE (GHUCCTS)

OLDER BREAST CANCER PATIENTS: RISK FOR COGNITIVE DECLINE

ENGLISH LANGUAGE FOLLOW PROGRAM

RESEARCH ON HLA TYPING TO SUPPORT MILITARY CONTINGENCY

PRH/RTU-SSR OBJECTIVE 4 - GU/IRH

RESEARCH ON HLA TYPING TO SUPPORT MILITARY CONTINGENCY

RESEARCH ON HLA TYPING TO SUPPORT MILITARY CONTINGENCY

NATIONAL TRAINING AND TECHNICAL ASSISTANCE CENTER FOR CHILD AND ADOLESCENT MENTAL HEALTH

THE INSTITUTE FOR SOFT MATTER SYNTHESIS AND METROLOGY AT GEORGETOWN UNIVERSITY

RESEARCH ON HLA TYPING TO SUPPORT MILITARY CONTINGENCY

INTEGRATION OF ER-RELATED SIGNALING IN BREAST CANCER

REHABILITATION AND PROPHYLAXIS OF ANOMIA IN PRIMARY PROGRESSIVE APHASIA

ROLE OF PROBDNF AND P75NTR IN HIV-MEDIATED AXONAL/DENDRITIC DEGENERATION

THE FUNCTION OF ANTIMALARIAL DRUG RESISTANCE PROTEINS

ENGLISH LANGUAGE FELLOWS PROGRAM

PRH/RTU-SSR OBJECTIVE 2 - GU/IRH

ORAL HEALTH

BIO-BEHAVIORAL RESEARCH AT THE INTERSECTION OF CANCER AND AGING

A RANDOMIZED, DOUBLE BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE IMPACT OF NILOTINIB TREATMENT ON SAFETY, TOLERABILITY, PHARMACOKINETICS AND BIOMARKERS IN DEMENTIA WITH LEWY BODIES (DLB)

RESEARCH ON HLA TYPING TO SUPPORT MILITARY CONTINGENCY

CENTER OF EXCELLENCE FOR HEALTH DISPARTIES IN THE NATION'S CAPITAL

MCH ADVANCED EDUCATION POLICY

CISS: CENTER FOR MATERNAL AND CHILD HEALTH

VALIDATION OF PROMIS IN DIVERSE CANCER POPULATIONS

NATIONAL CAPITAL AREA (NCA) MINORITY/UNDERSERVED NCORP

CYBERCORPS SCHOLARSHIP FOR SERVICE (RENEWAL): PREPARING CROSS-DISCIPLINARY CYBERSECURITY AND POLICY PROFESSIONALS -THIS RENEWAL CONTINUES THE CYBERCORPS? SCHOLARSHIP FOR SERVICE (SFS) PROJECT AT GEORGETOWN UNIVERSITY. THE FUNDING WILL SUPPORT APPROXIMATELY 33 STUDENTS WHO WORK IN TECHNOLOGY OR POLICY OR AT THE INTERSECTION OF THE TWO AREAS. STUDENTS WILL BE DRAWN FROM VARIOUS DEGREE PROGRAMS AT GEORGETOWN, INCLUDING COMPUTER SCIENCE, SECURITY STUDENTS, AND CYBERSECURITY RISK MANAGEMENT. THE PROJECT AIMS TO RECRUIT STUDENTS WHO WOULD OTHERWISE WORK IN THE PRIVATE SECTOR INTO FEDERAL GOVERNMENT POSITIONS THAT REQUIRE A HIGH LEVEL OF ANALYTICAL THINKING AND DECISION MAKING. THESE ROLES ARE ESSENTIAL FOR OVERSIGHT, RESEARCH, ANALYSIS, AND PLANNING. THE PROJECT TEAM WILL CONTINUE TO BUILD OFF PRIOR SUCCESS IN ATTRACTING STUDENTS TO GOVERNMENT SERVICE WHO ARE FROM GROUPS THAT ARE UNDERREPRESENTED IN THE CYBERSECURITY FIELD. FOR EXAMPLE, MORE THAN HALF OF THE STUDENT COHORTS TO DATE HAVE BEEN FEMALE. IN ADDITION, THE PRINCIPAL INVESTIGATORS HAVE ATTRACTED APPLICATIONS FROM HIGH SCHOOL STUDENTS WHO ARE MEMBERS OF GROUPS WHOSE PARTICIPATION IN THE FIELD LAGS BEHIND THEIR PROPORTION IN THE OVERALL POPULATION, BY DEVELOPING AND OFFERING A STEM TRACK FOR STUDENTS IN GEORGETOWN?S SUMMER COLLEGE IMMERSION PROGRAM (SCIP) AND FUNDING PARTICIPANT SUPPORT. SCIP IS A THREE-WEEK COLLEGE PREPARATION PROGRAM DESIGNED FOR RISING HIGH SCHOOL SENIORS FROM THE CRISTO REY NETWORK AND KIPP FOUNDATION SCHOOL SYSTEMS WHICH PREDOMINATELY SERVE UNDERPRIVILEGED COMMUNITIES. STUDENTS COMPLEMENT THEIR HIGH-QUALITY EDUCATION WITH APPLIED EXPERIENCES IN THE WASHINGTON DC AREA IN THE GEORGETOWN SFS PROJECT. STUDENTS PARTICIPATE IN INTERNSHIPS AT GOVERNMENT AGENCIES AND MEET WITH CYBERSECURITY AND GOVERNMENTAL LEADERS AT LOCAL EVENTS. THE PROJECT'S ACTIVITIES ALSO INCLUDE SIGNIFICANT PEER-MENTORING, HELPING TO FORM CROSS-AGENCY PROFESSIONAL NETWORKS. STUDENTS BENEFIT FROM WORKING WITH FACULTY WHO HAVE EXPERTISE IN CYBERSECURITY THAT SPANS DEEP TECHNICAL AREAS RANGING FROM ARTIFICIAL INTELLIGENCE TO LEGAL AND POLICY ISSUES SURROUNDING CYBER OPERATIONS AND PERSONAL PRIVACY. THE PROJECT ALSO EXPANDS AWARENESS OF GOVERNMENTAL POSITIONS FOR ALL GEORGETOWN STUDENTS BY WORKING WITH THE CAWLEY CAREER CENTER TO BRING IN GOVERNMENTAL SPEAKERS AND RECRUITERS. THESE COMBINED EFFORTS WILL HELP CREATE A GENERATION OF POLICYMAKERS AND MANAGERS WHO CAN HELP DEVELOP AND EXPAND THE NATION?S CYBERSECURITY CHALLENGES BY EDUCATING CROSS-DISCIPLINARY CYBERSECURITY LEADERS. 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.

HOW DO WE CONTEND WITH THE TRULY ALIEN? MOST STRATEGIES FOR BIOSIGNATURE DETECTION RELY UPON FINDING FEATURES KNOWN TO BE ASSOCIATED WITH TERRESTRIAL LIFE SUCH AS PARTICULAR CLASSES OF MOLECULES BUT LIFE MAY BE VASTLY DIFFERENT ON OTHER WORLDS. THIS WORK WILL FURTHER DEVELOP SEVERAL TRULY AGNOSTIC APPROACHES NONE OF WHICH PRESUPPOSE A PARTICULAR MOLECULAR FRAMEWORK. SOME OF THESE AREAS WILL INVOLVE NEW LINES OF INQUIRY THAT CAN BE ACCOMPLISHED USING INSTRUMENTATION THAT IS EITHER HIGH HERITAGE OR ON A PATH TOWARD HIGH TRL. OTHERS WILL NECESSITATE THE DESIGN OF COMPLETELY NEW ANALYTICAL TECHNIQUES. OUR NAI WILL NOT ONLY ADVANCE EACH OF THESE AGNOSTIC DETECTION CONCEPTS SEPARATELY BUT ALSO JOIN THESE TRADITIONALLY FRAGMENTED EFFORTS IN A UNIFIED RESEARCH PROGRAM ONE THAT DRAWS LESSONS FROM OUR OPERATIONAL EXPERIENCES IN PLANETARY EXPLORATION THUS FAR. WE WILL BRING TOGETHER THEORETICIANS AND EXPERIMENTALISTS AS AN INCUBATOR FOR NEW AGNOSTIC LIFE DETECTION APPROACHES CREATE A COMMON TRAINING SET OF BIOTIC AND ABIOTIC TEST SUBSTRATES ESTABLISH LIKELIHOODS AND THRESHOLDS WITH PROBABILISTIC MODELS AND DEVELOP A BROADER FORMULATION OF THE LADDER OF LIFE. IN THE PROCESS WE WILL MERGE THE BROAD AND NARROW ENDS OF THE LIFE DETECTION SPECTRUM INTO A COLLECTIVE DIALOGUE ONE THAT WILL HELP US SYNTHESIZE PRIORITIZE EVALUATE AND STRENGTHEN THE SEARCH FOR LIFE ON FUTURE SPACE MISSIONS.

CYBERSECURITY FELLOWS: THE SCHOLARSHIP FOR SERVICE PROGRAM AT GEORGETOWN UNIVERSITY

RESEARCH ON HLA TYPING TO SUPPORT MILITARY CONTINGENCY

OPTIMIZED COMBINATION ANTIMALARIAL DRUG THERAPY

GEORGETOWN-HOWARD UNIVERSITIES CENTER FOR CLINICAL AND TRANSLATIONAL SCIENCE (GHUCCTS)

ORAL HEALTH.

VISUAL STATISTICAL LEARNING IN HUMAN INFANTS

MECHANICAL SYSTEMS RENOVATION

SENSORY-MOTOR INTEGRATION IN THE AUDITORY DORSAL STREAM

GEORGETOWN UNIVERSITY/ALBERT FORNACE SPACE RADIATION AND INTESTINAL TUMORIGENESIS: RISK ASSESMENT A

INTERDISCIPLINARY PREDOCTORAL PROGRAM IN NEUROSCIENCE

GENERAL CLINICAL RESEARCH CENTER

MECHANISMS OF NUCLEAR AND CELL FUSION IN YEAST

MEPI STUDENT LEADERS

CELLULAR AND MOLECULAR MECHANISMS OF COCHLEAR INNERVATION

YK-4-279 SPECIFICALLY TARGETS ETS FAMILY FUSION-PROTEIN CANCERS IN CLINICAL TRIAL

NOVEL LIGANDS THAT SELECTIVELY DESENSITIZE ALPHA4BETA NACHRS FOR SMOKING CESSATIO

TRANSLATING DATA AND EVIDENCE INTO IMPACT PLUS (TIDE+) - GEORGETOWN UNIVERSITY CENTER FOR GLOBAL HEALTH PRACTICE AND IMPACT (GU), ALONG WITH 12 HAITIAN INDIGENOUS PARTNERS, SUBMITS THIS APPLICATION IN RESPONSE TO CDC-RFA-GH-24-0075: TARGETED SUPPORT FOR IMPROVING HIV TREATMENT CONTINUITY, ENSURING AVAILABILITY OF ALTERNATE SECURE HIV DRUG DELIVERY POINTS AND SERVICES, AND BUILDING CAPACITY OF COMMUNITIES IN HAITI UNDER PEPFAR.” OUR PROPOSED PROJECT ‘TRANSLATING DATA AND EVIDENCE INTO IMPACT – PLUS (TIDE+)’ BUILDS ON TIDE, IMPLEMENTED BY GU FROM 2020 – 2024. UPON COMPLETION, TIDE+ WILL HAVE SIGNIFICANTLY IMPROVED NOT ONLY TREATMENT CONTINUITY, BUT ALSO COMMUNITY PARTNERS’ INVOLVEMENT AND LEADERSHIP; SUSTAINABILITY OF THE HIV RESPONSE; AND HEALTH SERVICES AND OUTCOMES FOR PLHIV, AND WILL HAVE SUCCESSFULLY TRANSITIONED ALL ASPECTS OF THE PROGRAM TO LOCAL PARTNERS. TIDE+ BUILDS ON TIDE WITH 3 PROJECTS IN ALL 10 DEPARTMENTS OF HAITI: PROJECT 1- DIFFERENTIATED SERVICE DELIVERY MODELS/DSDM; PROJECT 2- PEER ENGAGEMENT AND COMMUNITY CAPACITATION/PEACC; AND PROJECT 3- TREATMENT RETENTION AND ENGAGEMENT TO RETURN/TREAT. COLLECTIVELY, THESE PROJECTS WILL: INCREASE AVAILABILITY OF DSDMS INCLUDING ALTERNATE, SECURE HIV DRUG DELIVERY POINTS AND SERVICES WITHIN COMMUNITIES; PREVENT TREATMENT INTERRUPTION AND RETURN PATIENTS TO CARE WHO INTERRUPT TREATMENT, INCLUDING THOSE LOST TO FOLLOW UP; TRAIN, PROFESSIONALIZE, AND EMPOWER PEER GROUPS OF PEOPLE LIVING WITH HIV AIDS (PLHIV), PLHIV ASSOCIATIONS, AND OTHER KEY POPULATION AND COMMUNITY-BASED ORGANIZATIONS (CBOS) TO PARTICIPATE MORE EFFECTIVELY IN HIV RESPONSE; AND IMPROVE THE OVERALL EXPERIENCE OF PLHIV WITHIN HIV CARE SERVICES. TIDE+ WILL ALSO ENHANCE THE USE OF STRATEGIC INFORMATION TO GENERATE EVIDENCE FOR INTERVENTIONS. THE TIDE+ TEAM BRINGS A COMPLEMENTARY MIX OF SKILLS: GU’S GLOBAL AND TIDE EXPERIENCE IMPLEMENTING HIV PROGRAMS, STRONG LOCAL EXPERTISE AND EXPERIENCE THROUGH PARTNERS AND STAKEHOLDERS INVOLVED IN THE HIV RESPONSE- PUBLIC AGENCIES: UNIVERSITÉ D'ÉTAT D'HAÏTI; TECHNOLOGY PARTNERS: SOLUTIONS S.A., PROMOTEURS OBJECTIF ZEROSIDA; KEY POPULATION ORGANIZATIONS: ORGANISATION ARC-EN-CIEL D'HAITI; PRIVATE SECTOR PARTNERS: ALLIANCE POUR LA GESTION DES RISQUES ET LA CONTINUITÉ DES ACTIVITÉS; ASSOCIATIONS OF PLHIV: FÉDÉRATION HAÏTIENNE DES ASSOCIATIONS DE PVVIH, ASSOCIATION DES FEMMES HAITIENNES INFECTÉES ET AFFECTÉES PAR LE VIH, ASSOCIATION DE SOLIDARITÉ NATIONALE AUX PERSONNES VIVANT AVEC LE SIDA, GRANDE IMPLICATION DES PERSONNES AFFECTÉES ET INFECTÉES PAR LE VIH/SIDA, FONDATION ESTHER BOUCICAULT STANISLAS; FAITH BASED ORGANIZATIONS: KAY MANMAN NOU, EGLISE DE LA COMMUNAUTE EVANGELIQUE. TIDE+ WILL COLLABORATE WITH THE HAITI MINISTRY OF HEALTH AND POPULATION AND KEY TECHNICAL DIVISIONS (NATIONAL AIDS CONTROL PROGRAM, NATIONAL PUBLIC HEALTH LABORATORY, AND NATIONAL TUBERCULOSIS PROGRAM), DEPARTMENTAL HEALTH DIRECTORATES, CDC/PEPFAR, USAID, TREATMENT FACILITIES, OTHER COMMUNITY PARTNERS, THE PRIVATE SECTOR, AND KEY HIV RESPONSE STAKEHOLDERS LIKE THE GLOBAL FUND TO FIGHT AIDS, TUBERCULOSIS, AND MALARIA. WITH EXTENSIVE IN-COUNTRY PRESENCE AND UNDERSTANDING OF THE LOCAL CONTEXT, TIDE+ WILL APPLY PROVEN AND INNOVATIVE INTERVENTIONS TO ACHIEVE ALL PROJECT GOALS AND OBJECTIVES. IT WILL DELIVER ON MSPP, CDC, AND PEPFAR/GLOBAL HEALTH SECURITY AND DIPLOMACY BUREAU GOALS AND PRIORITIES FOR ACHIEVING AND SUSTAINING HIV EPIDEMIC CONTROL IN HAITI. A ROBUST EVALUATION AND PERFORMANCE MEASUREMENT PLAN WILL TRACK AND ENSURE ACHIEVEMENT OF ALL STATED GOALS AND OBJECTIVES, AND ENSURE FULL DISSEMINATION OF RESULTS, KNOWLEDGE GAINED, AND EVIDENCE GENERATED TO STAKEHOLDERS. TIDE+ INCLUDES A TRANSITION TO SUSTAINABILITY STRATEGY TO ENSURE THAT AT PROJECT END, ALL ASPECTS OF TIDE+ ARE FULLY OWNED AND LED BY LOCAL PARTNERS OPERATING WITHIN A WELL-DEVELOPED ECOSYSTEM OF PUBLIC, PRIVATE, AND COMMUNITY-BASED STAKEHOLDERS MAINTAINING TREATMENT CONTINUITY AND HIV RESPONSE GAINS, AND SUSTAINS HIV EPIDEMIC CONTROL.

ROLE OF ESTROGEN RELATED RECEPTORS IN AGE RELATED KIDNEY DISEASE - THE PROPOSED STUDIES WILL TEST THE HYPOTHESIS THAT MITOCHONDRIAL DYSFUNCTION AND INCREASED INFLAMMATION MEDIATES AGE-RELATED KIDNEY DISEASE. WE PROPOSE THAT INCREASED EXPRESSION OF ESTROGEN RELATED RECEPTORS ERRA AND ERR IMPROVES MITOCHONDRIAL FUNCTION, AND DECREASES CGAS-STING SIGNALING, CELLULAR SENESCENCE AND INFLAMMATION, WHICH REVERSES AGE-RELATED KIDNEY DISEASE. IN ADDITION, THE EFFECTS OF ERRS ON SENESCENCE, INFLAMMATION, AND FIBROSIS ARE CGAS-STING DEPENDENT. FURTHERMORE, INCREASED EXPRESSION OF ERRA AND ERR OR INHIBITION OF CGAS-STING SIGNALING PREVENTS ACUTE KIDNEY INJURY MEDIATED BY FOLIC ACID, LPS, OR ISCHEMIA/REPERFUSION IN SPECIFIC AIM 1 WE WILL TEST THE HYPOTHESIS THAT INCREASED RENAL TUBULAR ERRA OR ERR WILL IMPROVE MITOCHONDRIAL FUNCTION AND INFLAMMATION AND REVERSE AGE-RELATED KIDNEY DISEASE. WE WILL DETERMINE: A) THE EFFECTS OF RENAL TUBULAR ERRA OR ERR OR SIMULTANEOUS ERRA/ERR INCREASED EXPRESSION ON KIDNEY MITOCHONDRIAL FUNCTION, INFLAMMATION AND KIDNEY DISEASE; B) IF RENAL TUBULAR INCREASES IN ERRS PREVENTS ACUTE KIDNEY INJURY MEDIATED BY A) FOLIC ACID, B) LPS, OR C) ISCHEMIA/REPERFUSION. THE RATIONALE FOR THESE STUDIES IS THAT ALL THREE MODELS RESULT IN DECREASED ERRA AND ERR EXPRESSION IN THE KIDNEYS; C) DIRECT EFFECTS OF INCREASED EXPRESSION OF ERRA, ERR, OR SIMULTANEOUS ERRA AND ERR IN HUMAN PROXIMAL TUBULAR CELLS. IN SPECIFIC AIM 2 WE WILL TEST THE HYPOTHESIS THAT THE EFFECTS OF ERRA OR ERR TO REVERSE INFLAMMATION AND KIDNEY DISEASE IN AGING ARE MEDIATED VIA A CGAS-STING DEPENDENT MECHANISM. WE WILL DETERMINE THE ROLES OF A) CGAS: GENERALIZED OR KIDNEY SPECIFIC CGAS KNOCKOUT MICE TREATED WITH ERR; B) STING: GENERALIZED OR KIDNEY SPECIFIC STING KNOCKOUT MICE TREATED WITH ERR; C) WE WILL DETERMINE IF TREATMENT OF MICE WITH STING INHIBITOR PREVENTS ACUTE KIDNEY INJURY MEDIATED BY A) FOLIC ACID, B) LPS, OR C) ISCHEMIA/REPERFUSION. THE RATIONALE FOR THESE STUDIES IS THAT ALL THREE MODELS RESULT IN INCREASED CGAS-STING EXPRESSION IN THE KIDNEYS. INNOVATION: 1) THESE STUDIES WILL DETERMINE IF INDUCIBLE INCREASED EXPRESSION OF ERR-A AND ERR- IN THE RENAL TUBULES WILL IMPROVE MITOCHONDRIAL DYSFUNCTION, CGAS-STING MEDIATED INFLAMMATION AND AGE-RELATED KIDNEY DISEASE. 2) WHILE THE EFFECTS OF ERRS IN REGULATION OF MITOCHONDRIAL FUNCTION HAS BEEN STUDIED, MAINLY IN OTHER TARGET ORGANS, THE EFFECTS OF ERRS IN REGULATION OF INFLAMMATION IS NOVEL AND HAS NOT BEEN STUDIED IN THE KIDNEY. TO THIS END WE WILL PERFORM MECHANISTIC STUDIES TO DETERMINE THE ROLE OF CGAS-STING IN REGULATING INFLAMMATION AND THE EFFECTS OF ERR IN THE KIDNEY.

OPTOGENETIC CONTROL OF SEIZURES VIA THE BASAL GANGLIA

GLYCANS IN HEPATOCELLULAR CARCINOMA

MCH LIBRARY SERVICES

IMPACT OF ENVIRONMENTAL METAL/METALLOID EXPOSURES ON MAMMOGRAPHIC BREAST DENSITY, A MARKER OF BREAST CANCER

CONTRIBUTIONS OF SPARED BRAIN STRUCTURES AND CONNECTIONS TO APHASIA RECOVERY

AREA HEALTH EDUCATION CENTERS (AHEC) PROGRAM

SPECIAL PROJECTS OF NATIONAL SIGNIFICANCE

A NOVEL MONKEY MODEL FOR PARKINSON'S DRUG DISCOVERY

INTERNATIONAL LABOR MIGRATION, ARMED CONFLICT AND DEMENTIA RISK IN NEPAL: A POPULATION STUDY - THE OVERALL OBJECTIVE OF THIS APPLICATION IS TO LAY THE FOUNDATION FOR A SUSTAINABLE PROGRAM OF POPULATION-BASED RESEARCH INTO ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD) IN NEPAL. TO THAT END, THE PROJECT SEEKS TO INITIATE A SERIES OF RESEARCH CAPACITY BUILDING ACTIVITIES AND DEVELOP A NEW, POPULATION-BASED, LONGITUDINAL COHORT STUDY OF ADRD AND RELATED AGE-ASSOCIATED CHRONIC HEALTH CONDITIONS IN THIS POPULATION. POPULATION AGING IS BECOMING INCREASINGLY MORE COMMON IN MANY LOW- AND MIDDLE-INCOME COUNTRIES (LMIC). AS A RESULT, THESE COUNTRIES FACE THE GROWING BURDEN OF COMMON AGE-ASSOCIATED CHRONIC ILLNESSES, INCLUDING ADRD. NEPAL IS A LOW MIDDLE-INCOME COUNTRY WHERE THE POPULATION IS NOW AGING, PUTTING A RISING NUMBER OF ADULTS AT RISK OF DEVELOPING ADRD. THERE IS VIRTUALLY NO RESEARCH CAPACITY IN NEPAL TO INVESTIGATE THE SCOPE AND PRIMARY DETERMINANTS OF ADRD, AND EVEN THE MOST BASIC INFORMATION ON ADRD IS CURRENTLY LACKING. SUCH INFORMATION IS URGENTLY NEEDED TO GUIDE THE DEVELOPMENT OF PREVENTION STRATEGIES AND REDUCE THE BURDEN OF ADRD IN THIS COUNTRY. CAPACITY BUILDING ACTIVITIES WILL FOCUS ON TRAINING IN SURVEY DATA COLLECTION METHODS WITH A PRIMARY FOCUS ON ASCERTAINMENT OF ADRD AND STATISTICAL METHODS FOR THE ANALYSIS OF COMPLEX DATA FROM LONGITUDINAL PANEL SURVEYS. THE ACTIVITIES WILL CONSIST OF WORKSHOPS WITH HANDS-ON EXPERIENCE IN THE DESIGN AND ADMINISTRATION OF COGNITIVE ASSESSMENTS TO IDENTIFY ADRD IN THE GENERAL POPULATION, AND IN STATISTICAL ANALYSIS METHODS FOR LONGITUDINAL DATA FROM COMPLEX SURVEYS. THE PROJECT WILL ALSO BEGIN A NEW, LONGITUDINAL COHORT STUDY OF ADRD DESIGNED TO FILL SUBSTANTIAL GAPS IN INFORMATION ON ADRD AND ITS PRIMARY RISK FACTORS IN NEPAL. IT WILL FOCUS ON TWO NOVEL RISK FACTORS WITH PARTICULAR SALIENCE TO UNDERSTAND THE BURDEN OF ADRD IN NEPAL. THE FIRST INVOLVES THE ROLE OF INTERNATIONAL LABOR MIGRATION: A SUBSTANTIAL PORTION OF NEPALI ADULTS SPEND PROLONGED PERIODS OF ADULTHOOD WORKING IN OTHER COUNTRIES TO EARN INCOME FOR THEIR FAMILIES, OFTEN IN CHALLENGING SITUATIONS. THE SECOND RISK FACTOR INVOLVES THE LONG-TERM EFFECTS OF EXPOSURE TO ARMED CONFLICT THAT HAS AFFECTED THIS POPULATION FOR 10 YEARS (1996-2006). THE IMPACT OF LABOR MIGRATION AND ARMED CONFLICT ON ADRD RISK IS CURRENTLY UNKNOWN. THE STUDY WILL LEVERAGE THE DATA COLLECTION INFRASTRUCTURE THAT HAS BEEN DEVELOPED FOR THE CHITWAN VALLEY FAMILY STUDY, A POPULATION SURVEY OF >10,000 PARTICIPANTS AGED 15-59 THAT STARTED IN 1996. THE COHORT IS NOW AGING, PROVIDING A UNIQUE OPPORTUNITY TO BEGIN A NEW POPULATION STUDY OF ADRD AND OTHER CHRONIC HEALTH CONDITIONS. THE STUDY WILL INCLUDE THE ESTIMATED 4,000 SURVIVING PARTICIPANTS WHO HAVE NOW BECOME AGE-ELIGIBLE (> 50) FOR THIS STUDY. THIS SAMPLE WILL BE INVITED FOR A BASELINE INTERVIEW, INCLUDING A DETAILED COGNITIVE ASSESSMENT, AND A FOLLOW-UP INTERVIEW TWO YEARS LATER. OUTCOMES FROM THE CAPACITY BUILDING AND RESEARCH ACTIVITIES WILL BE SHARED WITH RELEVANT STAKEHOLDERS AND ORGANIZATIONS IN NEPAL TO INFORM LOCAL SOLUTIONS AND POLICIES FOR THE PREVENTION AND TREATMENT OF ADRD IN THIS POPULATION. WE ANTICIPATE THAT MUCH OF THIS WORK WILL HAVE RELEVANCE FOR OTHER LOW-RESOURCE, LOW-INCOME COUNTRIES THAT FACE SIMILAR CIRCUMSTANCES AND CHALLENGES AS NEPAL.

COLLABORATING CENTERS OF EXCELLENCE IN REGULATORY SCIENCE AND INNOVATION (CERSI)

REDUCING THE THREAT FROM HIGH-RISK PATHOGENS CAUSING FEBRILE ILLNESS IN GUINEA

BIODEMOGRAPHY OF HEALTH, SOCIAL FACTORS & LIFE CHALLENGE

NEUROREHABILITATION AND RESTORATIVE NEUROSCIENCE NETWORK

ANTIBODY-TARGETED NK CELL ACTIVATION FOR CANCER THERAPY

A PHASE II RANDOMIZED CONTROLLED TRIAL TO EVALUATE THE ROLE OF BB-12 IN ANTIBIOTIC-ASSOCIATED DIARRHEA AND ITS EFFECTS ON THE GUT MICROBIOME

DEMENTIA AND RELATED HEALTH AND SOCIAL CHALLENGES IN LEBANON: A POPULATION STUDY

MECHANISTIC LINKS BETWEEN CHANGING ESTROGEN PROFILES, INFLAMMATION AND THE INCREASED RISK AND METASTASIS OF BREAST CANCER IN OBESE WOMEN

THE SLP PROGRAM AIMS TO FOSTER A NEW GENERATION OF CIVICALLY ENGAGED LEADERS AND SOCIAL ENTREPRENEURS TO ADDRESS THESE AND OTHER CHALLENGES FACING THEIR COMMUNITIES TO ADVANCE STABILITY IN THEIR COUNTRIES AND THE REGION.

INTEGRATING EVIDENCE-BASED SMOKING CESSATION INTERVENTIONS INTO LUNG CANCER SCREENING PROGRAMS: A RANDOMIZED TRIAL

BLOOD AND MARROW COLLECTION EDUCATION AND RESEARCH PROGRAM

AGGRESSIVE COLORECTAL CANCER SUBTYPES AND SOCIAL DISADVANTAGE IN A RACIALLY DIVERSE COHORT - ABSTRACT WHILE OVERALL COLORECTAL CANCER (CRC) INCIDENCE AND MORTALITY HAVE DECLINED OVER THE LAST SEVERAL DECADES, CRC INCIDENCE AND MORTALITY RATES CONTINUE TO BE HIGHER IN AFRICAN AMERICANS (AAS) THAN NON-HISPANIC WHITES (NHW). CONSENSUS CRC MOLECULAR TUMOR SUBTYPES ARE IMPORTANT INDICATORS OF CARCINOGENIC PATHWAY AND PROGNOSIS, AND AREA ASSOCIATED WITH SPECIFIC SOMATIC GENE MUTATIONS, MISMATCH REPAIR (MMR) PHENOTYPE, AND GENE-SPECIFIC METHYLATION, ALTHOUGH IT IS CURRENTLY UNKNOWN WHETHER RACIAL DIFFERENCES IN THESE SUBTYPES UNDERLIE RACIAL DISPARITIES IN CRC SURVIVAL AS THESE SUBTYPES WERE DERIVED FROM STUDIES LARGELY COMPRISED OF NHW CRCS. THE RELATIVE CONTRIBUTIONS OF GENETIC, BEHAVIORAL AND ENVIRONMENTAL FACTORS ON CRC-RELATED OUTCOMES IN AA INDIVIDUALS REMAIN LARGELY UNKNOWN AND THERE IS A CRITICAL NEED FOR INFORMATION ABOUT PATHOGENESIS TO IMPROVE APPROACHES TO SCREENING AND TREATMENT. THIS IS ESPECIALLY TRUE FOR AREA-LEVEL SOCIOECONOMIC FACTORS, SUCH AS INCOME AND HOUSING VALUES, THAT ARE ASSOCIATED WITH HIGHER RISK OF CRC BUT FOR WHICH THE BIOLOGIC CONSEQUENCES ARE NOT YET KNOWN. THE OVERALL GOAL OF THE STUDY IS TO IDENTIFY GENOMIC AND SOCIAL FACTORS ASSOCIATED WITH CRC PATHOGENESIS IN A WELL-CHARACTERIZED COHORT OF AA CRC CASES. WE HYPOTHESIZE THAT TUMOR BIOLOGY, HERE DEFINED BY SOMATIC AND EPIGENETIC ALTERATIONS IN TUMORS, EXPLAINS A SUBSTANTIAL PROPORTION OF THE RACIAL DISPARITIES IN CRC OUTCOMES, AND AREA-LEVEL FACTORS MODIFY THIS RELATIONSHIP. OUR LONG-TERM GOAL IS TO IMPROVE OUR ABILITY TO DIAGNOSE, TREAT AND PREVENT CRC THROUGH A COMPREHENSIVE UNDERSTANDING OF THE MOLECULAR EVENTS IN TUMORS THAT ARISE IN DIVERSE POPULATIONS.

THE MEPI STUDENT LEADERS PROGRAM IS AN INTENSIVE, FIVE-WEEK PROGRAM FOR APPROXIMATELY 100 CIVICALLY ENGAGED UNIVERSITY STUDENTS FROM THE MIDDLE EAST

METABOLIC IMPAIRMENT PLAYS A CRITICAL ROLE IN RADIATION-INDUCED T CELL IMMUNE DYSFUNCTION - ABSTRACT THE IMMUNE SYSTEM, ESPECIALLY THE T CELL COMPONENT, IS PARTICULARLY SENSITIVE TO IONIZATION RADIATION (IR), AND EPIDEMIOLOGIC DATA, SUCH AS THE A-BOMB COHORT, HAVE DEMONSTRATED DYSFUNCTION AND PERTURBED T CELL HOMEOSTASIS EVEN DECADES AFTER EXPOSURE. WHILE MEASURABLE ACUTE EFFECTS OF RADIATION ON T CELL POPULATIONS AND ACTIVATION HAVE BEEN OBSERVED IN VIVO AND IN VITRO, THE LONG-TERM PHYSIOLOGIC CONSEQUENCES ON T CELL IMMUNITY IN ACUTE-RADIATION-SYNDROME SURVIVORS AND MULTI-ORGAN INJURY MEDIATED BY IMMUNE DYSFUNCTION, AS WELL AS THE UNDERLYING MECHANISMS, STILL HAVE CONSIDERABLE UNCERTAINTY. USING A BACTERIAL INFECTION MODEL, WE HAVE RECENTLY OBSERVED THAT THE PATHOGEN LOADS WERE HIGHER IN THE IRRADIATED MICE AT MONTHS AFTER IR. WE CAN CONNECT THIS COMPROMISED PROTECTIVE IMMUNITY AGAINST PATHOGENS WITH IMPAIRED T CELL IMMUNITY, WHERE WE HAVE REPORTED ABNORMAL IMMUNE METABOLIC REPROGRAMMING AND PERTURBATIONS IN SPECIFIC METABOLIC PATHWAYS IN ACTIVATED T CELLS AFTER IR. WITH THE GROWING APPRECIATION OF INTERACTIONS BETWEEN METABOLISM AND IMMUNE CELL FUNCTION, IT IS INCREASINGLY APPRECIATED THAT DISTINCT METABOLIC NEEDS IN NAÏVE, EFFECTOR, AND MEMORY T CELLS REQUIRE PROPER METABOLIC REPROGRAMMING TO MAINTAIN EFFECTIVE T CELL IMMUNITY AFTER IR. ONE AIM WILL BE TO DISSECT METABOLIC PERTURBATIONS IN T CELLS IN VARIOUS ACTIVATION/DIFFERENTIATION STAGES AS THEY CONTRIBUTE TO PATHOGEN IMMUNITY. A BACTERIAL INFECTION MURINE MODEL WILL BE USED TO ASSESS THE LONG-LASTING EFFECTS OF IR ON CHANGES ON T CELL IMMUNITY IN A PHYSIOLOGIC CONTEXT. WE WILL FOCUS ON CD8+ T CELLS IN THIS STUDY, BECAUSE CD8+ SUBPOPULATIONS ARE MORE SENSITIVE TO IR-CAUSED DAMAGE THAN CD4+, AND SECONDLY, THEY ARE CRITICAL FOR IMMUNE DEFENSE AGAINST INTRACELLULAR PATHOGENS, INCLUDING VIRUSES AND BACTERIA. IN ADDITION TO ALTERING T CELL METABOLISM, WE EXPECT THAT IR ALSO INDUCES DISTINCT SYSTEMIC METABOLIC CHANGES, INCLUDING THOSE IN LYMPHOID TISSUE AND MUCOSAL NICHE, AS SHOWN IN OUR PUBLISHED METABOLOMIC STUDIES. PRO-INFLAMMATORY METABOLITES MAY SYNERGIZE WITH IR-INDUCED PREMATURE SENESCENCE AND DRIVE A POSITIVE FEEDBACK LOOP RESULTING IN MULTI-ORGAN INJURY. IN THIS PROJECT WE WILL EXAMINE THE IMPACT OF THE SENESCENCE-ASSOCIATED INFLAMMATORY PHENOTYPE ON T CELL METABOLISM AND IMMUNE FUNCTIONS, AND ASSESS INTERVENTIONS USING SENESCENT CELL ABLATION APPROACH. CONSIDERING THAT IN A REAL-LIFE NUCLEAR INCIDENT, AN EXPOSURE TO MIXED FIELDS OF NEUTRONS AND PHOTON IS HIGHLY LIKELY, WE HAVE ALREADY OBSERVED DISTINCT DIFFERENCES BETWEEN MIXED FIELD METABOLIC RESPONSES COMPARED TO SINGLE PHOTON OR NEUTRON BEAMS. SO WE WILL INVESTIGATE THE LATE EFFECTS OF MIXED NEUTRON/PHOTON RADIATION ON T CELLS’ METABOLISM. WE ALSO PLAN TO ADDRESS THE QUESTION HOW A RADIOMITIGATOR MODULATES THOSE IR-CAUSED LONG- LASTING EFFECTS INCLUDING A SENOLYTIC APPROACH. THE SUCCESSFUL COMPLETION OF THESE AIMS WILL HELP TO BETTER UNDERSTAND HOW RADIATION CAUSES PERSISTENT IMMUNE DYSFUNCTION IN ARS SURVIVORS. THE NEW CONCEPT OF METABOLIC PERTURBATIONS OF T CELLS IN SPECIFIC ACTIVATION/DIFFERENTIATION STAGES, E.G., NAÏVE VS MEMORY T CELLS, WILL LAY THE FOUNDATION FOR STRATEGIES FOR PREVENTATIVE INTERVENTION.

A RANDOMIZED TRIAL OF A MOBILE HEALTH AND SOCIAL MEDIA PHYSICAL ACTIVITY INTERVENTION AMONG ADOLESCENT AND YOUNG ADULT CHILDHOOD CANCER SURVIVORS

LONGITUDINAL ASSESSMENT OF BENEFITS AND HARMS OF CANNABIS USE AMONG COMMUNITY-BASED CANCER PATIENTS DURING INITIAL CANCER TREATMENT - DESPITE FEDERAL PROHIBITION ON THE SALE OR PRESCRIBING OF CANNABIS AND CANNABINOIDS (CAC), THEIR MEDICAL USE HAS BEEN LEGALIZED IN 37 STATES. ALTHOUGH THERE IS LIMITED EVIDENCE OF ITS EFFECTIVENESS, 18-42% OF PERSONS WITH CANCER REPORT USING CAC TO HELP MANAGE SYMPTOMS, MOST OF WHOM OBTAIN ADVICE FROM LOCAL CAC DISPENSARIES RATHER THAN THEIR ONCOLOGY PROVIDERS. ALMOST 50% OF ONCOLOGISTS RECOMMEND CAC FOR THEIR PATIENTS, BUT <30% FEEL SUFFICIENTLY INFORMED TO MAKE SPECIFIC RECOMMENDATIONS. THUS, THERE IS AN URGENT NEED FOR MORE RESEARCH TO GUIDE BOTH PATIENTS AND PROVIDERS ON THE OPTIMAL USE OF CAC IN ONCOLOGY CARE. THERE IS STRONG EVIDENCE ON THE BENEFITS OF CAC FOR THE TREATMENT OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING AND FOR MITIGATING GENERAL CHRONIC PAIN. THERE IS WEAKER EVIDENCE ON THE EFFECTIVENESS OF CAC TO HELP MANAGE OTHER SYMPTOMS THAT MANY PERSONS WITH CANCER REPORT USING IT FOR, INCLUDING APPETITE LOSS, DEPRESSION, ANXIETY, AND INSOMNIA. NO STUDIES HAVE BEEN DONE ON WHETHER CAC USE BY CANCER PATIENTS CHANGES THEIR USE OF STANDARD PALLIATIVE THERAPIES, SUCH AS OPIOIDS TO MANAGE PAIN, AND THE MECHANISM BY WHICH THIS OCCURS. WELL-KNOWN NEGATIVE EFFECTS OF CAC USE HAVE NOT BEEN WELL STUDIED, AND MAY INCLUDE AN INCREASED RISK OF INFECTIONS, INJURIES, REDUCED MEMORY AND CONCENTRATION, CANNABIS USE DISORDER, AND INCREASED USE OF TOBACCO AND ALCOHOL. IN RESPONSE TO THESE KNOWLEDGE GAPS, WE PROPOSE A LONGITUDINAL OBSERVATIONAL STUDY IN A COMMUNITY-BASED HEALTH CARE SETTING COMPARING CAC USERS TO NON-USERS ON THE SAFETY AND EFFECTIVENESS OF CAC. WE WILL ENROLL PERSONS WITH INCIDENT COLORECTAL OR NON-SMALL CELL LUNG CANCER, OR WITH NON-HODGKIN LYMPHOMA, WHO ARE INITIATING SYSTEMIC PRIMARY OR ADJUVANT CANCER THERAPY. WE ANTICIPATE THAT 25% OF THE STUDY COHORT WILL REPORT USING CAC BASED ON PRIOR SURVEYS AND OUR PRELIMINARY DATA. WE WILL SURVEY PERSONS SOON AFTER THERAPY IS STARTED, AND CONDUCT FOLLOW-UP SURVEYS 2, 4, 6, AND 12 MONTHS LATER. WE WILL USE VALIDATED SURVEY INSTRUMENTS TO COLLECT CAC USE, AND USE PROMISÒ MEASURES TO CAPTURE PATIENT REPORTED OUTCOMES (PROS). TO OBTAIN MORE GRANULAR DETAILS ON CAC USE FOR SYMPTOM CONTROL, WE WILL ALSO CONDUCT BRIEF (5 MINUTE), WEEKLY, DAILY ASSESSMENTS IN A SUBSET (N=500) OF SUBJECTS, INCLUDING ALL CAC USERS. WE WILL CONDUCT OUR STUDY WITHIN THE KAISER PERMANENTE SOUTHERN CALIFORNIA HEALTH PLAN TO CAPITALIZE ON THE AVAILABILITY OF A HIGH VOLUME OF ELIGIBLE CASES AND COMPREHENSIVE ELECTRONIC HEALTH RECORDS CONTAINING ESSENTIAL CLINICAL DATA. OUR SPECIFIC AIMS ARE TO: 1. ASSESS THE EFFECTS OF CAC USE ON PROS, FOCUSING ON PAIN, NAUSEA, ANXIETY, DEPRESSION, INSOMNIA, APPETITE LOSS, AND OVERALL HRQOL (DEFINED BY PHYSICAL, EMOTIONAL, SOCIAL FUNCTIONING) AMONG PERSONS UNDERGOING ACTIVE SYSTEMIC CANCER THERAPY; 2. ASSESS WHETHER AND HOW CAC USE AFFECTS THE USE OF STANDARD PALLIATIVE THERAPIES, SUCH AS REDUCING THE USE OF OPIOIDS; AND 3. ASSESS THE NEGATIVE EFFECTS FROM CAC USE. THE RAPID INCREASE IN CAC USE BY CANCER PATIENTS HAS OCCURRED DESPITE THE LACK OF EVIDENCE ABOUT ITS EFFECTIVENESS AND SAFETY. OUR STUDY WILL INFORM THE BEST CLINICAL STRATEGIES AND POLICIES FOR LIMITING POTENTIAL HARMS AND ENHANCING BENEFITS.

BII: PREDICTING THE GLOBAL HOST-VIRUS NETWORK FROM MOLECULAR FOUNDATIONS -THE VIRAL EMERGENCE RESEARCH INITIATIVE BIOLOGY INTEGRATION INSTITUTE (VERENA BII) WILL INTEGRATE DATA AND BIOLOGICAL THEORY ACROSS THE FIELDS OF MICROBIOLOGY, IMMUNOLOGY, ECOLOGY, EVOLUTION, AND GLOBAL CHANGE BIOLOGY, WORKING TOWARDS A UNIFIED UNDERSTANDING THAT IMPROVES OUR ABILITY TO PREDICT VIRAL EMERGENCE. THE COVID-19 PANDEMIC HIGHLIGHTS A PRESSING NEED TO UNDERSTAND THE ECOLOGY AND EVOLUTION OF EMERGING VIRUSES. THESE GLOBAL DYNAMICS ARE DETERMINED FIRST AND FOREMOST BY THE GENETIC CODE OF BOTH VIRUSES AND THEIR HOSTS, AND BY MICROSCOPIC INTERACTIONS BETWEEN THE TWO AT THE LEVEL OF PROTEINS AND CELLS. HOWEVER, BIOLOGISTS FREQUENTLY STRUGGLE TO CONNECT THEORY ACROSS THESE SCALES. AT THE HEART OF THIS RESEARCH EFFORT IS AN OPEN CLEARINGHOUSE OF BIG DATA, CREATING NEW OPPORTUNITIES TO APPLY ARTIFICIAL INTELLIGENCE TO REAL-WORLD PROBLEMS. TO FOSTER A CORE SET OF DATA FLUENCY AND INTERDISCIPLINARY RESEARCH SKILLS, THE LIGHTHOUSE LEARNING COMMUNITY WILL TRAIN PARTICIPANTS AT EVERY CAREER STAGE IN THE BOUNDARY-SPANNING SCIENCE OF THE HOST-VIRUS NETWORK, INCLUDING MORE THAN 100 EARLY CAREER SCIENTISTS. UNDERGRADUATES WILL BE INTRODUCED TO BOTH BIOLOGY AND DATA SCIENCE THROUGH A COURSE-BASED UNDERGRADUATE RESEARCH EXPERIENCE IN ?THE FUNDAMENTALS OF DISEASE SURVEILLANCE,? WHILE GRADUATE STUDENTS AND POSTDOCTORAL FELLOWS WILL EXPLORE THESE METHODS DEEPER THROUGH A BIOLOGY INTEGRATION WORKSHOP SERIES, INCLUDING A NEW SUMMER IN THE CAPITOL PROGRAM IN WASHINGTON, D.C. THIS COHORT OF EMERGING SCHOLARS WILL USE OPEN SOURCE MATERIALS, K-12 OUTREACH, AND DIGITAL MEDIA TO HARNESS PUBLIC INTEREST IN EMERGING DISEASES LIKE COVID-19, RAISING AWARENESS ABOUT KEY ISSUES WHILE SHARING THE IMPORTANCE OF BASIC BIOLOGICAL RESEARCH TO SAVE LIVES AND PROTECT ECOSYSTEMS. TO IDENTIFY THE MECHANISTIC AND MOLECULAR RULES OF LIFE THAT GOVERN HOST-VIRUS DYNAMICS AT PLANETARY SCALES, THE VERENA BII WILL LEVERAGE A UNIQUE MIX OF DATA SYNTHESIS, COMPUTATIONAL INNOVATION, FIELD SAMPLING, AND LABORATORY EXPERIMENTS TO IDENTIFY THE MOLECULAR UNDERPINNINGS OF HOST-VIRUS INTERACTIONS. AN UNPRECEDENTED COMPARATIVE STUDY OF THE CHIROPTERAN WITHIN-HOST ENVIRONMENT WILL GENERATE AND TEST HYPOTHESES ABOUT THE IMMUNOLOGICAL ADAPTATIONS THAT ALLOW BATS TO TOLERATE DEADLY VIRUSES. IN PARALLEL, MODEL-GUIDED EXPERIMENTS WILL MEASURE THE FEATURES OF THE INVERTEBRATE IMMUNE SYSTEM THAT PLAY THE GREATEST ROLE IN MOSQUITOES? COMPETENCE AS ARBOVIRAL VECTORS. TOGETHER, THESE MODEL SYSTEMS WILL ILLUMINATE THE HARD-CODED BASIS OF HOST-VIRUS COMPATIBILITY, SUPPORTING NEW MACHINE LEARNING METHODS TO PREDICT ECOLOGICAL AND EVOLUTIONARY NETWORKS AND ANTICIPATE GLOBAL RISKS OF VIRAL EMERGENCE IN A CHANGING CLIMATE. MORE BROADLY, THE VERENA BII WILL EXPAND AN EXISTING ROLE AS A HUB OF OPEN DATA, SOFTWARE, AND CYBERINFRASTRUCTURE FOR HOST-VIRUS INTERACTIONS, EXPERIMENTAL VIROLOGY, AND WILDLIFE DISEASE SURVEILLANCE. 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.

MOBILE ECOLOGICAL MOMENTARY DIET ASSESSMENT: A LOW BURDEN, ECOLOGICALLY-VALID APPROACH TO MEASURING DIETARY INTAKE IN NEAR-REAL TIME - ABSTRACT THE EXCESSIVE INTAKE OF SATURATED FAT AND ADDED SUGARS HAS BEEN IDENTIFIED AS A LEADING CAUSE OF PREMATURE MORTALITY AMONG ADULTS IN THE U.S. CONTRIBUTING TO APPROXIMATELY 700,000 DEATHS EACH YEAR. THE 2015-2020 DIETARY GUIDELINES FOR AMERICANS RECOMMEND LIMITING THESE NUTRIENTS TO <10% TOTAL ENERGY INTAKE TO PREVENT DISEASE. ACHIEVING THESE PUBLIC HEALTH RECOMMENDATIONS WILL REQUIRE UNDERSTANDING THE PATTERNS OF SATURATED FAT AND ADDED SUGAR INTAKE SO MORE EFFECTIVE DIETARY INTERVENTIONS CAN BE DEVELOPED. TRADITIONALLY, ESTIMATES OF SATURATED FAT AND ADDED SUGAR INTAKE ARE MEASURED USING FOOD FREQUENCY QUESTIONNAIRES OR 24-HR DIETARY RECALLS (24HR). THESE METHODS ARE TIME-INTENSIVE AND COGNITIVELY TAXING FOR USERS AND COSTLY FOR RESEARCHERS. THEY ARE ALSO HIGHLY PRONE TO RECALL BIAS AND MISREPORTING RELATED DUE, IN PART, TO THE RELIANCE ON A PERSON’S MEMORY OVER LONG RECALL INTERVALS AND ERRORS IN PORTION SIZE ESTIMATION. THE PROPOSED DIETARY ASSESSMENT METHOD AIMS TO ADDRESS THESE LIMITATIONS WITH ECOLOGICAL MOMENTARY ASSESSMENT (EMA). EMA USES UPDATED TECHNOLOGY AND SAMPLING METHODS THAT CAN UPDATE AND IMPROVE UPON TRADITIONAL ASSESSMENT METHODS. EMA STUDIES OFTEN USE MOBILE PHONE APPS TO ASSESS EVENTS WITH BRIEF, AUTOMATED SURVEYS DELIVERED PERIODICALLY THROUGHOUT THE DAY. EMA CAN, THEREBY, SHORTEN RECALL INTERVALS TO IMPROVE REPORTING ERRORS AND REDUCE USER AND RESEARCHER BURDEN WHILE MAXIMIZING THE ECOLOGICAL VALIDITY. TO DATE, MOBILE EMA METHODS FOR DIET ASSESSMENT (MEMDA) USED IN RESEARCH HAVE BEEN STUDY SPECIFIC. THEY HAVE NOT BEEN SYSTEMATICALLY DEVELOPED NOR OPTIMIZED FOR WIDESPREAD USE IN RESEARCH. THIS PROJECT WOULD REPRESENT THE FIRST RESEARCH-QUALITY AND FULLY AUTOMATED, EMA-BASED MOBILE DIETARY ASSESSMENT RESEARCH TOOL. IN RECENT PILOT WORK, WE DEMONSTRATED THE POTENTIAL UTILITY OF MEMDA. A BRIEF MOBILE SURVEY PERFORMED AS WELL AS WEB-ASSISTED 24HR TO ESTIMATE THE INTAKE OF PREDEFINED SNACK FOODS. HERE, THE GOAL OF THE PROPOSED PROJECT IS TO SYSTEMATICALLY DEVELOP AND TEST A MEMDA APP AND SAMPLING APPROACH TO ACCURATELY ESTIMATE THE INTAKE OF SATURATED FAT AND ADDED SUGARS IN A DIVERSE POPULATION. TO DO THIS WE WILL DERIVE A CULTURALLY- AND DEMOGRAPHICALLY REPRESENTATIVE LIST OF FOODS AND BEVERAGES THAT CONTRIBUTE A MAJORITY (>70%) OF THE SATURATED FAT AND ADDED SUGARS IN THE AMERICAN DIET USING RECENT NHANES DATA (AIM 1); DEVELOP WITH A USER-CENTERED DESIGN THE MEMDA APP AND ANALYSIS PLATFORM WITH VISUAL FOOD IMAGES FOR PORTION SIZE ESTIMATION AND NUTRIENT ANALYSIS CAPABILITIES (AIM 2); DETERMINE THE BEST MEMDA SAMPLING APPROACH (EVENT-CONTINGENT VS. INTERVAL-CONTINGENT SAMPLING) (AIM 3); AND COMPARE THE ACCURACY OF ESTIMATING ENERGY INTAKE FROM SATURATED FAT AND ADDED SUGARS USING THE OPTIMIZED MEMDA APP AND SAMPLING APPROACH VS. INTERVIEWER-ASSISTED 24HR IN A CONTROLLED-FEEDING STUDY. FUTURE APPLICATIONS OF THE MEMDA APP INCLUDE: (1) RELIABLY ASSESSING MOMENTARY INTAKES OF OTHER FOODS OR NUTRIENTS (E.G., FRUIT AND VEGETABLE INTAKE, SODIUM), (2) INTEGRATION WITH MOBILE INTERVENTION PLATFORMS TO GIVE REAL-TIME, DIETARY FEEDBACK TO PARTICIPANTS (3) CONCURRENT-CAPTURING MEAL CONTEXT VARIABLES (E.G., SOCIAL, ENVIRONMENTAL, AND PSYCHO-SOCIAL VARIABLES) FOR FUTURE, JUST-IN-TIME DIETARY INTERVENTIONS.

BRIDGING INFORMATION DIVIDES AND GAPS TO ENSURE SURVIVORSHIP: THE BRIDGES RANDOMIZED CONTROLLED TRIAL OF A MULTILEVEL INTERVENTION TO IMPROVE ADHERENCE TO CHILDHOOD CANCER SURVIVORSHIP - PROJECT SUMMARY MORE THAN 80% OF CHILDHOOD CANCER SURVIVORS (CCS) DEVELOP SERIOUS OR LIFE-THREATENING LATE EFFECTS. YET <20% OF CCS RECEIVE RECOMMENDED SURVIVORSHIP CARE, DESPITE THE AVAILABILITY OF CONSENSUS GUIDELINES FOR LIFELONG SURVEILLANCE FOR LATE EFFECTS STARTING 2 YEARS POST-THERAPY. THE “GOLD STANDARD” CANCER CENTER-BASED SURVIVORSHIP CLINIC PROVIDES HIGH-QUALITY CARE TO CCS WHO ATTEND, BUT PATIENTS AVOID REMINDERS OF THEIR PAST CANCER AND LACK KNOWLEDGE AND SELF-EFFICACY FOR SURVIVORSHIP CARE. OTHER BARRIERS INCLUDE TRAVEL DISTANCE, INADEQUATE INSURANCE, AND OUT-OF-POCKET COSTS—THESE STRUCTURAL ISSUES CONTRIBUTE TO HEALTH DISPARITIES. PARTNERING WITH COMMUNITY PRIMARY CARE PROVIDER (PCP) CLINICS IN A SHARED MODEL OF CARE IS A PROMISING STRATEGY TO OVERCOME THESE BARRIERS, BUT PCPS LACK KNOWLEDGE, SELF-EFFICACY, AND INTERACTIVE COMMUNICATION WITH THE CANCER CENTER AND ARE CONFUSED ABOUT THE DIVISION OF CARE RESPONSIBILITIES. OUR INTERVENTION IS SCALABLE AND DISTANCE-BASED, IS INFORMED DIRECTLY BY PATIENT AND PCP BARRIERS AND PREFERENCES FROM PREVIOUS STUDIES, AND IS BOOSTED BY A NATIONWIDE EXPLOSION IN TELEHEALTH SERVICES PRECIPITATED BY THE COVID-19 CRISIS. THE PROPOSED RANDOMIZED CONTROLLED TRIAL WILL ENROLL 240 CCS 2.0-4.0 YEARS POST-CHEMOTHERAPY/RADIATION TO INVESTIGATE AN INNOVATIVE MULTI-LEVEL INTERVENTION (I.E., INTERPERSONAL AND ORGANIZATIONAL LEVELS) CONSISTING OF 1) PATIENT SURVIVORSHIP EDUCATION VIA TELEHEALTH WITH THE CANCER CENTER, 2) ONGOING PATIENT-TAILORED EDUCATION PROGRAM WITHIN THE EHR'S PATIENT PORTAL, 3) A STRUCTURED INTERACTIVE PHONE COMMUNICATION BETWEEN THE CANCER CENTER AND THE PCP CLINIC (WITH 1-YEAR FOLLOW-UP CALL), AND 4) AN IN-PERSON VISIT WITH THE PCP CLINIC FOR SURVIVORSHIP CARE. THE COMPARISON GROUP WILL BE RANDOMIZED TO AN IN-PERSON VISIT WITH THEIR CANCER CENTER SURVIVORSHIP CLINIC. THIS STUDY INCLUDES 4 CENTERS WITH HIGH PROPORTIONS OF SUBGROUPS VULNERABLE TO SURVIVORSHIP CARE DISPARITIES (I.E., RURAL, BLACK, LATINX, SPANISH-SPEAKING, SOCIOECONOMICALLY DISADVANTAGED). BOTH GROUPS WILL BE ASKED TO BEGIN RECOMMENDED SURVEILLANCE FOR LATE EFFECTS WITHIN 1-YEAR POST-RANDOMIZATION, SEPARATE FROM TUMOR RECURRENCE MONITORING BY THE PRIMARY ONCOLOGIST. OUR SPECIFIC AIMS ARE TO AIM 1- DEMONSTRATE PATIENT COMPLETION OF GUIDELINE-RECOMMENDED SURVEILLANCE TESTS IN INTERVENTION PARTICIPANTS IS NOT INFERIOR, I.E. WITHIN 10%, TO THAT IN THE COMPARISON GROUP; AIM 2- ACHIEVE GREATER 1) PATIENT KNOWLEDGE, SELF-EFFICACY, AND ACTIVATION AND 2) PCP KNOWLEDGE AND SELF-EFFICACY WITH SURVIVORSHIP CARE AMONG INTERVENTION PARTICIPANTS AND THEIR PCPS COMPARED TO THE COMPARISON GROUP; AND AIM 3- ASCERTAIN PROCESS OUTCOMES FOR THE 1) PATIENT AND 2) PCP CLINIC. OUTCOMES WILL ALSO BE ASSESSED AMONG SUBGROUPS WITH SURVIVORSHIP CARE DISPARITIES. TRANSFORMATIVE IMPACT: IF OUR INTERVENTION DEMONSTRATES PATIENT COMPLETION OF RECOMMENDED SURVIVORSHIP CARE COMPARABLE TO CANCER CENTER SURVIVORSHIP CLINIC, OUR STUDY HAS THE ENORMOUS POTENTIAL TO DELIVER RECOMMENDED LIFELONG CARE TO A LARGER PROPORTION OF CCS AND REDUCE SURVIVORSHIP CARE DISPARITIES, WHILE ENGAGING PATIENTS AND PCPS TO INTEGRATE SURVIVORSHIP CARE AS PART OF OVERALL, LIFELONG HEALTH MAINTENANCE.

WHO CARES FOR OLDER BREAST CANCER SURIVORS AND HOW DOES IT AFFECT QUALITY?

LIMBIC-MIDBRAIN INTERACTIONS IN DEFENSE AND EMOTIONAL AROUSAL

BRAIN PATHOPHYSIOLOGY IN SARS-COV-2 DISEASE - SARS-COV-2, THE VIRUS UNDERLYING THE CURRENT COVID-19 PANDEMIC, NOT ONLY AFFECTS PERIPHERAL TISSUES, IT ALSO TARGETS THE BRAIN CAUSING MICROVASCULAR LESIONS, MICROHEMORRHAGES AND NEUROLOGICAL MANIFESTATIONS. THE INTERNALIZATION OF SARS-COV-2 IS INITIATED BY THE BINDING OF THE VIRUS SPIKE PROTEIN TO ANGIOTENSIN CONVERTING ENZYME 2 (ACE2) ON THE MEMBRANE OF HOST CELLS INCLUDING ENDOTHELIAL CELLS THROUGHOUT CEREBRAL CAPILLARIES. ACE2 IS INTERNALIZED ALONG WITH THE VIRUS THEREBY LEADING TO A STATE OF ACE2 DEFICIENCY. ACE2 IS A CRITICAL MEMBER OF THE RENIN-ANGIOTENSIN SYSTEM (RAS). THIS ENZYME CATABOLIZES THE OCTAPEPTIDE HORMONE ANGIOTENSIN-[1-8] THEREBY PROTECTING CELLS AND TISSUES FROM THE VASOCONSTRICTOR, PRO-INFLAMMATORY AND PRO-THROMBOTIC EFFECTS OF OVERACTIVE ANGIOTENSIN TYPE 1 RECEPTORS (AT1RS). BLOCKING AT1RS WITH AN AT1R ANTAGONIST PROTECTS MICE FROM BEHAVIORAL IMPAIRMENTS DUE TO ACE2 DEFICIENCY. LIPOPOLYSACCHARIDE (LPS) CAUSES MICROGLIA ACTIVATION AND NEURONAL CELL LOSS AND IS WIDELY USED AS AN EXPERIMENTAL MODEL OF NEUROINFLAMMATION. THE BRAIN PATHOPHYSIOLOGY INDUCED BY LPS SHARES MANY SIMILARITIES WITH SARS-COV-2 INFECTION. WE HYPOTHESIZE THAT UNDER CONDITIONS OF REDUCED ACE2 (I.E., ACE2 KNOCKOUT MICE OR SARS-COV-2-INFECTED HAMSTERS), AT1R ACTIVITY IS UPREGULATED IN THE MICROVASCULATURE. IN THE PRESENCE OF AN INFLAMMATORY INSULT (I.E., LPS OR SARS-COV-2), AT1RS PROMOTE ENDOTHELIAL DYSFUNCTION IN THE MICROVASCULATURE THROUGH PRO-INFLAMMATORY AND PRO-THROMBOTIC SIGNALING PATHWAYS LEADING TO BLOOD BRAIN BARRIER INJURY. DEFICITS IN COGNITION AND INCREASED ANXIETY ENSUE. WE WILL TEST THIS OVERALL HYPOTHESIS THROUGH THE FOLLOWING SPECIFIC AIMS: DETERMINE THE MECHANISMS OF THE PRO-INJURY (AIM 1) AND PROTECTIVE (AIM 2) ARMS OF THE RAS THAT REGULATE THE PATHOPHYSIOLOGY OF THE BRAIN IN ANIMAL MODELS OF NEUROINFLAMMATION AND COVID-19. (AIM 3) DETERMINE THE MECHANISMS UNDERLYING THE EFFECTS OF BIOLOGICAL SEX AND AGE IN THE BRAIN PATHOPHYSIOLOGY INDUCED BY LPS AND SARS-COV-2. STUDYING RAS MECHANISMS IN THE BRAIN WILL PROVIDE INSIGHT INTO ON-GOING AND FUTURE CLINICAL TRIALS OF THERAPEUTICS FOR TREATING BRAIN INJURY ASSOCIATED WITH COVID-19 AND OTHER DISEASES OF NEUROINFLAMMATION. IN ADDITION, FOCUSING ON MECHANISMS UNDERLYING THE EFFECTS OF BIOLOGICAL SEX AND AGE ON MICROVASCULATURE PATHOPHYSIOLOGY IN MODELS OF NEUROINFLAMMATION AND COVID-19 WILL SHED LIGHT INTO WHY MALE SEX AND AGE ARE MAJOR RISK FACTORS FOR COVID-19 SEVERITY.

ANGIOTENSIN RECEPTOR REGULATION BY UPSTREAM SHORT OPEN READING FRAMES

LEUKOCYTE-DERIVED BIOMARKERS AS PREDICTORS OF RISK AND PROGRESSION IN AD

LANGUAGE AND COGNITION AFTER PERINATAL STROKE

A COMPARISON OF THE NEURO-DEVELOPMENTAL BASIS OF READING IN TWO WRITING SYSTEMS

ROLE OF BRANCHED-CHAIN FATTY ACIDS IN PHYSIOLOGY AND VIRULENCE OF STAPHYLOCOCCUS AUREUS - 7. PROJECT SUMMARY/ABSTRACT WHILE SOME BACTERIAL INFECTIONS ARE CAUSED BY A SINGLE SPECIES, WE NOW KNOW THAT MOST INFECTIONS ARE POLYMICROBIAL IN ORIGIN. WE KNOW THAT THE ACTIVITIES OF THESE SPECIES ARE OFTEN SYNERGISTIC, AS INTERACTIONS BETWEEN SPECIES ENHANCES VIRULENCE, PERSISTENCE, AND TOLERANCE TO ANTIBIOTICS. THE END RESULT IS PATIENT OUTCOMES ARE TYPICALLY WORSE IN CO-INFECTION COMPARED TO MONO-INFECTION. STAPHYLOCOCCUS AUREUS IS THE LEADING CAUSE OF SKIN AND SOFT TISSUE INFECTIONS. THE BACTERIUM IS ALSO THE MOST COMMON ORGANISM ISOLATED FROM CHRONIC WOUNDS AND IS FREQUENTLY FOUND WITH THE OPPORTUNISTIC PATHOGENS ENTEROCOCCUS FAECALIS AND PSEUDOMONAS AERUGINOSA. INTERACTIONS BETWEEN S. AUREUS AND E. FAECALIS ARE RELATIVELY UNDERSTUDIED. MORE BROADLY, OUR KNOWLEDGE OF THE MOLECULAR MECHANISMS GOVERNING THESE INTERACTIONS IN CHRONIC WOUNDS IS INCOMPLETE. S. AUREUS RELIES HEAVILY ON THE DE NOVO SYNTHESIS OF BRANCHED-CHAIN FATTY ACIDS FOR MEMBRANE BIOGENESIS THAT CANNOT BE OBTAINED FROM THE HOST DURING INFECTION. THESE MEMBRANE FATTY ACIDS ARE ESSENTIAL FOR AVOIDING PHASE SEPARATION, PROTEIN AGGREGATION, AND CELL DEATH. THEY ARE ALSO REQUIRED TO PROMOTE THE ACTIVITY OF THE SAE TWO-COMPONENT SYSTEM, A MAJOR REGULATOR OF S. AUREUS VIRULENCE. THE PI’S LABORATORY RECENTLY DISCOVERED EVIDENCE FOR A NEW PATHWAY SPECIFIC TO HUMAN-ASSOCIATED STAPHYLOCOCCI FOR SALVAGING AND SYNTHESIZING BRANCHED-CHAIN FATTY ACIDS FROM THE METABOLIC BYPRODUCTS OF CO-INFECTING BACTERIA FOUND IN CHRONIC WOUNDS. THE OVERALL GOALS OF THIS APPLICATION ARE TO I) DETERMINE THE STEPS OF THIS NOVEL PATHWAY AND HOW ENTEROCOCCUS FAECALIS HELPS S. AUREUS CONSTRUCT ITS MEMBRANE USING THIS PATHWAY DURING INFECTION, AND II) DETERMINE HOW BRANCHED-CHAIN FATTY ACIDS PROMOTE SIGNALING VIA THE SAE TWO-COMPONENT SYSTEM TO INCREASE PATHOGENICITY. TO ACCOMPLISH THESE GOALS WE WILL USE PENETRATING GENETIC, BIOCHEMICAL, MOLECULAR BIOLOGICAL AND GLOBAL APPROACHES TO INTERROGATE THE FUNCTIONALITY OF THE PROTEINS WE ARE INTERESTED IN. IN ADDITION WE WILL USE CUTTING-EDGE NATIVE MASS SPECTROMETRY AND SPATIAL LIPIDOMICS APPROACHES ALONG WITH IN VITRO AND IN VIVO MURINE MODELS TO DEFINE MECHANISMS. DETAILED UNDERSTANDING OF THESE PROCESSES IS THE IMPORTANT FIRST STEP TOWARD DEVELOPING NOVEL THERAPEUTICS TO COMBAT THESE COMPLEX INFECTIONS.

TREATMENT DECISIONS AND PATIENT REPORTED OUTCOMES IN LOW RISK PROSTATE CANCER

ZUSHA!

TARGETED BIOMARKER PANELS AND PRE-PROCESSING DEVICE FOR THE RAPID ASSESSMENT OF RADIATION INJURY IN EASILY ACCESSIBLE BIOFLUIDS - THIS PROPOSAL BUILDS UPON OUR METABOLOMICS EXPERTISE IN UNTARGETED AND TARGETED METABOLOMICS FOR THE GENERATION OF HIGHLY SENSITIVE AND QUANTITATIVE TARGETED MULTIPLEX ASSAYS. THE IDEA BEHIND GENERATING SUCH ASSAYS FOR RADIATION ASSESSMENT AND RADIATION INJURY IN EASILY ACCESSIBLE BIOFLUIDS (URINE, BLOOD, SALIVA) IS TO RAPIDLY DETERMINE THE EXTENT OF EXPOSURE OF AN INDIVIDUAL AND DISTINGUISH BETWEEN THE WORRIED WELL AND THE EXPOSED INDIVIDUALS THAT MAY REQUIRE MEDICAL INTERVENTION. HIGHLY QUANTITATIVE APPROACHES WILL BE UNDERTAKEN THROUGH LIQUID CHROMATOGRAPHY TANDEM MASS SPECTROMETRY (LC-MS/MS) TO QUANTIFY EACH ALREADY IDENTIFIED RADIATION BIOMARKERS IN EACH BIOFLUID. SUCH INSTRUMENTS ARE CURRENTLY USED ROUTINELY IN CLINICAL LABORATORIES, THEREFORE MAXIMIZING THE AVAILABLE RESOURCES FOR RAPID EVALUATION OF THOUSANDS OF INDIVIDUALS DURING AN EMERGENCY. BASED ON CRITERIA FOR SENSITIVITY, HIGH SIGNAL-TO-NOISE RATIO, LOW SIGNAL SUPPRESSION FROM MATRIX EFFECTS, AND HIGH FOLD CHANGES COMPARED TO CONTROLS OR RELATIONSHIPS BETWEEN PAIRS OF METABOLITES, BIOSIGNATURES WILL BE ASSEMBLED AND CONCENTRATIONS CALCULATED. THE COMBINED BIOSIGNATURE WILL BE DEVELOPED IN A MULTIPLEX ASSAY, EFFECTIVELY REDUCING THE TIME BETWEEN SAMPLE PREPARATION TO RESULTS. THE GOAL IS TO DEMONSTRATE THAT THIS MULTIPLEX ASSAY METHOD HAS THE POTENTIAL TO BE DEPLOYED IN THE CASE OF AN EMERGENCY TO A PRE-DETERMINED NETWORK OF CLINICAL LABORATORIES THAT CAN ACCEPT AND RAPIDLY PROCESS A HIGH VOLUME OF SAMPLES. WHILE THE ULTIMATE GOAL WILL BE FOR SUCH A PANEL TO BE PREDICTIVE IN ALL CASES, EVEN A LIMITED FALSE POSITIVE RATE WOULD FACILITATE ASSESSMENT OF RADIATION INJURY IN A MASS CASUALTY SCENARIO: E.G. A 1% FALSE POSITIVE RATE WOULD REDUCE THE NUMBER OF INDIVIDUALS NEEDING FURTHER EVALUATION BY 100-FOLD. ADDITIONALLY, THIS ASSAY WILL BE FLEXIBLE AS IT COULD BE ENRICHED WITH BIOMARKERS FOR SPECIFICITY AND RADIATION QUALITY. THIS APPLICATION ALSO COMBINES THE ENGINEERING EXPERIENCE AND CAPABILITIES OF OUR COLLABORATORS TO FURTHER DEVELOP PRE-PROCESSING DEVICES WITH THE INTENTION OF STABILIZING THE SAMPLE DURING TRANSPORT TO A CLINICAL FACILITY. THE MATERIALS TO BE FABRICATED WILL ALSO AIM TO ENRICH THE BIOSIGNATURE FOR THE RADIATION-RELATED METABOLITES AND EXTRACT THEM EFFECTIVELY FROM SMALL AMOUNTS OF A BIOFLUID (URINE, SERUM, WHOLE BLOOD, SALIVA), TRANSPORTED AS A STABLE DRY MEMBRANE. ASSEMBLY OF SUCH MATERIALS IN A 96 WELL PLATE WILL FURTHER DECREASE THE SAMPLE PREPARATION TIME AND MINIMIZE HUMAN ERROR ASSOCIATED WITH SAMPLE PREPARATION. OUR UNIQUE APPROACH TO COMBINE LC-MS/MS APPLICATIONS WITH PRE-PROCESSING MATERIALS WILL AIM TO MOVE THIS TECHNOLOGY FROM THE FEASIBILITY STAGE TO TECHNOLOGY DEVELOPMENT, SATISFYING THE NEEDS FOR RAPID METHODS FOR RADIATION INJURY ASSESSMENT. !

SUPPLEMENT FOR SIKOYA ASHBURN TO "AN FMRI STUDY ON THE NEURAL BASIS OF COMBINED MATH AND READING DISABILITY"

STRUCTURAL AND FUNCTIONAL SEQUELAE OF NEONATAL ANTICONVULSANT EXPOSURE: DRUG-SEIZURE INTERACTIONS

NOVEL ROLES FOR P27 AS TRANSCRIPTIONAL CO-REGULATOR OF CJUN IN STEM CELLS AND DEVELOPMENT

ADOLESCENTS' LONG-TERM ADAPTATION TO FAMILIAL CANCER RISKS

LONGITUDINAL INVESTIGATION OF SOCIOCULTURAL AND BEHAVIORAL INFLUENCES ON SYMPTOM MANAGEMENT, BIOLOGICAL RESPONSE, AND FUNCTIONING BETWEEN CHINESE AND WHITE BREAST CANCER SURVIVORS. - PROJECT SUMMARY THE NUMBER OF US CANCER SURVIVORS IS GROWING RAPIDLY, INCLUDING A SIGNIFICANT NUMBER OF CHINESE AMERICANS (CA), A GROUP WITH AN ANNUAL BREAST CANCER GROWTH RATE OF 1.1% AND FAST POPULATION GROWTH DUE TO IMMIGRATION. OVER 63% OF CAS ARE IMMIGRANTS. OUR PRELIMINARY STUDY SHOWED THAT MORE CA IMMIGRANT BREAST CANCER SURVIVORS (BCS) HAD FATIGUE, PAIN, AND POOR PHYSICAL FUNCTIONING RELATIVE TO NON-HISPANIC WHITE (NHW) BCS. LOW-ACCULTURATED CAS REPORTED GREATER PSYCHOSOCIAL STRESS (E.G. GREATER PERCEIVED THREAT AND FEAR OF LOSING SOCIOECONOMIC RESOURCES); HOWEVER, THEY PARADOXICALLY REPORTED LESS DEPRESSION THAN NHWS. WE DO NOT KNOW WHY CA BCS APPEAR EMOTIONALLY RESILIENT WHEN THEY ARE PHYSICALLY VULNERABLE AND OFTEN LACK SOCIAL RESOURCES FOR COPING (I.E., SOCIAL SUPPORT, SOCIOECONOMIC RESOURCES AND HEALTHCARE ACCESS). IT IS UNCLEAR WHETHER SUCH RESILIENCE IS ACTUALLY A CULTURAL RESPONSE WHEN MANY CAS BELIEVE THAT EMOTIONAL STRESS CAUSES CANCER, AND THUS THEY MAY UNDERREPORT THEIR DISTRESS. UNEXPRESSED CHRONIC STRESS IS RELATED TO HIGHER CORTISOL AND INFLAMMATION LEVELS DETRIMENTAL TO HEALTH. IT IS ALSO UNKNOWN WHETHER CA BCS’ SYMPTOM BURDEN PERSISTS OVER TIME AND HOW CULTURE AND SOCIAL RESOURCES INFLUENCE THEIR WAYS OF MANAGING SYMPTOMS AND FURTHER IMPROVING QUALITY OF LIFE. PRIOR DATA SHOWED CA BCS EATING MORE SOY FOOD AND CRUCIFEROUS VEGETABLES THAN NHWS. HIGHER SOY INTAKE REDUCES MENOPAUSAL SYMPTOMS AND FATIGUE. YET, CA BCS HAD LOWER ADHERENCE TO PHYSICAL ACTIVITY GUIDELINES THAN NHWS. PSYCHOSOCIAL STRESS, POOR DIET, INSUFFICIENT EXERCISE, FATIGUE, AND PAIN ARE ALL RELATED TO CHRONIC INFLAMMATION. YET, CHINESE PRACTICES IN HEALTHY DIET AND EMOTIONAL BALANCE MAY DECREASE INFLAMMATION. OUR PRELIMINARY FINDINGS WERE BASED ON SELF-REPORTS, SO WE CANNOT EXPLAIN HOW THOSE MULTIFACETED SOCIOCULTURAL AND INDIVIDUAL FACTORS ARE INTERTWINED TO AFFECT INFLAMMATION IN THE BODY AND OUTCOME DIFFERENCES BETWEEN THE TWO RACIAL GROUPS. TO COMPREHENSIVELY UNDERSTAND SOCIOCULTURAL INFLUENCE ON INDIVIDUAL COPING BEHAVIORS AND HOW THEY IN TURN AFFECT RACIAL DIFFERENCES IN BIOLOGICAL RESPONSES (I.E., INFLAMMATION AND CORTISOL STRESS MARKERS), SYMPTOM SEVERITY, AND QUALITY OF LIFE, WE PROPOSE A BI-RACIAL, COHORT STUDY AMONG 260 CA BCS (1-5 YEARS POST DIAGNOSIS) WHO WILL BE AGE- AND STAGE-MATCHED TO 260 NHW BCS. UTILIZING A SOCIETY-BEHAVIOR-BIOLOGY MULTILEVEL FRAMEWORK, WE WILL INVESTIGATE THE DYNAMICS OF SOCIOCULTURAL, PSYCHOLOGICAL, AND BEHAVIORAL (DIET AND EXERCISE) INFLUENCES ON SYMPTOM SEVERITY, BIOLOGICAL RESPONSES, AND FUNCTIONAL OUTCOMES. PARTICIPANTS WILL COMPLETE TELEPHONE SURVEY INTERVIEWS AND PROVIDE BLOOD SAMPLES AT BASELINE AND 6- AND 12-MONTH POST- BASELINE FOLLOW-UPS. NEXT, IN-DEPTH INDIVIDUAL INTERVIEWS WITH A SUBSET OF SAMPLES WILL BE CONDUCTED TO INVESTIGATE IN DEPTH THE CAUSATIVE FACTORS IN THE PATHWAYS IN ORDER TO DEVELOP INDIVIDUALLY AND CULTURALLY APPROPRIATE INTERVENTIONS CONDUCIVE TO IMPROVING CLINICAL CARE FOR TARGETED CANCER SURVIVOR POPULATIONS. THIS IS WELL ALIGNED WITH THE CANCER MOONSHOT INITIATIVE AIMED AT INCREASING SYMPTOM CONTROL AND IMPROVING SURVIVAL.

DEVELOPMENT OF SELECTIVE HDAC6 INHIBITORS TO IMPROVE CANCER IMMUNOTHERAPY - PROJECT SUMMARY THE MEDIAN SURVIVAL FOR METASTATIC MELANOMA IS APPROXIMATELY 8–16 MONTHS, AND FEW THERAPIES OFFER A SIGNIFICANT IMPROVEMENT IN OVERALL SURVIVAL. HOWEVER, IMMUNOTHERAPEUTIC STRATEGIES THAT ABROGATE IMMUNOLOGIC CHECKPOINTS OR IMPROVE IMMUNOSURVEILLANCE HAVE SHOWN PROMISE, ESPECIALLY IN MELANOMA. WE HAVE FOUND THAT BOTH GENETIC ABROGATION AND PHARMACOLOGIC INHIBITION OF HDAC6 LEADS TO A DECREASED INFILTRATION OF PRO-TUMORAL TUMOR-ASSOCIATED MACROPHAGES AND DOWNREGULATION OF IMMUNOSUPPRESSIVE MEDIATORS. THESE EFFECTS TRANSLATED INTO A PRONOUNCED DELAY OF IN VIVO MELANOMA TUMOR GROWTH, WHICH IS, AT LEAST IN PART, DEPENDENT ON INTACT IMMUNITY, AS EVIDENCED BY THE RESTORATION OF TUMOR GROWTH AFTER CD4+ AND CD8+ DEPLETION. OUR FINDINGS DEMONSTRATE A SIGNIFICANT IMMUNOREGULATORY ROLE OF HDAC6 IN MELANOMA, PROVIDING A RATIONALE FOR THE USE OF SELECTIVE HDAC6IS TO IMPROVE ANTITUMOR IMMUNITY. WE ARE MOST INTERESTED IN IDENTIFYING HDAC6IS THAT ARE BEST ABLE TO REDUCE THE PRO-TUMORAL PHENOTYPE OF TUMOR-ASSOCIATED MACROPHAGES AND DECREASE THE EXPRESSION OF IMMUNOSUPPRESSIVE SURFACE MOLECULES SUCH AS PD-L1 AND PD-L2 WHILE SHOWING LITTLE CYTOTOXICITY ON THEIR OWN. OUR GOAL IS THUS TO DESIGN, SYNTHESIZE, AND TEST NEW HDAC6I BOTH IN VITRO AND IN VIVO FOR USE IN THE TREATMENT OF MELANOMA AND OTHER MALIGNANCIES. THE AIMS TO BE ACCOMPLISHED UNDER THIS GRANT ARE AS FOLLOWS: 1. USING MOLECULAR MODELING, DESIGN, AND SYNTHESIZE ~50 NEW HDAC6IS PER YEAR, FOR THE FIRST THREE YEARS AND TEST THESE FOR HDAC ISOZYME SELECTIVITY; THE LAST TWO YEARS OF THE GRANT WILL FOCUS ON COMPOUND SCALE-UP, PRECLINICAL TRANSLATIONAL STUDIES, AND ADVANCED ADMET TESTING. 2. EVALUATE COMPOUNDS THAT HAVE IC50 VALUES OF <50NM AND AT LEAST 400-FOLD HDAC6 SELECTIVITY USING IN VITRO MELANOMA MODELS TO MEASURE ACETYLATED TUBULIN, PSTAT3, PD-L1 LEVELS, AND CYTOTOXICITY. FOR COMPOUNDS FOUND TO DECREASE LEVELS OF PSTAT3 AND PD-L1, WHILE INCREASING ACETYLATED TUBULIN, CONDUCT EARLY-STAGE ADMET STUDIES (2 – 3/YEAR) USING A CRO, AND IF NEEDED, MODIFY THE COMPOUNDS USING PRINCIPLES OF MEDICINAL CHEMISTRY AND MOLECULAR MODELING BASED METHODS TO INCREASE THE COMPOUND’S DRUG-LIKE CHARACTER. 3. LASTLY, TEST THE BEST COMPOUNDS FOR THEIR ABILITY TO DELAY TUMOR GROWTH IN SYNGENEIC MURINE MELANOMA MODELS, BOTH AS STAND-ALONE AND IN COMBINATION WITH PD-1 BLOCKING ANTIBODIES. ADDITIONALLY, WE WILL EVALUATE OUR BEST CANDIDATES USING HUMANIZED PDX MODELS AND AS A CELL THERAPY PRE-TREATING MACROPHAGES TO AVOID THEIR SWITCH TO M2-LIKE PROTUMORAL PHENOTYPE. THOSE CANDIDATES SHOWING THE BEST IN VIVO EFFICACY WILL BE SENT FOR ADVANCED ADMET, INCLUDING CHRONIC TOXICITY STUDIES, CARDIAC ACTIVITY, AND PULMONARY ACTIVITY IN RATS. OUR PROPOSED WORK IS SIGNIFICANT AS IT HELPS TO FILL THIS CRITICAL KNOWLEDGE GAP AND THUS MOVES EPIGENETIC- BASED COMBINATION IMMUNOTHERAPIES TO A NEW LEVEL. THE CONCEPT TO BE VALIDATED IS NOVEL AS IT SIGNIFICANTLY DEVIATES FROM THE CLASSICAL CYTOTOXIC ROLE OF HDAC INHIBITORS AS ANTI-CANCER AGENTS.

USING DIGITAL SIGNALS FROM CREDIT DATA FOR EARLY DETECTION OF ALZHEIMER'S DISEASE AND RELATED DEMENTIAS - PROJECT SUMMARY THE VALUE OF EARLY DIAGNOSIS FOR ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD) IS INCREASINGLY RECOGNIZED. HOWEVER, AVAILABLE DIAGNOSTIC TOOLS RELY PRIMARILY ON THE MANIFESTATION OF COGNITIVE SYMPTOMS THAT INTERFERE WITH EVERYDAY ACTIVITIES, AND SCREENING TOOLS TO SUPPORT EARLIER IDENTIFICATION OF INDIVIDUALS WITH ADRD ARE LACKING. CREDIT DATA REPRESENT A UNIQUE FOUNDATIONAL DATA SOURCE UPON WHICH MACHINE LEARNING ALGORITHMS CAN BE DEVELOPED TO IDENTIFY INDIVIDUALS AT RISK FOR ADRD AND FACILITATE EARLIER DIAGNOSIS. THE STRENGTH OF THE INFORMATION SIGNAL FROM CREDIT DATA FOR IDENTIFYING THOSE AT RISK FOR ADRD IS SUPPORTED BY PREVIOUS RESEARCH THAT FINDS, FIRST, THAT SIGNIFICANT LIMITATIONS AND RAPID DECLINES IN FINANCIAL CAPACITY ARE A HALLMARK OF EARLY-STAGE DISEASE AND, SECOND, THAT AFFLICTED INDIVIDUALS AND THEIR FAMILIES EXPERIENCE NEGATIVE ECONOMIC CONSEQUENCES DURING EARLY-STAGE DISEASE. WE PROPOSE USING A MASSIVE DATABASE—THAT WE HAVE ALREADY CONSTRUCTED—OF CREDIT DATA FROM EQUIFAX WHICH IS THE BASIS OF THE FEDERAL RESERVE BANK OF NEW YORK’S CONSUMER CREDIT PANEL (CCP), MERGED AT THE INDIVIDUAL LEVEL USING A UNIQUE COMMON IDENTIFIER (SOCIAL SECURITY NUMBER), WITH MEDICARE ENROLLMENT AND CLAIMS DATA. THE DATA ENCOMPASS MORE THAN 84 MILLION PERSON-YEARS OF DATA IN TOTAL, WITH MORE THAN 1.7 MILLION INDIVIDUALS WHO HAVE BEEN DIAGNOSED WITH ADRD. OUR SPECIFIC AIMS ARE TO: (1) ESTIMATE THE EFFECTS OF EARLY-STAGE ADRD ON A WIDE RANGE OF FINANCIAL OUTCOMES MEASURED IN CREDIT DATA, ALLOWING FOR POTENTIAL DIFFERENCES IN THE EFFECTS OF EARLY-STAGE ADRD DEPENDING ON CHARACTERISTICS SUCH AS RACE/ETHNICITY, EDUCATION, GENDER, AND HOUSEHOLD STRUCTURE; (2) APPLY MACHINE LEARNING METHODS TO OUR ALREADY- DEVELOPED MASSIVE DATA BASE WITH MERGED CREDIT (CCP) AND MEDICARE DATA IN ORDER TO DEVELOP ALGORITHMS THAT ARE CAPABLE OF IDENTIFYING INDIVIDUALS AT RISK FOR ADRD; AND (3) ASSESS THE ROBUSTNESS OF THE ALGORITHM TO THE INCLUSION OF NEWLY AVAILABLE YEARS OF MEDICARE CLAIMS AND ENROLLMENT DATA. THE FINDINGS FROM SPECIFIC AIM 1 ARE IMPORTANT FOR IDENTIFYING AND UNDERSTANDING THE SPECIFIC FINANCIAL OUTCOMES INDIVIDUALS WITH ADRD ARE MOST SUSCEPTIBLE TO DURING THE EARLY STAGE OF DISEASE AND WILL HELP INFORM THE MACHINE LEARNING MODELS IN SPECIFIC AIMS 2 AND 3.

COGNITIVE AGING, ALZHEIMERS DISEASE, AND CANCER-RELATED COGNITIVE DECLINE

NATIONAL CENTER FOR CULTURAL COMPETENCE

DEVELOPMENT OF BRCA1-MIMETIC DRUGS FOR BREAST CANCER

STROKE CENTRAL ATLANTIC NETWORK FOR RESEARCH (SCANR)

SOCIAL DETERMINANTS OF HEALTH AS TRANSDUCERS OF CELLULAR AGING: A NEW MULTI-LEVEL PARADIGM TO REDUCE SURVIVORSHIP DISPARITIES AT THE INTERSECTION OF CANCER AND AGING - BY 2030, THREE-QUARTERS OF THE 22 MILLION US CANCER SURVIVORS WILL BE 65 AND OLDER AND THE NUMBER OF OLDER HISPANIC AND BLACK SURVIVORS WILL HAVE GROWN THREE TIMES FASTER THAN WHITES. THESE SHIFTING DEMOGRAPHICS ARE DRIVING A CRISIS IN CANCER CARE DUE TO A PAUCITY OF EVIDENCE TO GUIDE CARE FOR OLDER SURVIVORS, ESPECIALLY OLDER RACIAL/ETHNIC SURVIVORS FOR WHOM DATA IS VIRTUALLY LACKING. FILLING THESE GAPS WILL REQUIRE AN UNDERSTANDING OF SEVERAL COMPLEX MULTIDIRECTIONAL RELATIONSHIPS AT THE INTERSECTION OF HEALTH DISPARITIES, AGING AND CANCER. COMPARED TO OLDER WHITE SURVIVORS, OLDER RACIAL/ETHNIC MINORITY SURVIVORS HAVE HAD MORE LIFETIME EXPOSURES TO ADVERSE SOCIAL DETERMINANTS OF HEALTH. THESE EXPOSURES ACCELERATE AGING PROCESSES. AGING INCREASES THE RISK OF DEVELOPING CANCER THROUGH ACCUMULATED DAMAGE AND MUTATIONS. CANCER AND ITS THERAPIES, IN TURN, ARE DISEASE DRIVERS OF AGING. TOGETHER, THESE INTERSECTING FORCES ARE LIKELY TO EXACERBATE CURRENT RACIAL/ETHNIC CANCER DISPARITIES IN THE HEALTH AND QUALITY OF LIFE OF OLDER SURVIVORS. THE VISION FOR THIS OUTSTANDING INVESTIGATOR AWARD IS TO FUNDAMENTALLY SHIFT HOW WE APPROACH CANCER DISPARITIES BY PROVIDING A MECHANISTIC UNDERSTANDING OF THE ROLE OF CELLULAR AGING IN THE RELATIONSHIPS BETWEEN SOCIAL DETERMINANTS OF HEALTH AND SURVIVORSHIP OUTCOMES. I WILL USE A CONCEPTUAL MODEL THAT INTEGRATES A MULTI-LEVEL DISPARITIES FRAMEWORK WITH ONCOLOGY AND GEROSCIENCE PERSPECTIVES TO CONDUCT RESEARCH USING TRANSCRIPTOMIC AND OTHER -OMICS ANALYSES, EPIGENETICS, MACHINE LEARNING, MEDIATION MODELS, META-SYNTHESIS AND POPULATION SIMULATION METHODS. THE BROAD GOALS OF MY TRANSDISCIPLINARY RESEARCH PROGRAM ARE TO: 1) DISCOVER CELLULAR AGING PROCESSES IN LARGE COHORTS OF OLDER BLACK, HISPANIC AND WHITE SURVIVORS THAT EXPLAIN RELATIONSHIPS BETWEEN HEALTH DETERMINANTS AND QUALITY OF LIFE (E.G., VIA STRESS SIGNALING AND DOWNSTREAM EFFECTS ON CELLULAR AGING VIA INFLAMMATORY GENE EXPRESSION), 2) DEFINE MECHANISTIC PATHWAYS SUGGESTED BY COHORT RESULTS AND TEST THE IMPACT OF INTERVENTIONS TARGETING THOSE PATHWAYS IN A PRECLINICAL MODEL OF CANCER SURVIVORSHIP AND 3) TRANSLATE RESULTS TO PRACTICE AND POLICY. DURING MY CONTINUOUSLY NIH-FUNDED RESEARCH CAREER, I HAVE MADE TRANSFORMATIVE CONTRIBUTIONS THAT SUPPORT MY PROPOSED RESEARCH PROGRAM. THERE ARE FEW POPULATION SCIENTISTS WITH THE UNIQUE BACKGROUND AND PROVEN TRACK RECORD TO SUCCESSFULLY CONDUCT THIS IN-DEPTH RESEARCH PROGRAM SPANNING THE FULL TRANSLATIONAL CONTINUUM FROM PRECLINICAL TO COHORT STUDIES AND PRACTICE AND POLICY. COLLABORATION WITH SCIENTISTS FROM OUTSIDE MY DISCIPLINE WILL SUPPORT MY SUCCESS AND GENERATE NOVEL INSIGHTS. THE NEWLY ESTABLISHED GEORGETOWN LOMBARDI INSTITUTE ON CANCER AND AGING THAT I LEAD AND EXCEPTIONAL INSTITUTIONAL COMMITMENT AND INFRASTRUCTURE PROVIDE AN EXCEPTIONAL ENVIRONMENT. THIS OUTSTANDING INVESTIGATOR AWARD WILL PROVIDE ME WITH THE STABILITY NEEDED TO ACCELERATE KNOWLEDGE IN AN UNDERSTUDIED RESEARCH AREA WITH HIGH PUBLIC HEALTH SIGNIFICANCE AND CLINICAL RELEVANCE. IDENTIFICATION AND TESTING OF AGING MECHANISTICALLY-BASED INTERVENTIONS WILL SUPPORT EFFORTS TO TAILOR CLINICAL CARE FOR THE BURGEONING OLDER MINORITY SURVIVOR POPULATION AND COULD TO TRANSFORM HOW WE APPROACH CANCER DISPARITIES IN THE CONTEXT OF AGING.

TESTING A CULTURALLY TARGETED NARRATIVE VIDEO TO REDUCE DISPARITIES IN THE USE OF GENETIC COUNSELING AND TESTING IN LATINA WOMEN AT-RISK OF HBOC - ABSTRACT NATIONAL GUIDELINES RECOMMEND THAT WOMEN AT INCREASED RISK FOR HEREDITARY BREAST AND OVARIAN CANCER (HBOC) DUE TO BRCA1/2 MUTATIONS BE REFERRED FOR GENETIC COUNSELING AND CONSIDER GENETIC TESTING. AWARENESS OF A POSITIVE RESULT CAN INFORM TREATMENT DECISIONS FOR CANCER PATIENTS AND RISK MANAGEMENT PLANS IN BOTH CANCER SURVIVORS AND WOMEN UNAFFECTED WITH CANCER. THE SLOW TRANSLATION OF GUIDELINES INTO PRACTICE PARTICULARLY IMPACTS MINORITY POPULATIONS WHO RECEIVE SERVICES IN COMMUNITY HEALTH CLINICS. LATINA WOMEN HAVE LOWER AWARENESS AND USE OF GENETIC COUNSELING AND TESTING (GCT) THAN NON-LATINA WHITES. LATINAS FACE MULTIPLE HEALTH CARE, PRAGMATIC, AND PSYCHOSOCIAL BARRIERS TO GCT UPTAKE. LATINAS PREFER CULTURALLY TARGETED INTERVENTIONS IN SPANISH WITH PLAIN LANGUAGE, VISUAL AIDS, AND A NARRATIVE FORMAT. WE DEVELOPED A CULTURALLY TARGETED NARRATIVE VIDEO IN SPANISH FOR AT-RISK LATINAS. PILOTED IN A SINGLE-ARM TRIAL (N=40), LATINAS REPORTED HIGH SATISFACTION AND EXHIBITED A SIGNIFICANT INCREASE IN KNOWLEDGE FROM PRE- TO POST-TEST. NEARLY ALL PARTICIPANTS (95%) REPORTED AN INTEREST IN GCT, AND 62% COMPLETED GENETIC COUNSELING. WE WILL USE AN INNOVATIVE HYBRID RESEARCH DESIGN THAT COMBINES ELEMENTS OF TRADITIONAL EFFICACY STUDIES AS WELL AS BEST PRACTICES FROM IMPLEMENTATION RESEARCH TO ENHANCE THE QUALITY AND SPEED OF THE TRANSLATIONAL PROCESS. GUIDED BY AN EXPANDED INTEGRATED BEHAVIORAL MODEL, WE WILL CONDUCT A RCT TO EVALUATE THE EFFICACY OF OUR VIDEO VS. THE FORCE FACT SHEET ON ENHANCING GCT UPTAKE AND PSYCHOSOCIAL OUTCOMES. TO MAXIMIZE THE POTENTIAL FOR IMPLEMENTATION IN COMMUNITY CLINICS, WE WILL TRAIN CLINIC STAFF TO ADMINISTER THE REFERRAL SCREENING TOOL (RST), A VALIDATED TOOL TO IDENTIFY WOMEN AT-RISK OF HBOC. GUIDED BY THE CONSOLIDATED FRAMEWORK FOR IMPLEMENTATION RESEARCH, WE WILL CONDUCT AN IMPLEMENTATION FOCUSED PROCESS EVALUATION TO GATHER DATA ON CLINIC IMPLEMENTATION OUTCOMES FOR USE OF THE REFERRAL SCREENING TOOL AND THE VIDEO. WE WILL REFER PARTICIPANTS TO FREE SPANISH TELEPHONE GENETIC COUNSELING. WE WILL RANDOMIZE 300 AT-RISK LATINAS AT FOUR SITES WITH LARGE LATINX POPULATIONS. OUR PRIMARY OUTCOME IS GENETIC COUNSELING UPTAKE. AIM 1. EVALUATE THE IMPACT OF OUR VIDEO VS. FACT SHEET ON GCT UPTAKE. PARTICIPANTS IN THE VIDEO ARM WILL HAVE HIGHER GENETIC COUNSELING UPTAKE (H1.1.) AND HIGHER GENETIC TESTING UPTAKE (H1.2.) AT 4 MONTHS. AIM 2. EVALUATE THE IMPACT OF OUR VIDEO VS. FACT SHEET ON PSYCHOSOCIAL AND PROCESS EVALUATION OUTCOMES. H2.1: VIDEO PARTICIPANTS WILL HAVE HIGHER KNOWLEDGE, POSITIVE ATTITUDES, SUBJECTIVE NORMS, SELF-EFFICACY, AND POSITIVE ANTICIPATORY EMOTIONS. H2.2. VIDEO PARTICIPANTS WILL HAVE HIGHER ACCEPTABILITY AND FEASIBILITY RATINGS. EXPLORATORY AIM: EVALUATE MECHANISMS OF THE VIDEO'S IMPACT ON GENETIC COUNSELING UPTAKE (KNOWLEDGE, ATTITUDES, NORMS, SELF-EFFICACY, ANTICIPATORY EMOTIONS). IF COUNSELING UPTAKE DOES NOT DIFFER BY ARM, THEN WE WILL EVALUATE PREDICTORS OF UPTAKE. AIM 3. EXAMINE KEY IMPLEMENTATION OUTCOMES OF FEASIBILITY, ACCEPTABILITY, ADOPTION, FIDELITY, AND FUTURE SUSTAINABILITY OF USING THE REFERRAL SCREENING TOOL AND THE VIDEO AT THE COMMUNITY CLINICS.

REGULATION OF RENAL FUNCTION AND BP BY THROMBOXANE

UNIVERSITY CENTER FOR EXCELLENCE IN DEVELOPMENTAL DISABILITIES

PIRE: INTERNATIONAL RESEARCH PROGRAM IN COGNITIVE AND COMPUTATIONAL NEUROSCIENCE

RECRUITMENT AND SAMPLE COLLECTION FOR ANTECEDENT BIOMARKER DISCOVERY IN PARKINSON'S DISEASE

APPLICATION OF SINGLE CHAIN ANTIBODIES FOR PD THERAPY

GEORGETOWN UNIVERSITY CENTER FOR EXCELLENCE IN DEVELOPMENTAL DISABILITIES

A RCT TO PROMOTE MAMMOGRAPHY ADHERENCE AMONG CHINESE IMMIGRANT WOMEN

COLLABORATIVE RESEARCH IN INTEGRATIVE CANCER BIOLOGY

TELOMERE DYSFUNCTION, CHROMOSOME 9 INSTABILITY AND BLADDER CANCER RISK

TRAINING IN NEURAL INJURY AND PLASTICITY

THE ROLE OF SELF-REGULATION AND CLASSROOM SELF-REGULATORY SUPPORTS IN EARLY EDUCATION

FUNCTIONAL MECHANISMS AND THERAPEUTIC POTENTIAL OF EAG CHANNEL REGULATORS - ETHER-A-GO-GO (EAG) POTASSIUM SELECTIVE CHANNELS ARE IMPORTANT REGULATORS OF NEURONAL EXCITABILITY AND CANCER PROGRESSION. DEFECTS IN EAG CHANNEL FUNCTION ARE ASSOCIATED WITH NEUROLOGICAL DISORDERS AND CANCER. DESPITE THE PHYSIOLOGICAL IMPORTANCE OF EAG CHANNELS, MOLECULAR MECHANISMS OF EAG CHANNEL REGULATION BY INTRACELLULAR LIGANDS AND CLINICALLY RELEVANT EAG CHANNEL REGULATORS ARE NOT KNOWN. THE GOAL OF THIS PROPOSAL IS TO UNCOVER MOLECULAR MECHANISMS OF EAG CHANNEL REGULATION BY INTRACELLULAR LIGANDS RECENTLY DISCOVERED BY OUR LABORATORY AND TO DETERMINE A THERAPEUTIC POTENTIAL OF THESE LIGANDS FOR TREATMENT OF DISEASES LINKED TO EAG CHANNELS. IN SPECIFIC AIM 1 WE PLAN TO SOLVE X-RAY STRUCTURES OF THE INTRACELLULAR PER-ARNT-SIM (PAS) AND CYCLIC NUCLEOTIDE- BINDING HOMOLOGY (CNBH) DOMAINS OF EAG CHANNELS BOUND TO THE RECENTLY IDENTIFIED LIGANDS AND CONDUCT COMPUTATIONAL SIMULATIONS OF THE LIGAND BINDING TO THE PAS AND CNBH DOMAINS TO UNCOVER THE STRUCTURAL BASIS OF EAG CHANNEL REGULATION BY THE INTRACELLULAR LIGANDS. THE STRUCTURAL FINDINGS WILL BE THEN USED AS A ROAD MAP TO GUIDE FUNCTIONAL EXPERIMENTS ON THE MOLECULAR MECHANISMS OF EAG CHANNEL REGULATION BY THE LIGANDS. IN SPECIFIC AIM 2 WE PLAN TO USE SURFACE PLASMON RESONANCE METHOD TO IDENTIFY NOVEL EAG CHANNEL LIGANDS THAT AFFECT CHANNEL FUNCTION THROUGH PAS AND CNBH DOMAIN INTERFACE. WE WILL THEN USE ELECTROPHYSIOLOGY TO DETERMINE FUNCTIONAL IMPLICATIONS OF STRENGTHENING OR WEAKENING OF THE PAS/CNBH DOMAIN INTERFACE BY THE IDENTIFIED REGULATORS ON THE FUNCTION OF EAG CHANNELS. IN SPECIFIC AIM 3 WE PLAN TO USE TISSUE CULTURE AND ZEBRAFISH XENOGRAFT MODELS TO TEST THERAPEUTIC POTENTIAL OF THE IDENTIFIED REGULATORS FOR TREATMENT OF CANCER. THE RESULTS OF THESE STUDIES WILL BE CRUCIAL FOR UNDERSTANDING FUNDAMENTAL REGULATORY MECHANISMS OF EAG AND RELATED ERG AND ELK CHANNELS, AND FOR ATTAINING THERAPEUTIC POTENTIAL OF EAG CHANNEL REGULATORS.

APOE EFFECTS ON NEURON SIGNALING AND FUNCTION VIA APOER2

COMMUNITY CHILD HEALTH NETWORK: DISTRICT OF COLUMBIA

SUCCUMBING, SURVIVING, AND THRIVING: THE DEVELOPMENT OF LOW-INCOME STUDENTS IN THE LONG SHADOW OF COVID-19 - PROJECT SUMMARY THE COVID-19 PANDEMIC POSES A SUSTAINED THREAT TO THE WELLBEING OF ALL CHILDREN, BUT PARTICULARLY FOR LOW- INCOME, RACIALLY MINORITIZED, AND SPECIAL NEEDS SUBGROUPS. THIS UNPREDICTABLE, COMPLEX, RACIALIZED CRISIS HAS EXPOSED MILLIONS OF CHILDREN TO MASSIVE DISRUPTIONS OF THEIR EDUCATIONAL CONTEXTS WHEN SCHOOLS CLOSED, WITH GROWING ACCOUNTS OF ASSOCIATED LEARNING LOSS, SOCIAL ISOLATION, AND EMOTIONAL DISTRESS. SCHOLARS HAVE MOBILIZED TO STUDY THE PANDEMIC, YET MUCH OF THIS EMERGING RESEARCH DRAWS ON SMALL, RELATIVELY HOMOGENEOUS (MOSTLY WHITE) SAMPLES, LIMITING APPLICABILITY TO THE SUBGROUPS MOST AFFECTED BY THIS PANDEMIC AND ITS MULTISYSTEM DISRUPTIONS (E.G., LATINX [INCLUDING ELL]; BLACK; CHILDREN WITH SPECIAL NEEDS). LITTLE OF THIS NEW RESEARCH CONTAINS EXTENSIVE, REPEATED MEASURES OF PRE-COVID-19 CHILD FUNCTIONING. NOR DOES IT CAPTURE THE MULTISYSTEM CULTURALLY-EMBEDDED PROTECTIVE FACTORS LIKELY TO INFLUENCE SHORT- AND LONGER-TERM DEVELOPMENTAL RECOVERY FOR THE CURRENT US CHILD POPULATION. THUS, THERE IS AN URGENT NEED FOR CULTURALLY-RELEVANT, LONGITUDINAL RESEARCH SPANNING THE PERIOD FROM BEFORE THE PANDEMIC AND CONTINUING, ON DIVERSE SAMPLES OF CHILDREN TO INFORM CURRENT AND FUTURE PANDEMIC PREPARATION AND RESPONSE EFFORTS. THE PROPOSED PROJECT FILLS THIS GAP BY CAPTURING CHILDREN’S PRE-K-1ST GRADE PRE-PANDEMIC FUNCTIONING AND FOLLOWING THEM THROUGH - AND WELL BEYOND - THE PERIOD OF WIDESPREAD QUARANTINES AND SCHOOL CLOSURES, AS THEY ENTER ADOLESCENCE. LEVERAGING DATA FROM AN EXISTING, ONGOING, LARGE, HIGHLY DIVERSE SAMPLE OF LOW-INCOME STUDENTS IN TITLE I SCHOOLS WHO HAVE BEEN FOLLOWED SINCE THEY WERE PRESCHOOLERS IN 2016, THE PROPOSED STUDY WILL (AIM 1A) DETERMINE THE IMPACTS OF COVID-19 DISRUPTIONS WHEN SCHOOLS WERE CLOSED ON CHILDREN’S SHORT-TERM OUTCOMES IN THE YEARS IMMEDIATELY FOLLOWING SCHOOL REOPENING (3RD-5TH GRADE); (AIM 1B) INVESTIGATE HOW SHORT-TERM OUTCOMES ARE EXACERBATED OR MITIGATED BY INDIVIDUAL DIFFERENCES IN CHILDREN’S PRE-COVID-19 STRENGTHS AND VULNERABILITIES; (AIM 2A) EXPLORE THE LONGER- TERM IMPACTS OF DISRUPTION ON DEVELOPMENT BY ADDING REPEATED MEASUREMENT OF CHILDREN’S OUTCOMES IN THE LONGER TERM FOLLOWING SCHOOL REOPENING, THROUGH 9TH GRADE; AND (2B) IDENTIFY THE MOST POTENT FEATURES OF CHILDREN’S POST-SCHOOL-REOPENING FAMILY, SCHOOL, AND PEER CONTEXTS – INCLUDING CULTURALLY-EMBEDDED FAMILY FACTORS – THAT MITIGATE THE LONGER-TERM IMPACTS (THROUGH 9TH GRADE) OF COVID-19 DISRUPTION ON RECOVERY OF CONSEQUENTIAL EARLY ADOLESCENT OUTCOMES, INCLUDING MENTAL HEALTH. BY DETERMINING EFFECTS OF EDUCATIONAL AND FAMILY-BASED DISRUPTIONS DURING SCHOOL CLOSURES, AND FAMILY DISRUPTIONS THAT CONTINUE AFTER SCHOOLS REOPENED, ON VARYING DEVELOPMENTAL TRAJECTORIES, AND IDENTIFYING CULTURALLY-EMBEDDED PROTECTIVE FACTORS, THIS PROJECT MOVES WELL BEYOND IDENTIFYING RISK GROUPS TO SPECIFYING SHARED AND UNIQUE ASPECTS OF CHILDREN’S FAMILY, SCHOOL, AND PEER CONTEXTS THAT PROMOTE LONG-TERM RESILIENCE IN A HIGHLY DIVERSE SAMPLE. IT THUS HOLDS TREMENDOUS PROMISE FOR ADVANCING KNOWLEDGE TO IMPROVE PUBLIC HEALTH AND INFORM CURRENT AND FUTURE DISASTER PREPARATION, RELIEF, AND RECOVERY EFFORTS TAILORED TO CHILDREN ESPECIALLY SUSCEPTIBLE TO NEGATIVE OUTCOMES.

(PQ #8) BIOMARKERS OF EFFICACY AND ADVERSE EVENTS DUE TO TREATMENT WITH IMMUNE CHECKPOINT INHIBITORS

PATERNAL DDT EXPOSURE AND PROGRAMMING OF METABOLIC DYSFUNCTION AND CANCER IN OFFSPRING: UNDERSTANDING THE ROLE OF SPERM MIRNAS AND PLACENTA DEVELOPMENT - EXPOSURE TO CHEMICALS PRESENT IN THE ENVIRONMENT CAN INDUCE EPIGENETIC CHANGES IN PATERNAL SPERM AND AFFECT RISK OF DISEASE IN OFFSPRING. THIS MOLECULAR MEMORY OF PAST EXPOSURES CAN BE TRANSMITTED BETWEEN GENERATIONS VIA SPERM NON-CODING RNAS SUCH MIRNAS. OUR LONG-TERM GOALS TO UNDERSTAND HOW PARENTAL ENVIRONMENTAL EXPOSURES CAN PREDISPOSE CHILDREN TO DISEASES SUCH AS DIABETES AND CANCER ALIGNS WITH AIMS IN THE NIEHS’ STRATEGIC PLANNING. THE PESTICIDE DDT(DICHLORODIPHENYLTRICHLOROETHANE) IS AN ENVIRONMENTAL TOXICANT WITH ENDOCRINE DISRUPTOR (EDC) ACTIVITY. WHILE BANNED FROM WESTERN COUNTRIES FOR OVER 30 YEARS, DDT IS A PERSISTENT ENVIRONMENTAL POLLUTANT THAT IS STILL IS DETECTED IN THE AMERICAN POPULATION, PARTICULARLY IN MINORITIES AND RECENT IMMIGRANTS. CURRENTLY, THE MAJOR OF SOURCE OF THIS PESTICIDE IN THE U.S. IS FOOD IMPORTED FROM REGIONS WHERE DDT IS USED. OUR PRELIMINARY DATA, GENERATED IN A MOUSE MODEL, SHOW THAT PRE-CONCEPTION EXPOSURE TO DDT ALTERS MIRNAS IN PATERNAL SPERM. MORE IMPORTANTLY, PATERNAL DDT LEADS TO LOW BIRTH WEIGHT, A PHENOTYPE ASSOCIATED WITH REDUCED PLACENTA AND FETAL SIZE. OFFSPRING OF DDT FATHERS SHOW METABOLIC DYSFUNCTION AND ACCELERATED CANCER GROWTH. WE HYPOTHESIZE THAT PROGRAMMING OF OFFSPRING’S DISEASE BY PRE-CONCEPTION PATERNAL DDT EXPOSURE OCCURS VIA SPERM MIRNA WHICH ALTERS PLACENTA DEVELOPMENT AND FETAL GROWTH. WE ALSO HYPOTHESIZE THAT DDT EXPOSURE SIGNALS ARE RELAYED TO SPERM VIA EXTRACELLULAR VESICLES SECRETED BY EPIDIDYMAL CELLS. OUR HYPOTHESIS WILL BE TESTED IN A MOUSE MODEL AND IN CELL CULTURES BY FOCUSING ON THE FOLLOWING AIMS: 1) TO EXAMINE THE MECHANISMS BY WHICH ENVIRONMENTALLY RELEVANT DOSES OF DDT AND ITS METABOLITE, DDE, ALTER THE MIRNA (AND OTHER SMALL RNAS) CONTENT IN PATERNAL SPERM; 2) TO CHARACTERIZE THE MECHANISMS UNDERLYING ALTERATIONS IN PLACENTA DEVELOPMENT AND FUNCTION RESULTING FROM PATERNAL DDT EXPOSURE; 3) TO EVALUATE WHETHER MIRNAS (AND POSSIBLY OTHER SMALL RNAS) IN SPERM OF DDT EXPOSED MALES ARE MECHANISTICALLY LINKED TO ALTERATIONS IN PLACENTA AND FETAL DEVELOPMENT. WHILE THE EVIDENCE SHOWING THAT PATERNAL EXPOSURES PROGRAMS DISEASE IN OFFSPRING IS ROBUST, OUR UNDERSTANDING OF THE UNDERLYING MECHANISMS IS STILL LACKING. DEFINING THE MECHANISMS BY WHICH PATERNAL EXPOSURE TO DDT AND OTHER EDCS CAN PROMOTE CHANGES IN FETAL AND PLACENTA DEVELOPMENT IS CRITICAL TO IDENTIFYING PREVENTIVE TOOLS FOR DISEASE SUCH AS DIABETES AND CANCER. THIS STUDY WILL ALSO CONTRIBUTE THE GENERAL UNDERSTANDING OF ENVIRONMENTALLY-INDUCED NON-GENETIC INHERITANCE AND COULD LEAD TO PUBLIC HEALTH RECOMMENDATIONS TO MEN OF REPRODUCTIVE AGE. FINALLY, OUR FINDINGS COULD LEAD TO POTENTIAL PLACENTAL BIOMARKERS OF PARENTAL EXPOSURE.

ENGLISH LEARNERS’ EDUCATIONAL EXCELLENCE CAPITOL TEACHER TRAINING PROJECT (PROJECT ELEECT)

AGING AND ALZHEIMER'S RESEARCH TRAINING - THE GEORGETOWN UNIVERSITY “AGING AND ALZHEIMER’S RESEARCH TRAINING” (AART) PROGRAM IS DESIGNED FOR PREDOCTORAL STUDENTS AND POSTDOCTORAL FELLOWS WHOSE BACKGROUNDS HAVE NOT INCLUDED SUBSTANTIAL PREVIOUS TRAINING IN AGING OR ALZHEIMER’S DISEASE. IT IS DRIVEN BY A TRANSDISCIPLINARY GROUP OF RESEARCHERS ACROSS BIOMEDICAL TOPICS THAT ARE ASSOCIATED WITH COGNITIVE IMPAIRMENT WITH AGING (E.G., DIABETES, HIV-INFECTION, TRAUMATIC BRAIN INJURY, PROTEINOPATHIES, CHEMOTHERAPY, SEIZURES). THE AART PROGRAM WILL DIRECT ASPECTS OF THESE RESEARCH DISCIPLINES MORE DIRECTLY TO AGING AND AD RESEARCH THROUGH THE TRAINEES. PARTICIPATING FACULTY HAVE THE DEDICATED TIME AND THE UNIVERSITY SUPPORT TO ALLOW THE AART PROGRAM TO THRIVE. BEYOND THIS RESEARCH, THERE ARE TEN GENERAL AREAS OF REQUIRED TRAINING: 1) CLINICAL EXPOSURES IN THE MEMORY DISORDERS PROGRAM AND IN BRAIN CUTTINGS; 2) COURSEWORK IN AREAS OF BIOSTATISTICS, AGING, AND NEURODEGENERATION; 3) STRUCTURED PERSONAL INTERACTIONS EACH SEMESTER WITH RESEARCHERS FROM ALZHEIMER’S DISEASE RESEARCH CENTERS; 4) INTENSIVE GRANT WRITING FOR CURRENT RESEARCH PROJECTS AND NASCENT CAREERS; 5) ATTENDANCE AND PRESENTATIONS AT NATIONAL MEETINGS; 6) A NEW GEORGETOWN SYMPOSIUM ON AGING AND ALZHEIMER’S DISEASE; 7) COHORT WRITING OF A REVIEW PAPER ON AN INTERDISCIPLINARY RESEARCH TOPIC; 8) REGULAR TRAINING THE RESPONSIBLE CONDUCT OF RESEARCH AS WELL AS RIGOR AND REPRODUCIBILITY; 9) ROUNDTABLES TO PROMOTE THOUGHTFUL CONSIDERATION OF TRAINING EXPERIENCES, INCLUDING RESEARCH; AND 10) OUTREACH EXPERIENCES FOR PUBLIC EDUCATION AND SOCIAL GOOD. AS DEVELOPED, SEVERAL OF THESE REQUIRED ACTIVITIES ARE SPECIFIC TO THE AART COHORTS (E.G., PERSONAL INTERACTIONS WITH NATIONAL RESEARCH LEADERS, INSTRUCTION IN WRITING OF A PUBLISHABLE LITERATURE REVIEW, DATA PRESENTATIONS), AND SEVERAL MORE WOULD POSITIVELY IMPACT THE BROADER WASHINGTON, DC RESEARCH COMMUNITY (THE YEARLY AGING AND AD SYMPOSIUM; RESEARCH INTERACTIONS WITH REGIONAL ALZHEIMER’S DISEASE RESEARCH CENTERS). OTHER ACTIVITIES ENSURE THAT TRAINEES BENEFIT FROM CURRENT UNIVERSITY RESOURCES (JOURNAL CLUBS, EXISTING COURSEWORK, TRAINING IN QUANTITATIVE AND REPRODUCIBLE DATA ANALYSIS). TRAINEES WILL WORK WITH THE OFFICE OF CAREER STRATEGY AND PROFESSIONAL DEVELOPMENT, WHICH WILL ALSO AID IN THE RECRUITMENT OF INDIVIDUALS FROM UNDER-REPRESENTED MINORITY GROUPS. THE PROGRAM IS DIRECTED BY G. WILLIAM REBECK, WHO HAS CONTRIBUTED RESEARCH TO THESE AREAS FOR NEARLY 30 YEARS. OVERSIGHT IS PROVIDED BY AN EXECUTIVE COMMITTEE, AND BY INTERNAL AND EXTERNAL ADVISORY BOARDS. GEORGETOWN HAS THE ADVANTAGES OF A COHESIVE SET OF RESEARCHERS AND STRONG FINANCIAL SUPPORT FROM THE UNIVERSITY. FURTHERMORE, THERE ARE RESOURCES IN THE WASHINGTON DC AREA THAT ARE UNIQUE FOR BETTER TRAINING, INCLUDING RESEARCHERS AT THE NIH/NIA, HOWARD UNIVERSITY PROGRAMS, AND FEDERAL INTERACTIONS. THE GOAL OF THE AART IS TO TAKE STRONG EXISTING RESEARCH PROGRAMS AT GEORGETOWN RELATED TO CONDITIONS OF AGING, AND USE THEM TO TRAIN STUDENTS AND FELLOWS MORE INTENTIONALLY IN TOPICS OF AGING AND AD. THIS PROGRAM WILL ALSO DRIVE THESE RESEARCH LABS TO PRODUCE IMPACTFUL AGING AND AD RESEARCH.

BRAIN NETWORKS FOR READING IN STROKE ALEXIA AND TYPICAL AGING - PROJECT SUMMARY/ABSTRACT THE ABILITY TO READ IS FUNDAMENTAL TO LIVING IN MODERN SOCIETY. LOSS OF READING ABILITY DUE TO STROKE, CALLED ALEXIA, LIKELY AFFECTS OVER A MILLION AMERICANS AT ANY GIVEN TIME AND CAUSES DIFFICULTY PERFORMING MANY DAILY LIFE FUNCTIONS. TO IMPROVE DIAGNOSIS AND TREATMENT OF ALEXIA, WE MUST UNDERSTAND THE NEUROCOGNITIVE BASIS OF READING DEFICITS AFTER STROKE. HOWEVER, PRIOR SMALL-SCALE STUDIES USING BROAD DIAGNOSTIC CATEGORIES AND OLDER NEUROIMAGING METHODS HAVE YIELDED ONLY GENERAL LESION-BEHAVIOR ASSOCIATIONS IN ALEXIA. HERE, WE PROPOSE THE LARGEST STUDY TO DATE OF BOTH ALEXIA AND TYPICAL READING IN OLDER ADULTS, USING DETAILED MEASURES OF READING ABILITY AND THE MOST ADVANCED MULTIMODAL NEUROIMAGING METHODS AVAILABLE TO TEST A NEW NEUROCOGNITIVE MODEL. READING RELIES ON BRAIN NETWORKS THAT EVOLVED FOR SPEECH AND LANGUAGE PROCESSES, BUT NEUROCOGNITIVE MODELS OF READING HAVE NOT YET INCORPORATED RECENT ADVANCES IN OUR UNDERSTANDING OF THESE NETWORKS. WE PROPOSE A NEW MODEL OF READING INTEGRATED WITH SPEECH AND SEMANTICS (RISS) THAT PROVIDES A MORE SPECIFIC NEUROCOGNITIVE ARCHITECTURE FOR READING THAN PRIOR MODELS. WE HYPOTHESIZE THAT LESIONS OF SPECIFIC RISS NETWORK PROCESSORS AND CONNECTIONS ACCOUNT FOR SPECIFIC READING DEFICIT PATTERNS AFTER STROKE, AND THAT RESTORATION OF THE INJURED RISS PATHWAYS OR COMPENSATION IN UNINJURED PATHWAYS UNDERLIE ALEXIA RECOVERY. ALTHOUGH BRAIN NETWORKS FOR READING HAVE BEEN EXTENSIVELY MAPPED IN TYPICAL AND ATYPICAL YOUNG POPULATIONS, STROKE TENDS TO OCCUR IN THE AGING BRAIN AND IN PEOPLE OF LOW EDUCATION AND SOCIOECONOMIC STATUS (SES) WHO ARE TOO OFTEN LEFT OUT OF COGNITIVE NEUROSCIENCE RESEARCH. PATHOLOGICAL PATTERNS OF READING IN ALEXIA ARE ALSO OBSERVED TO A LESSER DEGREE IN TYPICAL READERS, AND AGE, EDUCATION AND SES ARE ALL KNOWN TO AFFECT READING ABILITIES. THEREFORE, ALEXIA CAN ONLY BE FULLY UNDERSTOOD BY EXAMINING HOW THESE FACTORS RELATE TO READING BEHAVIOR AND THE BRAIN IN TYPICAL OLDER ADULTS, AND REFERENCING READING DEFICITS TO THIS PERSONAL CONTEXT. IN THE FIRST STUDY OF THIS PROJECT, WE WILL COLLECT AN EXTENSIVE BATTERY OF READING AND LANGUAGE TESTS ALONG WITH ADVANCED MULTIMODAL MRIS IN 100 OLDER ADULTS DEMOGRAPHICALLY MATCHED TO STROKE SURVIVORS. WE WILL TEST HYPOTHESES BASED ON RISS AND EXAMINE HOW AGE, EDUCATION, AND SES RELATE TO BOTH BEHAVIOR AND THE BRAIN. WE WILL FREELY DISSEMINATE ALL TESTING MATERIALS AND BOTH BEHAVIORAL AND IMAGING DATA TO FACILITATE FURTHER RESEARCH IN THIS AREA. IN THE SECOND STUDY, WE WILL PERFORM THE SAME BEHAVIORAL BATTERY IN 200 CHRONIC STROKE SURVIVORS PROSPECTIVELY SELECTED BASED ON LESION ATTRIBUTES FROM A NEW IMAGING DATABASE OF THOUSANDS OF STROKE SURVIVORS. WE WILL MODEL THE EFFECTS OF THE LESIONS ON PROCESSORS AND CONNECTIONS IN RISS AND TEST BRAIN-BEHAVIOR HYPOTHESES USING LESION-NETWORK MAPPING ANALYSES. IN THE THIRD STUDY, WE WILL COLLECT DETAILED BEHAVIORAL DATA AND MULTIMODAL MRIS IN 50 STROKE SURVIVORS DURING THE SUBACUTE PERIOD AND AGAIN 12 MONTHS LATER TO TEST HYPOTHESES REGARDING MECHANISMS OF ALEXIA RECOVERY BASED ON RISS. THIS PROJECT WILL SUBSTANTIALLY ADVANCE OUR UNDERSTANDING OF THE NEUROCOGNITIVE BASIS OF READING IN BOTH ALEXIA AND TYPICAL AGING.

OPTIMIZING PERSONALIZED CARE USING ECONOMIC STUDIES OF GENOMIC TESTING

PROVIDING TOBACCO TREATMENT TO PATIENTS UNDERGOING LUNG CANCER SCREENING AT MEDSTAR HEALTH: A RANDOMIZED TRIAL - PROVIDING SMOKING CESSATION TREATMENT IN CONJUNCTION WITH THE RECENTLY EXPANDED LUNG CANCER SCREENING GUIDELINES IS ESTIMATED TO SUBSTANTIALLY REDUCE LUNG CANCER DEATHS AND INCREASE LIFE-YEARS GAINED COMPARED TO CONDUCTING LUNG SCREENING ALONE. ALTHOUGH CMS RECOMMENDS THAT INDIVIDUALS UNDERGOING LUNG SCREENING WHO CURRENTLY SMOKE ARE OFFERED CESSATION TREATMENT, THERE ARE MULTIPLE BARRIERS TO TREATMENT DELIVERY. IMPROVING THE EVIDENCE-BASE OF CESSATION TREATMENT FOR PATIENTS UNDERGOING LUNG SCREENING AND METHODS TO PROMOTE THE SYSTEMATIC UPTAKE OF CESSATION TREATMENT INTO ROUTINE PRACTICE, PARTICULARLY AMONG DIVERSE POPULATIONS, IS ESSENTIAL FOR REALIZING THE MAXIMUM BENEFIT OF LUNG SCREENING. GUIDED BY THE PRACTICAL, ROBUST, IMPLEMENTATION & SUSTAINABILITY FRAMEWORK, WE WILL EXTEND OUR PRIOR WORK (CA R01207228). WE PROPOSE A HEALTH SYSTEM-LEVEL, PRAGMATIC, RANDOMIZED TRIAL TO COMPARE THE EFFECTIVENESS OF TWO EVIDENCE-BASED CESSATION TREATMENTS, WITH IMPLEMENTATION STRATEGIES DESIGNED TO ADDRESS BARRIERS TO REACH AND ENGAGEMENT, PARTICULARLY AMONG UNDERSERVED GROUPS (E.G., RACIAL AND ETHNIC MINORITY GROUPS, UNDERINSURED PATIENTS, AND PATIENTS NOT READY TO QUIT) WHO ARE LESS LIKELY TO RECEIVE CESSATION TREATMENT. TO MAXIMIZE GENERALIZABILITY TO OTHER HEALTH SYSTEMS AND TO IMPROVE REACH AMONG HETEROGENEOUS GROUPS, ALL PATIENTS SCHEDULED AT ONE OF THE 10 LUNG SCREENING SITES AT MEDSTAR HEALTH, THE LARGEST AND MOST DIVERSE HEALTH SYSTEM IN THE MID-ATLANTIC, WILL BE IDENTIFIED VIA THE EHR, CONTACTED FOR ENROLLMENT USING AN OPT-OUT APPROACH, AND RANDOMIZED TO: 1) QUITLINE E-REFERRAL (QL-E; N=594) VIA THE EHR AND QUITLINE INTEGRATED SYSTEM, INCLUDING PROACTIVE OUTREACH AND STANDARD PHONE-BASED COUNSELING+ NICOTINE REPLACEMENT PROVIDED BY THE QUITLINE VS. 2) MEDSTAR HEALTH SYSTEM (MHS; N=594), A CENTRALIZED, PHONE-BASED+ NRT INTERVENTION ADAPTED AND IMPROVED FROM OUR PRIOR TRIAL, WITH A RANDOMIZED STEPPED CARE INTERVENTION FOR THOSE WHO ARE NOT ABSTINENT AT 3 MONTHS. SPECIFIC AIMS ARE: 1. TO COMPARE E-REFERRAL TO THE QUITLINE VS. THE CENTRALIZED HEALTH SYSTEM INTERVENTION. PRIMARY OUTCOMES ARE: BIOVERIFIED ABSTINENCE FROM CIGARETTES AT 3- AND 6-MONTHS. WE WILL ASSESS INTERVENTION MEDIATORS (E.G., TREATMENT ENGAGEMENT) AND MODERATORS (E.G., READINESS TO QUIT) AT 6-MONTHS. 2. TO EVALUATE REACH AND ENGAGEMENT OVERALL AND BY SUBGROUP (E.G., RACE AND ETHNICITY, UNDERINSURED, READINESS TO QUIT) AND USING MIXED-METHODS TO UNDERSTAND THE CONTEXTUAL FACTORS RELATED TO THE FEASIBILITY AND ACCEPTABILITY OF THE INTERVENTIONS AND IMPLEMENTATION STRATEGIES. 3. TO CONDUCT AN ECONOMIC ANALYSIS TO EVALUATE COSTS, AVERAGE AND INCREMENTAL COST PER QUIT, AND BUDGET IMPACT OF THE INTERVENTION AT 3- AND 6-MONTHS FROM THE HEALTH SYSTEM PERSPECTIVE. PROPOSAL STRENGTHS INCLUDE TESTING THE EFFECTIVENESS AND ECONOMIC OUTCOMES OF TWO CESSATION INTERVENTIONS WHILE SIMULTANEOUSLY LAYING THE GROUNDWORK FOR FUTURE IMPLEMENTATION WITHIN THIS AND OTHER DIVERSE HEALTH SYSTEMS. OUR INNOVATIVE APPROACH CAPITALIZES ON THE EHR FOR RECRUITMENT, PROVIDES MULTILEVEL TRAINING FOCUSED ON DIVERSE POPULATIONS, AND ACCOUNTS FOR INTERVENTION CONTEXT TO INFORM FUTURE CARE DELIVERY.

DEVELOP SCIENTIFIC, MEDICAL AND TECHNOLOGICAL ADVANCES TO SUPPORT MILITARY CONTINGENCIES

O-GLYCOPROTEINS IN THE PROGRESSION OF LIVER DISEASE

FY2008 NEAR EAST AND SOUTH ASIA UNDERGRADUATE EXCHANGE PROGRAM

MODELING THE POLICY IMPACT OF CIGARETTE AND SMOKELESS USE ON US MORTALITY

CAN MEDICAID MANAGED CARE MITIGATE RACE/ETHNIC HEALTH DISPARITIES IN DIABETES? - ABSTRACT THIS STUDY REPRESENTS A TIMELY INVESTIGATION THAT ADDRESSES RACE/ETHNIC DISPARITIES IN TYPE 2 DIABETES (T2DM) CARE OVER A PERIOD THAT INCLUDED A MAJOR PANDEMIC SHOCK. T2DM IS BURDENSOME AND DISPROPORTIONATELY IMPACTS VULNERABLE AND DISENFRANCHISED POPULATIONS; OF NOTE, THERE ARE STARK RACE/ETHNIC DISPARITIES IN T2DM CARE GOALS, EMERGENCY DEPARTMENT (ED) VISITS, AND HOSPITALIZATIONS. MEDICAID COVERS 25% OF AMERICANS WITH T2DM. MORE THAN 80% OF MEDICAID BENEFICIARIES NATIONALLY RECEIVE AT LEAST SOME OF THEIR CARE FROM MEDICAID MANAGED CARE ORGANIZATIONS (MMCO). STATES CONTRACT WITH PRIVATE (NON-PROFIT OR FOR-PROFIT) MMCOS TO LOWER COSTS, INCREASE QUALITY, AND PASS ON FINANCIAL RISKS OF COVERING MEDICAID BENEFICIARIES. HETEROGENEITY ACROSS AND WITHIN STATE PROGRAMS CAN HAVE IMPLICATIONS FOR QUALITY OF T2DM CARE AND, SPECIFICALLY, RACE/ETHNIC DISPARITIES THROUGH BENEFIT GENEROSITY OR BY AFFECTING MMCO ENTRY AND POST-ENTRY BEHAVIOR. STATE POLICYMAKERS ALSO HAVE SIGNIFICANT INFLUENCE OVER MARKETPLACES IN WHICH MMCOS COMPETE, WHICH CAN HAVE CONSEQUENCES FOR RACE/ETHNIC DISPARITIES, GIVEN THAT MEDICAID DISPROPORTIONATELY COVERS NON-WHITE POPULATIONS. LITTLE IS KNOWN ABOUT WHETHER AND HOW MMCOS AND THE STATE PROGRAMS THEY OPERATE IN INFLUENCE DISPARITIES IN T2DM CARE AND, IF OR HOW THE COVID-19 PANDEMIC CHANGED THE TRAJECTORY OF HEALTH DISPARITIES. WE PROPOSE TO ANSWER THESE UNKNOWNS USING A CONVERGENT MIXED-METHODS STUDY: WE WILL COMPILE A DATABASE OF MMCO/STATE PROGRAM FEATURES THAT COULD INFLUENCE CARE USING A HEALTH DISPARITIES CONCEPTUAL FRAMEWORK (AIM 1); WE WILL EMPIRICALLY EXPLORE RACE/ETHNIC DISPARITIES AMONG ADULTS WITH T2DM AND WHETHER THESE VARY BY MMCO/STATE FEATURES AND PRE-/POST-COVID-19 USING COMPREHENSIVE DATA FROM THE TRANSFORMED MEDICAID STATISTICAL INFORMATION SYSTEM OVER 2016-2025 (AIMS 2 AND 3); AND WE WILL COLLECT AND ANALYZE QUALITATIVE DATA FROM MEDICAID STAKEHOLDERS TO TRIANGULATE AND CONTEXTUALIZE THE QUANTITATIVE FINDINGS (AIM 4). WE FOCUS ON NON- DISABLED, NON-PREGNANT 18-64-YEAR-OLD ADULTS WITH T2DM WHO TEND TO REMAIN STABLY COVERED BY MEDICAID OVER TIME. TO REDUCE SELECTION BIAS, WE FOCUS OUR ANALYSES ON 12 STATES AND THE DISTRICT OF COLUMBIA THAT MANDATE ENROLLMENT IN COMPREHENSIVE MMCOS. WE WILL USE PANEL DATA MODELS TO EXAMINE RACE/ETHNIC AND SEX-SPECIFIC RECEIPT OF KEY T2DM SERVICES AND ED VISITS AND HOSPITALIZATIONS, OVERALL AND BY MMCO/STATE FEATURES. WE WILL ALSO FOLLOW A CONTINUOUSLY ENROLLED COHORT OVER 2020-2025 TO ASSESS IF AND HOW MMCO/STATE PROGRAM FEATURES MODERATE THE PANDEMIC’S EFFECTS ON T2DM DISPARITIES. SENSITIVITY ANALYSES WILL EXPLORE THE INFLUENCE OF CHURN. FURTHER, OUR PRELIMINARY ANALYSES IDENTIFY KENTUCKY AND FLORIDA AS HAVING THE LOWEST AND HIGHEST DISPARITIES IN T2DM CARE, RESPECTIVELY; WE WILL CONDUCT INTERVIEWS IN THESE STATES TO EXAMINE WHAT MMCO/STATE FEATURES AND IMPLEMENTATION MIGHT EXPLAIN THESE DISPARITIES. THIS POLICY-RELEVANT WORK WILL PROVIDE CRITICAL INSIGHTS INTO HOW MEDICAID MANAGED CARE PROGRAMS CAN BE DESIGNED TO REDUCE DISPARITIES IN CHRONIC DISEASE BURDENS.

PREDICTORS OF ADJUVANT ENDOCRINE THERAPY ADHERENCE IN WOMEN WITH BREAST CANCER

ASSURING PUBLIC HEALTH INTERNATIONAL AND DOMESTIC SECURITY (APHIDS)

NEW; TITLE: A METABOLOMICS AND MOUSE MODELS APPROACH TO STUDY INFLAMMATORY AND IMMUNE RESPONSES TO RADIATION; PI: ALBERT FORNACE

DE-DUPLICATION OF CASE PAIRS IN THE NATIONAL HIV SURVEILLANCE SYSTEM USING THE BLACK BOX

SYSTEMS METABOLOMICS FOR BIOMARKER DISCOVERY - PROJECT SUMMARY METABOLOMICS OFFERS A COMPREHENSIVE ANALYSIS OF THOUSANDS OF SMALL MOLECULES IN BIOLOGICAL SAMPLES. IT CAN PLAY AN INDISPENSABLE ROLE IN THE GROWING SYSTEMS BIOLOGY APPROACHES TO UNRAVEL THE RELATIONSHIPS BETWEEN METABOLITES AND DISEASES. LIQUID CHROMATOGRAPHY COUPLED TO MASS SPECTROMETRY (LC-MS) AND GAS CHROMATOGRAPHY COUPLED TO MASS SPECTROMETRY (GC-MS) HAVE BEEN USED FOR HIGH-THROUGHPUT ANALYSIS OF THOUSANDS OF METABOLITES. HOWEVER, THE POTENTIAL VALUES OF MANY DISEASE-ASSOCIATED METABOLITES DISCOVERED BY USING THESE PLATFORMS HAVE BEEN INADEQUATELY EXPLORED IN SYSTEMS BIOLOGY APPROACHES FOR BIOMARKER DISCOVERY DUE TO LACK OF COMPUTATIONAL TOOLS AND RESOURCES TO: (1) ACCURATELY DETERMINE THE IDENTITY OF MOST OF THE METABOLITES; (2) INVESTIGATE THE REWIRING INTERACTIONS AMONG THE METABOLITES DUE TO DISEASES; AND (3) INTEGRATE METABOLITE PROFILES WITH THOSE FROM OTHER OMICS STUDIES TO EVALUATE THE RELATIONSHIPS BETWEEN THE METABOLITES AND THE DISEASES AT THE SYSTEMS LEVEL. PARTLY DUE TO THESE LIMITATIONS, POOR GENERALIZABILITY OF PREVIOUSLY IDENTIFIED METABOLITE BIOMARKER CANDIDATES HAS BEEN OBSERVED, ESPECIALLY WHEN THEY ARE EVALUATED THROUGH INDEPENDENT PLATFORMS AND VALIDATION SETS. THEREFORE, NEW METHODS ARE SOUGHT TO FIND MORE GENERALIZABLE METABOLITE BIOMARKER CANDIDATES. THE GOAL OF THIS RESEARCH PROGRAM IS TO FILL THE GAPS IN METABOLITE IDENTIFICATION AND MULTI- OMICS INTEGRATION BY USING SYSTEMS METABOLOMICS APPROACHES THAT WILL ENHANCE THE ROLE OF METABOLOMICS IN SYSTEMS BIOLOGY APPROACHES FOR BIOMARKER DISCOVERY. SPECIFICALLY, THE PROPOSED RESEARCH PROGRAM WILL UTILIZE MULTIPLE RESOURCES (BIOLOGICAL DATABASES, SPECTRAL LIBRARIES, ETC.) AND INNOVATIVE STATISTICAL, MACHINE LEARNING, AND NETWORK-BASED METHODS FOR: (1) DEVELOPING A COMPREHENSIVE WORKFLOW FOR RANKING PUTATIVE METABOLITE IDS; (2) DIFFERENTIAL ANALYSIS OF METABOLITE PROFILES BASED ON CHANGES IN THE LEVELS OF INDIVIDUAL METABOLITES AND PAIRWISE INTERACTIONS IN DISEASE VS. CONTROL GROUPS; AND (3) INTEGRATION OF METABOLOMICS DATA WITH GENOMICS, TRANSCRIPTOMICS, PROTEOMICS, AND GLYCOPROTEOMICS DATA TO IDENTIFY HIGHLY PROMISING METABOLITE BIOMARKER CANDIDATES. OUR RECENT PROGRESS HAS LED TO ACQUISITION OF MULTI-OMICS DATA AND DEVELOPMENT OF COMPUTATIONAL TOOLS FOR METABOLITE IDENTIFICATION AND INTEGRATIVE ANALYSIS. THE PERFORMANCE OF THE PROPOSED METABOLITE IDENTIFICATION WORKFLOW IN RANKING PUTATIVE METABOLITE IDS WILL BE EVALUATED THROUGH EXPERIMENTAL METHODS USING REFERENCE COMPOUNDS. THE DIFFERENTIAL AND INTEGRATIVE ANALYSIS METHODS WILL BE USED FOR SELECTION OF CANDIDATE BIOMARKERS VIA MULTI-OMICS DATA ACQUIRED IN BIOMARKER DISCOVERY STUDIES. THE SELECTED CANDIDATES WILL BE EVALUATED BY TARGETED QUANTITATION USING INDEPENDENT SAMPLES AND PLATFORMS COMPARED TO THOSE USED FOR DISCOVERY. THE OUTCOMES OF THESE EXPERIMENTAL EVALUATIONS WILL BE USED NOT ONLY TO HELP REFINE THE COMPUTATIONAL METHODS BUT ALSO TO IDENTIFY PROMISING BIOMARKER CANDIDATES. IN SUMMARY, THE PROPOSED RESEARCH PROGRAM SEEKS TO CAPITALIZE ON THE POWER OF NETWORK MODELING, MACHINE LEARNING, AND MULTI-OMICS DATA INTEGRATION TO IMPROVE THE ABILITY TO FIND DISEASE BIOMARKERS THAT ARE LIKELY TO SUCCEED IN FUTURE LARGE-SCALE BIOMARKER VALIDATION STUDIES.

MECHANISMS OF EPIGENETIC PLASTICITY IN PDAC - PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) IS ONE OF THE MOST DEADLY HUMAN CANCERS AND IN ~95% OF CASES DRIVEN BY ONCOGENIC MUTATIONS OF KRAS. UNFORTUNATELY, ATTEMPTS TO DIRECTLY INHIBIT ONCOGENIC KRAS OR RAS EFFECTOR PATHWAYS HAVE BEEN LARGELY INEFFECTIVE IN TREATING PDAC DUE TO THE DEVELOPMENT OF RESISTANCE. YAP (YES-ASSOCIATED-PROTEIN), AN ONCOGENIC TRANSCRIPTION REGULATOR, NOT ONLY IS REQUIRED FOR PDAC PROGRESSION BUT ALSO CONFERS RESISTANCE TO EXTINCTION OF ONCOGENIC KRAS SIGNALING AND OTHER THERAPEUTIC AGENTS IN ADVANCED PDAC TUMORS. USING A NEXT- GENERATION INDUCIBLE GENETIC ENGINEERED MOUSE MODEL, WE DISCOVERED THAT EVEN THOUGH PDAC TUMORS RELY ON YAP TO MAINTAIN THE TRANSCRIPTIONAL OUTPUT NECESSARY FOR TUMOR GROWTH AND SURVIVAL, A SUBPOPULATION OF TUMOR CELLS WITH STEM/PROGENITOR-LIKE CHARACTERISTICS UNDERGO EPIGENETIC REPROGRAMMING EVENTUALLY OVERCOMING THEIR YAP ADDICTION IN LATE STAGE PDAC. IN THIS GRANT WE PROPOSE A MULTI-FACETED EFFORT TO ELUCIDATE THE MOLECULAR/CELLULAR DRIVERS OF ADAPTIVE REPROGRAMMING IN YAP-ABLATED, ADVANCED PDAC TUMORS, AND EXPLORE NOVEL THERAPEUTIC STRATEGIES TO OVERCOME RESISTANCE TO YAP BLOCKADE. FURTHERMORE, WE WILL USE AN INDUCIBLE GENETIC LINEAGE- TRACING MODEL TO TRACK HOW THE CANCER “STEM/PROGENITOR” NICHES CONTRIBUTE TO PDAC INVASION, METASTASIS AND RESISTANCE TO YAP ABLATION. TOGETHER, THESE EXPERIMENTS WILL NOT ONLY PROVIDE CRITICAL INSIGHTS INTO THE MECHANISMS UNDERLYING PDAC PLASTICITY, BUT ALSO INFORM POTENTIAL NEW STRATEGIES TO OVERCOME THERAPEUTIC RESISTANCE IN PDAC.

THE CCK-B RECEPTOR SIGNALING PATHWAY AS A DRIVER OF PANCREATIC CELLULAR PLASTICITY AND CARCINOGENESIS - ABSTRACT IT HAS BECOME WELL RECOGNIZED THAT INFLAMMATION FROM CHRONIC PANCREATITIS IS ASSOCIATED AN 8-FOLD INCREASED RISK FOR THE DEVELOPMENT OF PANCREATIC CANCER. WHEN CELLS ARE INJURED OR STRESSED, THEY CAN TRANSFORM TO A CELL WITH A DIFFERENT PHENOTYPE THROUGH A PROCESS CALLED METAPLASIA. IN THE PANCREAS, ACINAR-DUCTAL METAPLASIA (ADM) OCCURS WITH PANCREATITIS AND THIS PROCESS IS USUALLY REVERSIBLE. HOWEVER, WITH CHRONIC INFLAMMATION OR MATURATION ARREST, THE DUCTAL PHENOTYPE CELLS DO NOT REVERSE TO THEIR NORMAL ACINAR PHENOTYPE BUT MAY PROGRESS TO PANCREATIC INTRAEPITHELIAL NEOPLASIA (PANINS) AND PANCREATIC CANCER. THERE IS A GAP IN OUR UNDERSTANDING OF THE MECHANISMS INVOLVED IN THIS RECOVERY OR LOSS OF THE ABILITY TO RECOVER. OUR LAB HAS BEEN STUDYING G-PROTEIN COUPLED RECEPTORS AND FOUND THAT THE CHOLECYSTOKININ-B RECEPTOR (CCK-BR) THAT IS FOUND IN DUCTAL CELLS BUT NOT ACINAR CELLS BECOMES EXPRESSED DURING CHRONIC PANCREATITIS AND PANIN FORMATION, AND IS MARKEDLY OVER-EXPRESSED IN PANCREATIC CANCER. TREATMENT WITH A CCK-RECEPTOR ANTAGONIST, PROGLUMIDE, HASTENS RECOVERY OF ADM, DECREASES INFLAMMATION, AND RESTORES THE PANCREAS TO A NORMAL PHENOTYPE. IN MORE ADVANCED DISEASE WITH PANINS OR WITH PANCREATIC CANCER, PROGLUMIDE TREATMENT ALSO ALTERS THE PANCREAS EXTRACELLULAR MATRIX OR TUMOR MICROENVIRONMENT, BY DECREASING COLLAGEN PRODUCTION FROM PANCREATIC STELLATE CELLS OR CANCER-ASSOCIATED FIBROBLASTS AND CHANGING THE IMMUNE CELL SIGNATURE TO A MORE NORMAL PHENOTYPE. WE HYPOTHESIZE THAT THE CCK-BR SIGNALING PATHWAY IS A NOVEL AND KEY PATHWAY IN PANCREATIC PLASTICITY; STRATEGIES TO SUPPRESS THIS PATHWAY WILL DECREASE PANCREATIC CANCER. PROGLUMIDE HAS ALREADY BEEN TESTED IN HUMAN SUBJECTS IN A PHASE 1 CLINICAL TRIAL AND DEEMED TO HAVE A BROAD SAFETY PROFILE. IN THIS PROPOSAL WE WILL STUDY THE ROLE OF PROGLUMIDE AND THE CCK-BR IN PANCREATIC CELL PLASTICITY AND HOW THIS PATHWAY CAN BE TARGETED TO NORMALIZE THE PANCREATIC PHENOTYPE AND RENDER IT LESS ONCOGENIC TO PREVENT PANCREATIC CANCER. THE FOLLOWING AIMS ARE PROPOSED: AIM #1, DETERMINE HOW THE CCK-BR SIGNALING PATHWAY IS INVOLVED IN ACINAR-DUCTAL METAPLASIA; AIM #2, EXAMINE HOW ACTIVATION OF THE CCK-B RECEPTOR PATHWAY MODULATES PANCREATIC STELLATE CELLS AND IF CCK- RECEPTOR BLOCKADE CAN CHANGE THE PHENOTYPE TO RENDER THE FIBROBLASTS LESS CARCINOGENIC; AND AIM #3, EVALUATE HOW ACTIVATION OF THE CCK-BR INDUCES TISSUE INFLAMMATION AND POLARIZATION OF IMMUNE CELLS. IN THIS INVESTIGATION, WE WILL USE MURINE MODELS OF PANCREATITIS IN WILD-TYPE AND IN CCK-BR-KNOCKOUT MICE WITH STATE OF THE ART TECHNIQUES AS LASER MICRODISSECTION OF ADM AND STROMA, REVERSE PHASE PROTEIN ARRAY, MASS CYTOMETRY AND RNA SEQUENCING TO UNDERSTAND PLASTICITY OF PANCREATIC CELLS. WE WILL ALSO EXAMINE THE ROLE OF THE CCK-BR ON THE PANCREATIC STELLATE CELLS IN VITRO USING MURINE AND HUMAN CELLS. OUR GOAL IS TO UNDERSTAND HOW PROGLUMIDE REPROGRAMS A METAPLASTIC OR DYSPLASTIC PANCREAS TO A MORE NORMAL PHENOTYPE AND THUS PREVENTING DEVELOPMENT OF PANCREATIC CANCER.

UNIVERSITY CENTER FOR EXCELLENCE IN DEVELOPMENTAL DISABILITIES

DEVELOPING WOODCHUCKS SUSCEPTIBLE TO HEPATITIS B VIRUS INFECTION BY MODIFYING THE VIRUS OR HOST - ABSTRACT CHRONIC INFECTION WITH HEPATITIS B VIRUS (HBV) IS A CRITICAL PUBLIC HEALTH PROBLEM AFFECTING APPROXIMATELY 296 MILLION INDIVIDUALS WORLDWIDE AND RESULTING IN 820,000 DEATHS EVERY YEAR DUE TO SEVERE LIVER DISEASE PROGRESSION. DEVELOPING NEW ANTIVIRALS FOR THE INTERVENTION OF CHRONIC HBV INFECTION AND A BETTER UNDERSTANDING OF THE UNDERLYING MECHANISMS OF HBV PERSISTENCE ARE URGENTLY NEEDED FOR INCREASING THE LOW HBV CURE RATE IN PATIENTS, WHICH IS HAMPERED BY DEFICIENCIES IN CURRENT ANIMAL MODELS SUSCEPTIBLE TO HBV INFECTION. THE EASTERN WOODCHUCK (MARMOTA MONAX), NATURALLY INFECTED WITH THE WOODCHUCK HEPATITIS VIRUS (WHV) THAT IS CLOSELY RELATED TO HBV, IS A WELL-ESTABLISHED, IMMUNOCOMPETENT AND OUTBRED ANIMAL MODEL FOR THE STUDY OF HBV INFECTION AND FOR THE PRECLINICAL EVALUATION OF NEW ANTI-HBV DRUGS. HOWEVER, SEQUENCE AND STRUCTURAL DIFFERENCES BETWEEN HBV AND WHV MAKE THE DEVELOPMENT OF HBV-SPECIFIC DRUGS RATHER CHALLENGING IN THIS MODEL. OUR PRELIMINARY IN VITRO AND IN VIVO DATA DEMONSTRATE THAT A MODIFIED HBV CONSTRUCT MAINTAINS REPLICATION COMPETENCE IN HUMAN AND WOODCHUCK HEPATIC CELL LINES AND THAT CELL CULTURE-DERIVED VIRIONS INFECT ADULT WOODCHUCKS, ALTHOUGH AT A VERY LOW LEVEL. OTHER PRELIMINARY IN VITRO DATA INDICATE THAT MODIFIED WOODCHUCK HEPATOMA CELLS SUPPORT THE ENTIRE LIFE CYCLE OF HBV. THUS, WE PROPOSE TO EXPLORE THE POSSIBILITY OF PRODUCTIVELY INFECTING WOODCHUCKS WITH HBV BY EITHER A MODIFIED VIRUS IN AIM 1 OR A MODIFIED HOST IN AIM 2 FOR CONTINUED DEVELOPMENT OF THE WOODCHUCK AS AN ANIMAL MODEL FOR CHRONIC HBV INFECTION. UNDER AIM 1, THIS WILL BE ACHIEVED BY ADDITIONAL PASSAGE OF HBV- CONTAINING WOODCHUCK SERUM FROM OUR PRELIMINARY STUDY IN ADULT WOODCHUCKS. ANIMALS WILL BE EITHER IMMUNOCOMPETENT TO ALLOW CONTINUED VIRAL ADAPTION TO THE WOODCHUCK IMMUNE SYSTEM, AS WELL AS HEPATOCYTES, OR IMMUNOSUPPRESSED TO PROVIDE MORE TIME AND OPPORTUNITIES FOR VIRAL EVOLUTION AND CONTINUED HOST ADAPTION IN THE ABSENCE OF IMMUNE PRESSURE. SEQUENCE ANALYSIS OF ADAPTED/EVOLVED HBV IN SERUM AND LIVER OF THESE ANIMALS WILL IDENTIFY POSSIBLE MUTATIONS IN VIRAL PROMOTER/ENHANCER ELEMENTS AND THE CORE GENE CRITICAL FOR WOODCHUCK ADAPTION, AND THUS WILL ALLOW TO ENGINEER ADDITIONAL HBV CONSTRUCTS WITH INCREASED INFECTION EFFICIENCY FOR SUBSEQUENT EVALUATION IN ADULT WOODCHUCKS. THE BEST PERFORMING HBV, EITHER ADAPTED/EVOLVED OR ENGINEERED, WILL THEN BE USED FOR THE INFECTION OF NEONATAL WOODCHUCKS TO ALLOW THE ESTABLISHMENT OF CHRONIC HBV INFECTION AND LIVER DISEASE PROGRESSION, INCLUDING DEVELOPMENT OF HEPATOCELLULAR CARCINOMA, AS IT IS TYPICALLY OBSERVED IN HUMANS. UNDER AIM 2, THIS WILL BE ACCOMPLISHED BY INFECTION OF ADULT WOODCHUCKS WITH WILDTYPE OR ENGINEERED HBV AFTER RENDERING THE HOST’S LIVER CELLS PERMISSIVE TO THE VIRUS. THESE ANIMALS WILL BE EITHER IMMUNOCOMPETENT FOR PROOF-OF-CONCEPT OF TRANSIENT, RESOLVING HBV INFECTION OR IMMUNOSUPPRESSED TO ENABLE CHRONIC HBV INFECTION IN THE ABSENCE OF AN IMMUNE RESPONSE. SUCCESSFUL COMPLETION OF THE PROPOSED RESEARCH WILL HAVE A SIGNIFICANT IMPACT ON DEVELOPING NEW ANTIVIRALS IN WOODCHUCKS WITH CHRONIC HBV INFECTION.

LEADERSHIP EDUCATION IN NEURODEVELOPMENTAL AND RELATED DISORDERS TRAINING PROGRAM

ISOLATION AND SMALL MOLECULE TARGETING OF EWING'S SARCOMA STEM CELLS

UPIT: UNLEASH THE POTENTIAL OF INTESTINAL TRANSPLANTATION

A PHYSICIAN-BASED TRIAL TO INCREASE COLORECTAL CANCER SCREENING IN CHINESE

AN ADVANCED FUNCTIONAL MRI STUDY OF FRONTOSTRIATAL INJURY IN ADULTS WITH HIV - PROJECT SUMMARY/ABSTRACT IN THE ERA OF COMBINATION ANTIRETROVIRAL THERAPY (CART), THE PREVALENCE OF HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS, OR HAND, REMAINS HIGH IN PEOPLE WITH HIV (PWH); AS A RESULT, THERE IS INCREASING PRESSURE TO IDENTIFY NEURAL TARGETS FOR EFFECTIVE THERAPIES. HOWEVER, TO DEVELOP EFFECTIVE HAND TREATMENTS, A STRONG NEED EXISTS FOR THE DEVELOPMENT OF SENSITIVE BEHAVIORAL TESTS THAT CAN QUICKLY SCREEN AND EFFECTIVELY IDENTIFY PROBABLE NEUROCOGNITIVE IMPAIRMENT IN PWH AND BIOMARKERS THAT CAN ACCURATELY DETERMINE HAND STATUS AND EVALUATE THERAPEUTIC EFFECTS. THIS 5-YEAR PROSPECTIVE, CONTROLLED, CROSS-SECTIONAL AND LONGITUDINAL OBSERVATIONAL STUDY IS THEORETICALLY DRIVEN AND SPECIFICALLY DESIGNED TO TACKLE THESE CHALLENGES. NEURAL INJURY TO THE FRONTOSTRIATAL CIRCUITS (PLUS HIPPOCAMPUS, THALAMUS, AND OTHER ASSOCIATED REGIONS) HAS LONG BEEN RECOGNIZED AS A KEY COMPONENT IN HAND; HOWEVER, THE ASSOCIATION BETWEEN FRONTOSTRIATAL INJURY AND HAND STATUS REMAINS TO BE ELUCIDATED. RECENT FINDINGS SUGGEST THAT INJURY TO DIFFERENT KEY REGIONS IN THE FRONTOSTRIATAL CIRCUITS MAY PLAY DIFFERENTIAL ROLES IN HAND: FRONTAL INJURY IS MORE PREVALENT IN PWH, BUT STRIATAL INJURY BETTER PREDICTS HAND STATUS. THIS SUGGESTS THAT AN ACCURATE ASSESSMENT OF NEURAL INJURY AT DIFFERENT FRONTOSTRIATAL REGIONS (IN ADDITION TO OTHER KEY REGIONS SUCH AS THE HIPPOCAMPUS AND THALAMUS) MAY HAVE THE POTENTIAL TO SERVE AS A BIOMARKER TO ASSIST WITH HAND DIAGNOSIS AND CHARACTERIZATION. TO TEST THIS HYPOTHESIS, WE WILL INVESTIGATE FRONTOSTRIATAL INJURY IN PWH USING TWO BEHAVIORAL PARADIGMS THAT ARE KNOWN TO INVOLVE DISTINCT FRONTOSTRIATAL REGIONS, ALONG WITH TWO ADVANCED FUNCTIONAL MRI (FMRI) TECHNIQUES: FMRI- ADAPTATION (FMRI-A) AND MULTIVARIATE PATTERN ANALYSIS (MVPA). COMPARED TO CONVENTIONAL FMRI TECHNIQUES, FMRI-A AND MVPA TECHNIQUES CAN BETTER ESTIMATE NEURAL TUNING/SELECTIVITY THAT CAN BE QUANTITATIVELY RELATED TO BEHAVIORAL PERFORMANCE. BRIEFLY, WE HYPOTHESIZE THAT FRONTOSTRIATAL INJURY – A CENTRAL COMPONENT IN HAND – IS HIGHLY PREVALENT IN PWH AND CAN BE ASSESSED BEHAVIORALLY VIA TWO BEHAVIORAL PARADIGMS (AIM 1A), AND NEURALLY VIA FMRI-A & MVPA (AIM 1B). NEURAL INJURY TO OTHER REGIONS/NETWORKS WILL BE ASSESSED USING A MULTIMODAL MRI APPROACH (AIM 2). THE INTEGRATION OF BEHAVIORAL & FMRI DATA FROM AIM 1 WITH MULTIMODAL MRI DATA FROM AIM 2 WILL HELP TO ASSESS THE DEGREE OF NEURAL INJURY AT FRONTOSTRIATAL AND OTHER REGIONS/NETWORKS, WHICH IN TURN MAY SERVE AS A BIOMARKER FOR HAND STATUS (AIM 3). THE PROBABLE IMPACT OF COMMON COMORBIDITIES WILL ALSO BE INVESTIGATED. IN SUMMARY, THIS PROPOSAL IS THEORETICALLY DRIVEN AND HIGHLY INNOVATIVE, WITH A STRONG PROMISE FOR FUTURE CLINICALLY RELEVANT DEVELOPMENT. THE FEASIBILITY OF THE PROPOSED RESEARCH IS SUPPORTED BY A STRONG FOUNDATION IN COGNITIVE NEUROSCIENCE AND NEUROHIV, STRONG PRELIMINARY DATA, AND AN ESTABLISHED RESEARCH TEAM. THE SUCCESS OF THIS PROPOSED PROJECT MAY HELP TO DEVELOP SENSITIVE BEHAVIORAL TESTS THAT CAN EFFECTIVELY DETECT MILD NEUROCOGNITIVE IMPAIRMENT IN PWH, AND A BIOMARKER THAT CAN ASSIST IN DETERMINING HAND STATUS/SEVERITY.

CADHERIN11 IN CANCER & RHEUMATOID ARTHRITIS: COMMON TARGET, COMMON THERAPIES? (5)

BREAST CANCER IS THE MOST COMMON MALIGNANCY IN WOMEN WORLDWIDE AND IT IS PREDICTED THAT IN THE USA 1 IN 8 WOMEN WILL DEVELOP INVASIVE BREAST CANCER IN HER LIFETIME

SENSORY CORTICAL ORGANIZATION AND CROSS-MODAL PLASTICITY IN BLIND SUBJECTS

GAMMA-OHPDG AS A PROGNOSTIC BIOMARKER OF HCC RECURRENCE AND ITS PREVENTION

GEORGETOWN PROJECT LAUNCH - THE DC SAMHSA PROJECT LAUNCH PROJECT WILL SERVE MORE THAN 1,300 YOUNG CHILDREN, PARENTS, EARLY CHILDHOOD EDUCATORS AND PRIMARY PEDIATRIC CARE PROVIDERS IN WARDS 7 AND 8 AND PORTIONS OF WARD 5 WHERE LACK OF ACCESS TO MENTAL HEALTH RESOURCES AND STIGMA LIMIT THE TYPE OF SCREENING AND INTERVENTION THAT COULD POSITION CHILDREN FOR ACADEMIC SUCCESS AND LIFE-LONG WELLNESS. THE DISTRICT OF COLUMBIA HAS A HIGH INCIDENCE OF RISK FACTORS AND BARRIERS TO MENTAL HEALTH (MH) CARE, COMBINED WITH LOW RATES OF MH CARE ACCESS. OVER 22% OF CHILDREN HAVE EXPERIENCED TWO OR MORE ADVERSE CHILDHOOD EVENTS (ACES) INCLUDING TRAUMA, ABUSE, AND NEGLECT- ALL OF WHICH ARE STRONGLY CORRELATED TO MH ISSUES. THE DC DEPARTMENT OF BEHAVIORAL HEALTH REPORTS THAT 70,000 YOUTH FROM HISTORICALLY MARGINALIZED COMMUNITIES IN WASHINGTON, DC., HAVE MH CONDITIONS, YET ONLY 20% OF YOUTH FROM THESE COMMUNITIES UNDER THE AGE OF 18 RECEIVE CARE. ONLY 30% OF CHILDREN IN D.C. WHO ARE DIAGNOSED WITH A MH NEED ARE SERVED THROUGH MEDICAID AND MENTAL HEALTH REHABILITATION SERVICES. OUR PROJECT WILL INCREASE THE WORKFORCE SKILLS, CAPACITY, AND CULTURAL COMPETENCY CAN HELP CLOSE THIS GAP. THE PROJECT TEAM WILL RECRUIT AND TRAIN NINE COMMUNITY MENTAL HEALTH WORKERS (CMHWS) WITH LIVED EXPERIENCE AND PLACE THEM IN EARLY CHILDHOOD EDUCATION (ECE) CENTERS AND PRIMARY PEDIATRIC CLINICS (PPCS) TO SCREEN MORE THAN 500 CHILDREN AND 350 PARENTS OVER FIVE YEARS. 330 ECE STAFF, 15 ECE MENTAL HEALTH CONSULTANTS, AND 10 PPC STAFF WILL ENGAGE IN PROVIDER WELLNESS TRAINING (PWT) AND 60 ECE AND PPC STAFF WILL ENGAGE IN ADDITIONAL FACILITATING ATTUNED INTERACTIONS (FAN) AND TRAUMA-INFORMED STRENGTHENING FAMILY COPING RESOURCES (SFCR) INTERVENTIONS TRAINING AND OTHER PROFESSIONAL DEVELOPMENT TO INCREASE THE QUALITY OF MH CARE IN THE DISTRICT. OUR PROJECT PARTNERS INCLUDE CHILDREN'S NATIONAL HOSPITAL (CNH) AND MEDSTAR GEORGETOWN UNIVERSITY HOSPITAL DIVISION OF COMMUNITY PEDIATRICS (DCP) AND UNITED PLANNING ORGANIZATION (UPO), A MAJOR PROVIDER OF EARLY HEAD START AND HEAD START ECE IN D.C. WE WILL BUILD ON EXISTING PARTNERSHIPS TO ESTABLISH A YOUNG CHILD WELLNESS COUNCIL (YCWC) THAT INCLUDES 22 PROJECT LAUNCH PARTNERS, DC GOVERNMENT AGENCIES, HEAD START, MH PRACTICIONERS, AND FAMILIES TO PROMOTE COORDINATION AMONG EARLY CHILDHOOD STAKEHOLDERS. CENTRONIA, DC COUNCIL, DC FAMILY CHILD CARE ASSOCIATION, DC DBH, NATIONAL CHILDREN'S CENTER, ZERO TO THREE, THE GEORGE WASHINGTON UNIVERSITY, APPLETREE INSTITUTUTE, ASCEND AT THE ASPEN INSTITUTE, ALLIANCE FOR EARLY SUCCESS, HOUSE OF RUTH KIDSPACE, MARY'S CENTER. NEW PARTNERS TO JOIN WITH THESE PARTNERS TO COMPROMISE THE YCWC: DC CHILD AND FAMILY SERVICES ADMINISTRATION, MGUH DCP, CNH, MGUH CAP, GUCCHD, D.C. CENTER FOR MENTAL HEALTH SERVICES, SAMHSA: CNH WILL HOST PROJECT ECHO MODEL TELEMONITORING AND QUALITY IMPROVEMENT (QI) TRAINING THAT WILL BE AVAILABLE TO CMHWS, AND ECE, PPC, AND YCWC STAFF AND LEADERSHIP. MEMBERS OF THE YCWC WILL WORK TOGETHER TO LEVERAGE EXISTING DIGITAL ASSETS TO COLLABORATIVELY MARKET THE PROGRAM, AND CMHWS WILL CO-CREATE AND SHARE RESOURCES FOR FAMILIES TO DESTIGMATIZE MENTAL HEALTH IN THE COMMUNITIES THEY SERVE.

LIMBIC-BASAL GANGLIA CIRCUITRY IN PTSD

I-REACH: INFRASTRUCTURE FOR RESEARCH IN EQUITY, AGING, CANCER AND HEALTH - CANCER IS THE SECOND MOST COMMON CHRONIC DISEASE AND CAUSE OF DEATH IN OLDER ADULTS. BY 2030, THREE- QUARTERS OF THE 22 MILLION CANCER SURVIVORS WILL BE 65 AND OLDER AND THE NUMBER OF SURVIVORS FROM RACIAL/ETHNIC MINORITY GROUPS WILL INCREASE BY 99% VS. 31% FOR WHITES. THESE TRENDS ARE CREATING AN ETHNOGERIATRIC AND FISCAL IMPERATIVE, WITH HEALTHCARE COSTS OF DISPARITIES DOUBLING TO $50 BILLION BY 2050 DUE TO AGING OF MINORITY GROUPS AND PERSISTENTLY LOW QUALITY OF LIFE AND SURVIVAL. WE ARE ILL-PREPARED TO ADDRESS THESE CRISES BECAUSE THERE IS LIMITED EVIDENCE TO GUIDE CLINICAL CARE OR EFFORTS TO REDUCE DISPARITIES AMONG OLDER CANCER SURVIVORS. THIS PAUCITY OF DATA IS EXACERBATED BY THE LOW NUMBERS OF UNDERREPRESENTED MINORITY (URM) SCIENTISTS LEADING STUDIES AND LIMITED ENGAGEMENT OF MINORITY STAKEHOLDERS TO ENHANCE TRUST IN RESEARCH, RESULTING IN AN UNDER- REPRESENTATION OF OLDER MINORITY SURVIVORS IN STUDIES. PROGRESS HAS BEEN FURTHER HAMPERED BY THE FACT THAT WHILE RESEARCHERS FROM AGING AND ONCOLOGY EACH STUDY DISPARITIES, THERE IS NO INFRASTRUCTURE INTEGRATING THESE DISCIPLINES. TO FILL THIS URGENT GAP, THE “INFRASTRUCTURE FOR RESEARCH IN EQUITY, AGING, CANCER AND HEALTH” (I- REACH) WILL USE A MULTI-LEVEL DISPARITIES FRAMEWORK TO INTEGRATE GEROSCIENCE AND STAKEHOLDER PERSPECTIVES INTO TRANSDISCIPLINARY RESEARCH BRIDGING THE FIELDS OF AGING, DISPARITIES AND CANCER. I-REACH BRINGS TOGETHER UNDER ONE UMBRELLA THE ACCUMULATED EXPERTISE OF FOUR CANCER CENTER HUBS (GEORGETOWN, UNIVERSITY OF MARYLAND, KARMANOS/WAYNE STATE, UCLA), STAKEHOLDERS, ALL THE MAJOR NIA CENTER PROGRAMS AND NATIONAL GERIATRICS, GERONTOLOGY AND CANCER ORGANIZATIONS. THE GOALS OF I-REACH ARE TO: 1) EXPAND THE SCIENTIFIC WORKFORCE AND INCREASE THE PROPORTION OF URM SCIENTISTS COMMITTED TO, AND SUPPORTED IN CAREERS AT THE INTERSECTION OF AGING, DISPARITIES AND CANCER, AND 2) DEPLOY THIS WORKFORCE TO ACCELERATE DISCOVERY AND PROVIDE EVIDENCE FOR INTERVENTIONS TO IMPROVE THE HEALTH OF ALL OLDER CANCER SURVIVORS. THESE GOALS WILL BE ACCOMPLISHED WITH THREE CORES AND TWO PROGRAMS IN OVERLAPPING PHASES USING A DISTRIBUTED RESOURCE, DISTANCE-LEARNING APPROACH. IN THE TWO-YEAR R21 PHASE, WE DEVELOP, IMPLEMENT AND BEGIN TO EVALUATE CORES (AIM 1) AND PREPARE FOR R33 TRANSITION: A CAREER DEVELOPMENT CORE PROVIDING A MENTORING PROGRAM AND A FOUNDATIONAL CURRICULUM; A DATA RESOURCES CORE ENABLING USE OF SECONDARY DATA TO FILL KNOWLEDGE GAPS IN OUR DISPARITIES FRAMEWORK; AND A STAKEHOLDER CORE TO INTEGRATE STAKEHOLDER PERSPECTIVES AND SUPPORT RECRUITMENT OF OLDER MINORITIES. IN THE THREE-YEAR R33 PHASE, THE CORES WILL BE DEPLOYED TO PROVIDE A TWO-YEAR MENTORED SCHOLARS PROGRAM FOR PRE- DOCTORAL, DOCTORAL AND EARLY STAGE TO SENIOR SCIENTISTS (AIM 2) AND A PILOT PROGRAM (AIM 3) FUNDING SMALL GRANTS TO ADDRESS EVIDENCE GAPS IN OUR MULTI-LEVEL FRAMEWORK AND BUILD SUSTAINABILITY AND DISSEMINATE RESULTS (AIM 4). EIGHTY-SIX SCIENTISTS (65% WOMEN AND 36% URM) HAVE ALREADY AGREED TO PARTICIPATE. I-REACH WILL PROVIDE VALUE-ADDED TO THE NIH BY BRIDGING NIA AND NCI PRIORITIES AND ADDRESSING AREAS NOT COVERED IN OTHER PROGRAMS. I-REACH IS IDEALLY TIMED TO ADDRESS NEEDS OF A RAPIDLY GROWING DIVERSE, OLDER POPULATION.

FACILITATED EDUCATION AND TESTING IN BRCA POSITIVE FAMILIES