Magee-Womens Research Institute And Foundation

MICROBICIDE TRIALS NETWORK

MATRIX - MICROBICIDE 2021 R&D PROJECT: ADVANCING THE RESEARCH AND DEVELOPMENT OF INNOVATIVE HIV PREVENTION PRODUCTS FOR WOMEN

MICROBICIDE TRIALS NETWORK

LABORATORY CENTER (LC): MICROBICIDE TRIALS NETWORK

FILM ANTIRETROVIRAL MICROBICIDE EVALUATION

ALTERNATIVE FORMULATIONS OF TENOFOVIR AND UC781

GENETICS OF MALE INFERTILITY: A MARKER OF OVERALL HEALTH

COMBINATION HIV ANTIRETROVIRAL RECTAL MICROBICIDE PROGRAM

BUILDING INTERDISCIPLINARY RESEARCH CAREERS IN WOMEN'S HEALTH

PRESERVING MALE FERTILITY AFTER CANCER THERAPY

MICROBICIDE SAFETY AND ACCEPTABILITY IN YOUNG MEN

PLURIPOTENT STEM CELLS IN DEVELOPMENT AND DISEASE

MECHANISMS OF PREECLAMPSIA: IMPACT OF OBESITY

PREGNANCY AND DRUG METABOLIZING ENZYMES AND TRANSPORTERS

FRONTIERS IN AGING AND REGENERATION RESEARCH (FRARR)

POROSITY AND TENSIONING: CRITICAL FACTORS TO CONSIDER WHEN CHOOSING A PROLAPSE MESH

MOLECULAR AND CELLULAR CONTROLS OF PLACENTAL METABOLISM

PREECLAMPSIA AND THE BRAIN: SMALL VESSEL DISEASE AND COGNITIVE FUNCTION IN EARLY MIDLIFE - CEREBRAL SMALL VESSEL DISEASE (CSVD) PREDISPOSES TO VASCULAR COGNITIVE IMPAIRMENT AND DEMENTIA, INCLUDING ALZHEIMER’S DISEASE. PREECLAMPSIA (PE), A PREGNANCY-SPECIFIC DISORDER WITH ACUTE HYPERTENSION AND PLACENTAL SVD, IS EMERGING AS A SEX-SPECIFIC RISK FACTOR FOR DEMENTIA LATER IN LIFE. HOW PE IS IMPLICATED IN THE ETIOLOGY OF DEMENTIA IS NOT KNOWN. WOMEN WITH PE HAVE SVD ALSO IN OTHER VASCULAR BEDS, INCLUDING THE BRAIN, AFTER PREGNANCY AND WORSENING WITH OLDER AGE, SUGGESTING THIS PROCESS EVOLVES OVER TIME. HOWEVER, STUDIES ON SVD IN MIDLIFE ARE SPARSE. MIDLIFE IS AN IDEAL TIME TO ASSESS THIS RISK AS PE-DIFFERENCES IN COGNITION ARE ALREADY DETECTABLE, AND YET THERE IS TIME TO MITIGATE PROGRESSION TO DEMENTIA. CEREBRAL SVD (CSVD) IN MIDLIFE MAY HOLD THE KEY TO UNDERSTAND HOW PE IS IMPLICATED IN COGNITIVE IMPAIRMENT. PLACENTAL SVD, KNOWN AS MATERNAL VASCULAR MALPERFUSION (MVM) PREDICTS WORSE SHORT-TERM PREGNANCY OUTCOMES. WE FIND MVM AND PE COMBINED PREDICT LONG-TERM WORSE MATERNAL VASCULAR HEALTH IN CARDIAC, SUBLINGUAL, AND CEREBRAL BEDS. IN OUR PILOT STUDY (N=24) MVM AND PE COMBINED PREDICTED LOWER CEREBROVASCULAR REACTIVITY (CVR, AN EARLY STAGE OF CSVD), ESPECIALLY IN FRONTO-PARIETAL AREAS; IN TURN, LOWER CVR IN THESE REGIONS WAS ASSOCIATED WITH, AND APPEARED TO EXPLAIN, PE-RELATED WORSE COGNITION. IMPORTANTLY, THESE FINDINGS WERE INDEPENDENT OF HYPERTENSION, SUGGESTING PE HAS DIRECT AND LASTING VASCULAR EFFECTS . PE AND MVM MAY BE EARLY INDICATORS OF A FUTURE CEREBROVASCULAR PHENOTYPE, MANIFESTING IN MIDLIFE AS LOWER CVR, AND MAY EXPLAIN HOW PE AFFECTS COGNITION. WE PROPOSE TO STUDY MIDLIFE WOMEN WITH AND WITHOUT PRIOR PE TO: 1) CHARACTERIZE THE NEURAL BASIS OF PE-RELATED POORER COGNITIVE PERFORMANCE, 2) ASSESS WHETHER PLACENTAL SVD (MVM) PREDICTS CSVD AND COGNITION, AND 3) EXPLORE WHETHER SUBLINGUAL SVD AND CIRCULATING MARKERS OF SVD ARE MARKERS OF CSVD AND COGNITION. WE PROPOSE A NEUROCOGNITIVE STUDY TO CAPTURE EARLY STAGES OF CSVD AND COGNITIVE STATUS IN A RACIALLY DIVERSE COHORT OF 450 WOMEN (1:1 PE AND NON PE) FROM OUR ONGOING WINDOWS STUDY, MEAN AGE=45, 15 YEARS POST- PREGNANCY, 30% BLACK, WITH EXISTING DATA ON PE, MVM, AND SUBLINGUAL SVD 10 YEARS AFTER PREGNANCY. WE WILL USE OUR ADVANCED MULTIMODAL NEUROIMAGING PROTOCOLS TO QUANTIFY CSVD (INCLUDING CVR, BLOOD FLOW, CONNECTIVITY), STANDARDIZED VALIDATED PROTOCOLS TO MEASURE COGNITION, AND NON-INVASIVE MARKERS OF SVD (SUBLINGUAL SVD, AND CIRCULATING BIOMARKER PROFILES) . OUR PROJECT IS UNIQUELY POSITIONED TO IDENTIFY A PREVIOUSLY OCCULT HIGH-RISK GROUP THAT CAN BE IDENTIFIED AT DELIVERY BY PLACENTAL PATHOLOGY, AND WHO MAY BENEFIT FROM RISK- STRATIFICATION FOR DEMENTIA, TO MITIGATE OR DELAY DISEASE PROGRESSION.

NEXT GENERATION THERAPIES FOR FERTILITY PRESERVATION IN MALE CANCER PATIENTS

OVERCOMING COMPLICATIONS OF POLYPROPYLENE PROLAPSE MESHES: DEVELOPMENT OF NOVEL ELASTOMERIC AUXETIC DEVICES

MAGEE-WOMENS BASIC AND TRANSLATIONAL REPRODUCTIVE HEALTH TRAINING PROGRAM

OPTIMIZATION OF DRUG DOSING IN PREGNANT WOMEN THROUGH RESEARCH AND EDUCATION

LONG ACTING FILM TECHNOLOGY FOR CONTRACEPTION AND HIV PREVENTION (LATCH)

EXTRACELLULAR VESICLES AND THEIR NCRNA CARGO AS MARKERS OF TROPHOBLAST INJURY

CHARACTERIZATION OF MALE GERMLINE STEM CELLS IN A RHESUS MODEL OF INFERTILITY

MULTIMODAL ANALYSIS OF GESTATIONAL HEALTH AND PLACENTAL INJURY IN OPIOID-AFFECTED PREGNANCIES - PROJECT SUMMARY OPIOIDS ARE MEDICALLY USED FOR SAFE PAIN RELIEF AND MANAGEMENT. HOWEVER, ILLICIT OPIOID USE HAS SUBSTANTIALLY INCREASED ACROSS THE US IN THE PAST DECADE, WITH FURTHER WORSENING DURING THE COVID-19 PANDEMIC, LEADING TO A PROFOUND IMPACT ON HUMAN HEALTH. SPECIFICALLY, OPIOID USE DISORDER (OUD) DURING PREGNANCY POSES AN INCREASED RISK OF PREGNANCY-ASSOCIATED MATERNAL MORBIDITY AND MORTALITY, FETAL GROWTH RESTRICTION (FGR) AND RELATED COMPLICATIONS, NEONATAL OPIOID WITHDRAWAL SYNDROME, AND LONG-TERM NEUROBEHAVIORAL EFFECTS. SOME OF THESE RISKS PERSIST DESPITE THE USE OF SAFER OPIOIDS, SUCH AS BUPRENORPHINE AND METHADONE, MEDICATIONS FOR OUD (MOUD) PATIENTS. WHEREAS CURRENT STUDIES CENTER MAINLY ON TRANSPLACENTAL OPIOID TRANSPORT TO THE FETUS AND THE ADVERSE EFFECTS OF OPIOIDS ON INFANTS, THE DIRECT IMPACT OF ILLICIT AND PRESCRIPTION OPIOIDS ON PLACENTAL DEVELOPMENT, DIFFERENTIATION, AND FUNCTION ARE LARGELY UNEXPLORED. THE PLACENTAL FLOATING VILLI MEDIATE MATERNAL- FETAL GAS EXCHANGE, NUTRIENT UPTAKE, WASTE RELEASE IMMUNE DEFENSE AND THE PRODUCTION OF HORMONES AND EXTRACELLULAR VESICLES (EVS). THESE VILLI ARE COVERED BY A LAYER OF MULTINUCLEATED, TERMINALLY DIFFERENTIATED SYNCYTIOTROPHOBLASTS (STBS), WHICH FORMS THE FETO-PLACENTAL FRONTLINE THAT IS DIRECTLY EXPOSED TO OPIOIDS IN THE MATERNAL BLOOD. SUBJACENT TO THIS LAYER ARE MONONUCLEATED, PROGENITOR CYTOTROPHOBLASTS (CTBS), WHICH REPLENISH THE STB LAYER THROUGH THE PROCESS OF DIFFERENTIATION AND FUSION. IMPORTANTLY, INJURIES TO THE STB AND CTB LAYERS ARE IMPLICATED IN PREGNANCY-ASSOCIATED COMPLICATIONS, INCLUDING FGR AND STILLBIRTH. HERE WE SEEK TO INVESTIGATE OPIOID-DEPENDENT PLACENTAL INJURY, FOCUSING ON THE MOST CRITICAL AND UNIQUE LAYER OF PLACENTAL TROPHOBLASTS. WE WILL ENROLL PARTICIPANTS WITH OUD, INCLUDING ILLICIT OPIOIDS AND MOUD (BUPRENORPHINE, METHADONE), EXAMINE THEIR PREGNANCY COURSE AND THEIR CHILDREN’S HEALTH THROUGH THE FIRST YEAR POSTPARTUM. USING BIOSPECIMENS FROM EACH PARTICIPANT, INCLUDING MATERNAL PLASMA AND URINE ACROSS THE THREE TRIMESTERS, PLACENTAL BIOPSIES AND FETAL CORD BLOOD AT DELIVERY, WE WILL EMPLOY MULTIMODAL CUTTING-EDGE TECHNOLOGIES, INCLUDING SINGLE-CELL RNASEQ, SPATIAL TRANSCRIPTOMICS, PROTEIN CHIP CYTOMETRY AND PLACENTA EV RNA PROFILING, AND EXPLORE THE MOLECULAR AND CELLULAR PROCESSES AFFECTED BY OPIOIDS IN THE MATERNAL-PLACENTAL-FETAL TRIO- ECOSYSTEM. TO GAIN MECHANISTIC INSIGHTS INTO THE FUNCTIONAL CHANGES IN GENE EXPRESSION AND EV CARGO, WE WILL USE AN ARRAY OF MODEL SYSTEMS, INCLUDING HUMAN TROPHOBLAST STEM CELLS AND CULTURED PRIMARY HUMAN TROPHOBLASTS, AND MECHANISTICALLY INTERROGATE PATHWAYS UNDERLYING OPIOID INJURY. WE WILL FURTHER CORRELATE KEY MOLECULAR SIGNATURES WITH CLINICAL ASSESSMENT, INCLUDING MATERNAL GESTATIONAL DISORDERS, PERINATAL AND INFANT NEURODEVELOPMENTAL OUTCOMES. TOGETHER, OUR STRATEGIC PLAN, BOLSTERED BY OUR TRANSDISCIPLINARY TEAM, ENABLES US TO ADDRESS CRITICALLY IMPORTANT KNOWLEDGE GAPS RELATED TO HUMAN PLACENTA BIOLOGY IN OPIOID-AFFECTED PREGNANCIES.

PHARMACOLOGICALLY-BASED STRATEGIES FOR BUPRENORPHINE TREATMENT DURING PREGNANCY

SLEEP DISORDERED BREATHING, OBESITY, AND PREGNANCY STUDY

IMPROVING POSTPARTUM CONTRACEPTIVE DECISION-MAKING AMONG WOMEN WITH SUBSTANCE USE DISORDERS - THE REPRODUCTIVE HEALTH NEEDS OF WOMEN WITH SUBSTANCE USE DISORDERS (SUDS) ARE UNMET. OVER 80% OF PREGNANCIES AMONG WOMEN WITH SUDS ARE UNINTENDED, COMPARED TO 45% OF THE GENERAL POPULATION, AND OVER 20% OF WOMEN WITH SUDS HAVE HAD A SHORT INTERPREGNANCY INTERVAL (I.E. PREGNANCY WITHIN 18 MONTHS OF A PREVIOUS BIRTH). PREGNANCY IS A UNIQUE OPPORTUNITY TO ADDRESS CONTRACEPTIVE NEEDS DUE TO INCREASED HEALTHCARE ACCESS FROM EXPANDED MEDICAID ELIGIBILITY, INCREASED ACCESS TO HIGHLY EFFECTIVE CONTRACEPTIVE METHODS SUCH AS LONG-ACTING REVERSIBLE CONTRACEPTION (LARC) AND ENHANCED MOTIVATION TO AVOID RAPID, REPEAT PREGNANCY. DESPITE THIS, OVER 75% OF WOMEN WITH OPIOID USE DISORDER FAIL TO USE POSTPARTUM CONTRACEPTION AND LESS THAN 2% RECEIVE LARC IN THE POSTPARTUM PERIOD. CURRENTLY, THERE ARE NO EFFECTIVE STRATEGIES TO IMPROVE POSTPARTUM CONTRACEPTIVE DECISION-MAKING FOR WOMEN WITH SUDS. TO ADDRESS THIS GAP, WE WILL CONDUCT A HYBRID TYPE 1 EFFECTIVENESS- IMPLEMENTATION RANDOMIZED CONTROLLED TRIAL AMONG 350 POSTPARTUM WOMEN WITH SUDS TO TEST THE EFFECT OF A NOVEL PATIENT-CENTERED, REPRODUCTIVE PLANNING DECISION SUPPORT TOOL, DEVELOPED BY THE RESEARCH TEAM, CALLED MYPATH ON POSTPARTUM CONTRACEPTIVE METHOD CHOICE AND CONTINUATION, CONTINUOUS CONTRACEPTIVE USE, UNINTENDED PREGNANCY AND INTERPREGNANCY INTERVAL UNTIL 18 MONTHS POSTPARTUM. THE PRIMARY RESEARCH AIMS ARE TO 1) ASSESS THE EFFECT OF PATIENT-CENTERED, REPRODUCTIVE PLANNING DECISION SUPPORT (MYPATH) ON POSTPARTUM CONTRACEPTIVE UTILIZATION AND REPRODUCTIVE HEALTH OUTCOMES AMONG WOMEN WITH SUDS; 2) DETERMINE IF THE RELATIONSHIP BETWEEN MYPATH AND CONTRACEPTIVE UTILIZATION IS MEDIATED BY DECISION QUALITY; AND 3) IDENTIFY BARRIERS AND FACILITATORS TO INTEGRATING MYPATH INTO ROUTINE POSTPARTUM CLINICAL CARE. THIS RESEARCH IS SIGNIFICANT BECAUSE USING A PATIENT-CENTERED, REPRODUCTIVE PLANNING APPROACH TO CONTRACEPTIVE DECISION-MAKING REPRESENTS A PARADIGM SHIFT IN BOTH HOW WE FRAME AND APPROACH REPRODUCTIVE HEALTH OUTCOMES AMONG WOMEN WITH SUDS. OUR FINDINGS WILL HAVE HIGH IMPACT IF SUCCESSFUL AS DECISION SUPPORT TOOLS ARE A LOW-COST, SCALABLE SOLUTION THAT CAN BE USED IN MOST CLINICAL SETTINGS AND OUR STUDY DESIGN ENHANCES THE POTENTIAL FOR RAPID TRANSLATION OF OUR FINDINGS INTO ROUTINE CLINICAL PRACTICE. FINALLY, IT IS FEASIBLE BECAUSE IT BUILDS ON PRIOR WORK BY A RESEARCH TEAM WITH EXPERTISE IN DECISION SCIENCES, IMPLEMENTATION, FAMILY PLANNING, OBSTETRICS AND SUDS.

NICHD MATERNAL-FETAL MEDICINE UNITS (MFMU) NETWORK

FRONTIERS IN STEM CELLS IN CANCER

PROJECT STEPUP: A PRENATAL PROVIDER EDUCATION AND TRAINING PROGRAM TO IMPROVE MEDICATION-ASSISTED TREATMENT USE DURING PREGNANCY AND MATERNAL AND CHILD HEALTH OUTCOMES

SOCIAL DISADVANTAGE AND FETAL PROGRAMMING OF NEWBORN-INFANT TELOMERE BIOLOGY

FRONTIERS IN ADDICTION RESEARCH AND PREGNANCY

CELLULAR MECHANISMS OF CHEMOTHERAPY-INDUCED MALE INFERTILITY: STEM CELL OR NICHE

ELIMINATING RACIAL DISPARITIES IN SEVERE MATERNAL MORBIDITY BY ADDRESSING HYPERTENSION IN THE YEAR AFTER DELIVERY - ABSTRACT THE INCREASING RATE OF SEVERE MATERNAL MORBIDITY AND MORTALITY EVENTS IN THE U.S. DISPROPORTIONATELY BURDENS BLACK WOMEN. BLACK WOMEN ARE 3 TO 4 TIMES MORE LIKELY THAN WHITE WOMEN TO SUFFER OR DIE FROM COMPLICATIONS DURING OR AFTER PREGNANCY. HYPERTENSIVE DISORDERS OF PREGNANCY (HDP) (E.G., PREECLAMPSIA, GESTATIONAL HYPERTENSION) ARE MAJOR CONTRIBUTORS TO SEVERE MATERNAL MORBIDITY AND MORTALITY, AS WELL AS LONG-TERM CARDIOVASCULAR DISEASE (CVD). BLACK WOMEN ARE MORE LIKELY THAN WHITE WOMEN TO HAVE SEVERE FORMS OF HDP AND SEVERE POST-PARTUM COMPLICATIONS SUCH AS CHRONIC HYPERTENSION, STROKE AND CVD. WE HAVE COMPELLING PRELIMINARY DATA THAT DOCUMENTS RACIAL DISPARITIES IN THE POST-PARTUM BLOOD PRESSURE RECOVERY PROFILE AMONG WOMEN WITH HDP AT 6 WEEKS AND 12 MONTHS AFTER DELIVERY. DESPITE AN OVERALL DOWNWARD TREND IN POST-PARTUM BLOOD PRESSURES AMONG WOMEN WITH HDP, BLACK WOMEN HAVE HIGHER BLOOD PRESSURES AND ARE MORE LIKELY TO HAVE STAGE 2 HYPERTENSION (=140/90 MMHG) AT 6 WEEKS POSTPARTUM COMPARED TO WHITE WOMEN (32.4% VERSUS.18.2%, P <0.001); TRENDS THAT PERSIST TO ONE YEAR AFTER DELIVERY. WE PROPOSE TO DECREASE THE RACIAL DISPARITY IN BLOOD PRESSURE CONTROL AT ONE YEAR POSTPARTUM AMONG WOMEN WITH HDP BY LEVERAGING OUR HOSPITAL-INITIATED 6-WEEK HOME BLOOD PRESSURE MONITORING PROGRAM (HBPM) FOR WOMEN WITH HDP AND OUR NOVEL COMMUNITY-PARTNERED MULTI-LEVEL INTERVENTION WITH HEALTHY START INC. WE AIM TO: 1) TEST AN ENHANCED CARE INTERVENTION STRATEGY (6 WEEKS OF HBPM, POSTPARTUM DOULA EDUCATION AND SUPPORT, 12 MONTHS OF WIRELESS HBPM AND WEIGHT MONITORING) COMPARED TO USUAL CARE CONTROL (6 WEEKS OF HBPM) TO IMPROVE THE BLOOD PRESSURE PROFILE AMONG WOMEN WITH HDP; 2) DETERMINE IF AN ENHANCED CARE STRATEGY WILL ELIMINATE RACIAL DISPARITIES IN BP PROFILES, AND 3) DETERMINE THE ACCESS TO AND DELIVERY OF EQUITABLE CLINICAL CARE THAT IS ESSENTIAL FOR ALL WOMEN TO SUCCESSFULLY RECOVER FROM HDP WITHIN ONE YEAR POSTPARTUM. WE HYPOTHESIZE THAT THE ENHANCED CARE INTERVENTION ROOTED WITHIN A HEALTH EQUITY FRAMEWORK WILL IMPROVE THE POST-PARTUM BLOOD PRESSURE RECOVERY PROFILE AMONG WOMEN WITH HDP AND WILL CLOSE THE BLOOD PRESSURE DISPARITY BETWEEN BLACK AND WHITE WOMEN IN THE YEAR AFTER DELIVERY. OUR APPROACH WILL BE TO CONDUCT A PARALLEL, TWO-ARM TRIAL THAT RANDOMIZES 454 WOMEN WITH HDP (75% BLACK, 25% WHITE) INTO USUAL CARE OR AN ENHANCED CARE INTERVENTION TO IMPROVE BLOOD PRESSURE CONTROL IN THE YEAR AFTER DELIVERY. IMPROVING BLOOD PRESSURE CONTROL IS ESSENTIAL TO PREVENT PROGRESSION TO CHRONIC HYPERTENSION, REDUCE RACIAL DISPARITIES IN HYPERTENSION, AND IMPROVE WOMEN’S HEALTH OVERALL.

QUANTIFICATION OF IMMUNE CELLS IN WOMEN USING CONTRACEPTION

CHARACTERIZATION OF A MEIOTIC CROSSOVER SURVEILLANCE SYSTEM

GENOMIC BASIS OF PREMATURE OVARIAN INSUFFICIENCY

PRIMARY HUMAN TROPHOBLASTS AND THE TRANSFER OF VIRAL RESISTANCE

NON-INVASIVE DETECTION OF FETAL ANEUPLOIDY BY NEXT-GENERATION DNA SEQUENCING

ALDH INHIBITION AS MODULATOR OF TUMOR IMMUNOBIOLOGY

LONG ACTING FILM TECHNOLOGY FOR CONTRACEPTION AND HIV PREVENTION (LATCH) - PROJECT ABSTRACT SEVERAL STUDIES (ASPIRE, VOICE) HAVE SHOWN THAT ADHERENCE IS PARAMOUNT TO THE SUCCESS OF HIV PREVENTION METHODS IN WOMEN. PROVIDING WOMEN WITH OPTIONS THROUGH ALTERNATIVE DRUG DELIVERY TECHNOLOGIES CAN POSITIVELY IMPACT ADHERENCE. A COMPELLING STRATEGY INCLUDES CO-DELIVERY OF AN ANTI-HIV AGENT WITH A CONTRACEPTIVE AGENT TO PREVENT PREGNANCY. THIS PROPOSAL PLANS TO DEVELOP A NEXT GENERATION MULTIPURPOSE PREVENTION TECHNOLOGY (MPT) FILM PLATFORM FOR ONCE A MONTH INTRAVAGINAL ADMINISTRATION OF THE 4'-ETHYNYL-2-FLUORO-2'-DEOXYADENOSINE (EFDA) PRODRUG (EFDA-P) AND A PROGESTIN (LEVONORGESTREL (LNG) OR ETONOGESTREL (ENG)) TO ACHIEVE THE DUAL GOAL OF PREVENTING HIV INFECTION AND PREGNANCY. EFDA-P SHOWED INCREASED BIOAVAILABILITY AND TISSUE PERMEABILITY COMPARED TO THE PARENT EFDA, A HIGHLY POTENT EXCITING NEW ANTIVIRAL DRUG. THIS VERSATILE EXTENDED RELEASE MPT FILM PLATFORM IS INTENDED TO PROVIDE A DISCRETE, LOW COST AND CONVENIENT ALTERNATIVE TO WOMEN AT HIGH RISK OF HIV INFECTION AND UNINTENDED PREGNANCY. RECENT DATA FROM OUR LAB SHOWS THAT FILMS CAN DELIVER AN ANTI-HIV AGENT IN THE VAGINA FOR UP TO 1 MONTH EVEN IN THE CONTEXT OF MENSES AND SEXUAL INTERCOURSE. USING THIS KNOWLEDGE AND OUR EXPERTISE IN THE DEVELOPMENT OF INTRAVAGINAL FILMS, THIS PROPOSAL WILL DEVELOP A FILM PLATFORM FOR CO-DELIVERY OF A PROGESTIN (LICENSED CONTRACEPTIVE AGENT) AND EFDA-P AT A PREDETERMINED RATE FOR AT LEAST 1 MONTH. MPT FILMS CONTAINING EFDA WILL ALSO BE GENERATED FOR COMPARISON. THE R61 PHASE OF THIS MILESTONE DRIVEN PROPOSAL WILL GENERATE CRITICAL PREFORMULATION DATA FOR EFDA/EFDA-P AND LNG/ENG DRUG COMBINATIONS AND OPTIMIZE THE MPT FILM FORMULATION TO ACHIEVE ONE- MONTH DELIVERY OF BOTH DRUGS WITH DESIRED SHORT-TERM STABILITY. THIS PHASE WILL ALSO ESTABLISH THE COMPATIBILITY OF FILM PROTOTYPE WITH VAGINAL TISSUE AND MICROBIAL FLORA IN VITRO FOLLOWED BY VAGINAL RETENTION STUDIES IN THE NON- HUMAN PRIMATE (NHP) MODEL. THE R61 PHASE WILL DEMONSTRATE THE ABILITY OF THE MPT FILM PROTOTYPE TO ATTAIN DESIRED RELEASE PROFILES OF BOTH DRUGS IN VIVO (NHP MODEL). USING A CLEARLY DEFINED GO / NO GO CRITERIA, A LEAD MPT FILM WILL BE TRANSITIONED TO THE R33 PHASE. THE R33 PHASE WILL INVOLVE IND-ENABLING ACTIVITIES INCLUDING DRUG- DRUG INTERACTION, IN VITRO TRANSPORTER AND METABOLISM STUDIES, MANUFACTURING SCALE UP AND ESTABLISHING LONG-TERM STABILITY OF THE LEAD MPT FILM. IT WILL ALSO DEMONSTRATE THE SAFETY (RAT, RABBIT, AND NHP) AND EFFICACY OF THE LEAD MPT FILM AGAINST SHIV INFECTION IN NHP MODEL. IT WILL ALSO CONFIRM THE ABILITY OF THE FILM TO FUNCTION IN THE CONTEXT OF SEXUAL ACTIVITY AND ITS ABILITY TO DELIVER CONTRACEPTIVE LEVELS OF PROGESTIN IN THE NHP MODEL. THE SUCCESSFUL COMPLETION OF PROPOSED WORK WILL GENERATE A NOVEL EXTENDED RELEASE MPT FILM PLATFORM THAT CAN BE APPLIED TO OTHER DRUG COMBINATIONS.

COMPREHENSIVE EVALUATION OF PROLAPSE MESHES BY AN INTERDISCIPLINARY RESEARCH TEAM

COMMUNICATION ON ILLICIT DRUG AND/OR ALCOHOL USE IN OBSTETRICS

REGULATORY MECHANISMS GOVERNING IMPRINTED DOMAINS DURING EARLY DEVELOPMENT - ABSTRACT GENOMIC IMPRINTING IS AN EPIGENETIC REGULATORY PROCESS THAT RESTRICTS EXPRESSION OF SPECIFIC GENES TO ONE PARENTAL ALLELE. UNDERSTANDING GENOMIC IMPRINT REGULATION DURING EARLY DEVELOPMENT HAS SIGNIFICANT MEDICAL AND SOCIETAL IMPLICATIONS, INCLUDING FOR MEDICALLY ASSISTED REPRODUCTION, WHICH IS ASSOCIATED WITH RARE IMPRINTING DISORDERS. HOWEVER, SIGNIFICANT KNOWLEDGE GAPS EXIST FOR THE REGULATION OF GENOMIC IMPRINTING DURING PREIMPLANTATION DEVELOPMENT. WHILE DNA METHYLATION AT IMPRINTING CONTROL REGIONS (ICRS) PLAYS A CRITICAL ROLE IN EMBRYOS AS AN INHERITED SILENCING MARK, THE SPECIFIC MECHANISMS THAT ESTABLISH AND/OR MAINTAIN AN ACTIVE TRANSCRIPTION COMPARTMENT AT THE UNMETHYLATED ICR, PERMITTING LONG NONCODING RNA (LNCRNA) TRANSCRIPTION AND IN TURN, REPRESSIVE FUNCTION ACROSS AN IMPRINTED DOMAIN, REMAIN UNCLEAR. TO ADDRESS THESE GAPS, WE PERFORMED AN INNOVATIVE, RNA INTERFERENCE SCREEN FOR EPIGENETIC REGULATORS OF THE KCNQ1OT1 IMPRINTED DOMAIN (AS A MODEL DOMAIN) IN MOUSE EXTRAEMBRYONIC ENDODERM (XEN) STEM CELLS. WE IDENTIFIED 41 CANDIDATES, INCLUDING CHROMATIN REMODELERS, ACTIVATORS AND REPRESSORS. OUR INVESTIGATION OF ONE CANDIDATE, NUCLEOPORIN (NUP) 107, LED TO THE DISCOVERY OF A NOVEL NUP107 AND NUP153 MECHANISM OF IMPRINTED DOMAIN REGULATION. HERE, WE HYPOTHESIZE THAT NUP107 AND NUP153 FUNCTION AS A NUCLEAR SCAFFOLD FOR PROMOTING AN ACTIVE TRANSCRIPTION COMPARTMENT AT ICRS IN ZYGOTES BY RECRUITING CHROMATIN REMODELERS AND ACTIVATORS FOR LNCRNA TRANSCRIPTION, WHICH IN TURN, LEADS TO ALLELIC SILENCING OF NEIGHBORING GENES. IN AIM 1, WE WILL EXAMINE THE POSTFERTILIZATION ROLE OF NUP107 AND NUP153 AT THE KCNQ1OT1 ICR BY ASSESSING PHYSICAL INTERACTIONS BETWEEN THESE PROTEINS, THE KCNQ1OT1 DOMAIN AND ITS LNCRNA IN LATE 1-CELL TO BLASTOCYST-STAGE EMBRYOS. WILDTYPE EMBRYOS WILL BE COMPARED TO EMBRYOS WITH NUP107 OR NUP153 DEGRADATION, 2 MATERNAL GENOMES (PARTHENOTES) OR 2 PATERNAL- LIKE GENOMES (MATERNAL DNMT3A/3B NULL). NEXT, WE WILL ASSESS GENOMIC LOCALIZATION OF NUP107 AND NUP153, AS WELL AS CHROMATIN STATE, USING ULTRALOW-INPUT CUT&RUN IN THESE EMBRYOS. TO FURTHER DEFINE THEIR FUNCTION AT IMPRINTED DOMAINS, CHIP-SEQ WITH NUP107 AND NUP153 ANTIBODIES AND RNA-SEQ WILL BE CONDUCTED ON CONTROL, NUP107- AND NUP153-DEPLETED XEN CELLS. IN AIM 2, WE WILL DETERMINE THE FUNCTION OF CHROMATIN REMODELERS, SMARCA5 AND SMARCC2, AND ACTIVATORS, KAT2A AND TAF6L, IN GENERATING ACTIVE TRANSCRIPTION COMPARTMENTS AT ICRS. USING CANDIDATE DEPLETION IN XEN CELLS, WE WILL ASCERTAIN THE ROLE OF THESE PROTEINS ON KCNQ1OT1 LNCRNA EXPRESSION AND ITS LOCALIZATION AT THE DOMAIN, OPEN/ACTIVE CHROMATIN FORMATION, ALLELIC REPRESSION OF NEIGHBORING GENES IN THE KCNQ1OT1 DOMAIN, AS WELL AS THEIR FUNCTION AT OTHER IMPRINTED DOMAINS. NEXT, WE WILL ANALYZE NUP107 AND NUP153’S ABILITY TO RECRUIT THESE CHROMATIN REMODELERS AND ACTIVATORS TO CARRY OUT THEIR FUNCTION AT ICRS. FINALLY, WE WILL ASSESS THE ROLE OF SMARCA5, SMARCC2, TAF6L AND KAT2A IN ESTABLISHING ACTIVE TRANSCRIPTION AT ICRS IN PREIMPLANTATION EMBRYOS. THIS WORK WILL LEAD TO THE DISCOVERY OF NOVEL MECHANISMS OF IMPRINTED DOMAIN REGULATION DURING EARLY DEVELOPMENT.

FRONTIERS IN EMERGING, REEMERGING AND ZOONOTIC DISEASES AND DIVERSITY (FRERZD2) - PROJECT SUMMARY OUR NATION IS NEARLY PARALYZED BY THE TWIN PANDEMICS OF COVID-19 AND PAINFUL INEQUITIES IN HEALTH OUTCOMES AMONG COVID-19 INFECTED AMERICANS OF DIFFERING ETHNICITIES. TO HELP ADDRESS THESE, WE SEEK SPONSORSHIP TO TRAIN THE NEXT GENERATION OF PANDEMIC AND EMERGING DISEASE RESEARCHERS IN THE FRONTIERS IN EMERGING, RE-EMERGING AND ZOONOTIC DISEASES AND DIVERSITY. FRERZD2 WILL LAUNCH AND SUSTAIN THREE VITAL UNDERTAKINGS: SOPHISTICATED COURSES FOR SKILLS DEVELOPMENT; RELEVANT VITAL RESEARCH EXPERIENCES; AND CAREER MENTORING ACTIVITIES. RESPONSIVE TO PAR-20-289, IT IS DESIGNED FOR 16 TRAINEES WHO ARE GRADUATE AND MEDICAL STUDENTS, MEDICAL RESIDENTS, POSTDOCTORAL FELLOWS, AND/OR EARLY-CAREER FACULTY, AND WHO ALSO ARE US CITIZENS OR PERMANENT RESIDENTS. THE WEEK-LONG COURSE WILL HELP TO ENSURE THAT CLINICALLY ACTIVE SCIENTISTS (ESPECIALLY PHYSICIANS) ARE ABLE TO OBTAIN PERMISSION TO PARTICIPATE. TOO FEW LABORATORIES ARE LED BY UNDER-REPRESENTED MINORITY (URM) SCIENTISTS, AND NOT ENOUGH NEW URM TRAINEES GRADUATE. WE SEEK 5 YEARS OF SPONSORSHIP TO OFFER FRERZD2 COURSES AT MOREHOUSE SCHOOL OF MEDICINE (MSM), AN HBCU, IN 2021, 2023, AND 2025 AND PONCE HEALTH SCIENCES UNIVERSITY (PHSU), A HISPANIC-SERVING INSTITUTION, IN 2022 AND 2024. UNDER THE OVERALL DIRECTORSHIP OF GERALD SCHATTEN FROM PITTSBURGH, ALONG WITH JONATHAN STILES AT MSM, IDHALIZ FLORES FROM PHSU, AND CALVIN SIMERLY, ALSO FROM PITTSBURGH, FRERZD2 IS OVERSEEN BY AN EXTERNAL SCIENTIFIC ADVISORY COMMITTEE. IT OFFERS DYNAMIC ADVANCED TRAINING COURSES CONSISTING OF DAILY LECTURES ON EMERGING CONCEPTS, FOLLOWED BY EXTENDED DISCUSSION, LABORATORY RESEARCH, TECHNOLOGICALLY INTENSE WORKSHOPS, AND INFORMAL SEMINARS. OUR SIMILAR TRAINING PROGRAMS HAVE RECRUITED PARTICIPANTS OF WHOM 34% SELF-IDENTIFY AS AFRICAN AMERICAN/BLACK AND 30% AS HISPANIC AMERICANS; 66% ARE WOMEN, AND 62% ARE FROM URM INSTITUTIONS. SIX SPECIFIC AIMS ARE PROPOSED. AIM 1. PROVIDE CONCEPTUAL EDUCATION AND EXPERIMENTAL TRAINING. AIM 2. PROVIDE BACKGROUND INFORMATION AND SELF-REFLECTIVE EXERCISES AND DEMONSTRATIONS TO UNDERSTAND, APPRECIATE, AND ADDRESS THE HISTORIC AND CURRENT UNDERPINNINGS OF INEQUITIES IN THE RESEARCH WORKFORCE’S DIVERSITY AND DISPARITIES IN HEALTH CARE. AIM 3. SPONSOR MEANINGFUL MENTORED RESEARCH. AIM 4. DISCUSS CAREER PLANNING. AIM 5. EDUCATE PARTICIPANTS ON THE RESPONSIBLE CONDUCT OF RESEARCH. AIM 6. PROVIDE UNBIASED, QUANTITATIVE, INDEPENDENT MECHANISMS TO TRACK TRAINEES’ CAREERS, COMPREHENSIVELY AND LONGITUDINALLY. THE PROGRAM’S NAME, FRONTIERS IN EMERGING, RE-EMERGING AND ZOONOTIC DISEASES AND DIVERSITY, ACKNOWLEDGES OUR HOPE THAT THE COVID PANDEMIC MAY SOON RECEDE SIGNIFICANTLY AND OUR REALIZATION THAT OTHER EMERGING, REEMERGING, AND ZOONOTIC DISEASES WILL ARISE THAT MUST BE TIMELY ADDRESSED. OVERALL, IN CONDUCTING THIS PROGRAM, WE WILL CONTINUE TO ENHANCE AND EXPAND THE RESEARCH CAREERS OF THE MOST PROMISING SCIENTISTS, WITH SENSITIVITY TO ENSURING FULL DIVERSITY IN THE NIAID WORKFORCE.

EQUIPMENT SUPPLEMENT FOR R01GM127569-01A1: ROLE OF GCNA IN PRESERVING GENOME INTEGRITY AND FERTILITY

IDENTIFYING MOLECULAR SIGNATURES OF GENOMIC IMPRINTING ERRORS - ABSTRACT ALARMINGLY, ~50 MILLION COUPLES WORLDWIDE ARE UNABLE TO CONCEIVE AFTER 5 YEARS OF UNPROTECTED SEX. MEDICALLY ASSISTED REPRODUCTIVE TECHNOLOGIES (ARTS) CONSTITUTE IMPORTANT TREATMENT MODALITIES FOR INFERTILE COUPLES TRYING TO CONCEIVE. WHILE GENERALLY CONSIDERED SAFE, ARTS ARE ASSOCIATED WITH HIGHER INCIDENCES OF PRETERM BIRTH, INTRAUTERINE GROWTH RESTRICTION, AND LOW BIRTH WEIGHT. MOREOVER, THERE ARE MORE BECKWITH-WIEDEMANN, SILVER- RUSSELL, ANGELMAN AND PRADER-WILLI SYNDROME CHILDREN IN THE ART POPULATION HARBORING IMPRINTED METHYLATION ERRORS COMPARED TO THOSE IN THE GENERAL POPULATION. SINCE ART USAGE COINCIDES WITH IMPORTANT STAGES OF IMPRINTED DNA METHYLATION PROGRAMMING DURING GAMETE AND PREIMPLANTATION DEVELOPMENT, IT IS POSSIBLE THAT ARTS LEAD TO IMPRINTING ERRORS. STUDIES IN FERTILE MICE SUPPORT THIS. SUPEROVULATION DURING OOGENESIS AND/OR EMBRYO CULTURE DURING PREIMPLANTATION, TWO NEARLY UNIVERSAL ART PROCEDURES, LEAD TO SIGNIFICANT NUMBERS OF EMBRYOS WITH IMPRINTED METHYLATION ERRORS. TO DATE, LITTLE IS KNOWN ABOUT THE REGULATION OF IMPRINTED METHYLATION MAINTENANCE DURING PREIMPLANTATION DEVELOPMENT, AND MOREOVER, HOW ARTS LEAD TO DISRUPTION IN THIS MAINTENANCE. THIS PROPOSAL WILL ADDRESS THESE KNOWLEDGE GAPS. IN AIM 1, WE WILL TEST THE HYPOTHESIZE THAT EMBRYOS ARE PREDISPOSED TO IMPRINTED METHYLATION ERRORS BECAUSE ARTS DISRUPT CRUCIAL MATERNAL-EFFECT TRANSCRIPTS IN OOCYTES THAT ARE REQUIRED IN EMBRYOS TO MAINTAIN IMPRINTED METHYLATION. CANDIDATE MATERNAL- EFFECT TRANSCRIPTS WILL BE IDENTIFIED USING SINGLE CELL RNA-SEQ ON CONTROL AND SUPEROVULATED OOCYTE, 1-CELL AND 2- CELL EMBRYOS, REPRESENTING THE PERIOD OF OOCYTE-TO-EMBRYO TRANSITION. CANDIDATE FUNCTION WILL THEN BE DETERMINED THOUGH PROTEIN DEGRADATION METHODS. NEXT, WE WILL DETERMINE WHETHER ALTERED MATERNAL-EFFECT TRANSCRIPTS IN POLAR BODIES, AS A PROXY FOR OOCYTES, CORRELATES WITH IMPRINTED METHYLATION ERRORS IN RESULTING EMBRYOS, ULTIMATELY LEADING TO IDENTIFICATION OF TRANSCRIPT BIOMARKERS THAT ARE PREDICTIVE OF IMPRINTED METHYLATION ERRORS. AIM 2 WILL TEST THE IMPORTANCE OF NUCLEAR IMPORT IN IMPRINT MAINTENANCE USING PHARMACOLOGICAL AND PROTEIN DEGRADATION METHODS, AND WHETHER IT IS DISRUPTED BY ARTS. IN AIM 3, WE HYPOTHESIZE THAT THE 4 TO 8-CELL STAGES REPRESENT A WINDOW OF SUSCEPTIBILITY WHEN FAST DEVELOPING ART EMBRYOS ACQUIRE DNA METHYLATION ERRORS, PARTICULARLY IN OUTER, TROPHOBLAST CELLS. WE WILL DETERMINE WHEN EMBRYO DEVELOPMENT IS ALTERED BY ARTS USING TIME-LAPSE ANALYSIS, AND THEN COMPARE DNA METHYLATION PERTURBATION IN SLOW AND FAST DEVELOPING EMBRYOS USING WHOLE GENOME BISULFITE MUTAGENESIS. THIS WILL DISTILL A MOLECULAR SIGNATURE OF DNA METHYLATION ERRORS. NEXT, WE WILL INVESTIGATE THIS MOLECULAR SIGNATURE DURING EARLY DEVELOPMENT TO DETERMINE WHEN DNA METHYLATION ERRORS ARISE AND IN WHICH LINEAGES OF ART EMBRYOS, AS WELL AS IN CELLS INDUCED TO TROPHOBLAST FATE. FINALLY, WE WILL TEST THE PREDICTIVE POWER OF DEVELOPMENTAL AND MORPHOKINETIC PARAMETERS AS A NONINVASIVE PROCEDURE FOR EMBRYOS WITH A MOLECULAR SIGNATURE OF IMPRINTED METHYLATION ERRORS. RESULTS FROM THIS PROPOSAL WILL PROVIDE THE BIOLOGICAL BASIS FOR IMPROVEMENTS TO FERTILITY TREATMENTS AIMED AT IDENTIFYING AT-RISK EMBRYOS.

DEVELOPING AND TESTING AN EVIDENCE-BASED TOOLKIT FOR NURSING HOME CARE OF RESIDENTS WITH OBESITY

DEVELOPING A HUMAN IN MOUSE CANCER MODEL WITH A COMPLETELY HUMANIZED STROMA

ADVANCING NATIVE AMERICAN DIVERSITY IN AGING RESEARCH THROUGH UNDERGRADUATE EDUCATION (NATIVE AMERICAN ADAR) - PROJECT SUMMARY THIS APPLICATION, RESPONSIVE TO PAR-17-290, SEEKS R25 FUNDING FOR “ADVANCING NATIVE AMERICAN DIVERSITY IN AGING RESEARCH THROUGH UNDERGRADUATE EDUCATION.” BY OFFERING ANNUAL COURSES AND MENTORED RESEARCH—ALONG WITH ONLINE VIRTUAL EDUCATION AND MENTORING DURING THIS COVID-19 PANDEMIC—WE RECRUIT STUDENTS FROM NATIVE AMERICAN BACKGROUNDS, BOTH URBAN AND NON-URBAN, TO ENCOURAGE THEM TO PURSUE CAREERS INVESTIGATING ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD) AND AGING MECHANISMS, AND HELP TO LAUNCH THEIR SCIENTIFIC CAREERS. THE ADRD AND AGING FIELDS CONTINUE TO GROW SWIFTLY, AS DOES THE ELDERLY POPULATION, YET THERE ARE TOO FEW LABORATORIES LED BY UNDER-REPRESENTED MINORITY (URM) SCIENTISTS, LET ALONE NATIVE AMERICAN PIS, AND TOO FEW NEW URM TRAINEES. THIS R25 IS DIRECTED BY GERALD SCHATTEN, PHD (PITT), AND LAURA NIEDERNHOFER, MD, PHD (MINNESOTA), WHO JOIN DAVID BURGESS, PHD (CHEROKEE, BOSTON COLLEGE); MELISSA WELLS, PHD (BOIS FORTE & COUCHICHING FIRST NATION ANISHINAABE, JOHNS HOPKINS - DULUTH); PAUL ROBBINS, PHD (MINNESOTA); AND CALVIN SIMERLY, PHD (PITT) AS THE EXECUTIVE COMMITTEE. THE COURSE IS HELD AT MINNESOTA’S INSTITUTE ON THE BIOLOGY OF AGING AND METABOLISM, DIRECTED BY LAURA NIEDERNHOFER, MD, PHD, AND PAUL ROBBINS, PHD. DAILY LECTURES, ACTIVE LEARNING, AND EXTENDED DISCUSSIONS ON EMERGING CONCEPTS, FOLLOWED BY LAB AND GROUP EXERCISES AND INFORMAL SEMINARS ARE HELD OVER A WEEK (AUGUST 15-21, 2021). BOTH HANDS-ON AND ONLINE TRAINING FOR 16 PARTICIPANTS ON RECENT DISCOVERIES REGARDING ADRD’S ROOT CAUSES AND TREATMENTS IS PRESENTED, WITH SPECIAL ATTENTION DEVOTED TO NATIVE AMERICANS; THE BIOLOGY OF AGING IS ALSO CONSIDERED. FREQUENT INTERACTIONS ARE MAINTAINED WITH EACH TRAINEE AFTERWARDS, TO EVALUATE THE COURSE AND PROVIDE ONGOING MENTORING. CONDUCTED WITH SENSITIVITY TO TRIBAL HISTORIES, FIVE SPECIFIC AIMS ARE PROPOSED: I. PROVIDE CONCEPTUAL EDUCATION AND RESEARCH TRAINING IN ADRD AND THE BIOLOGY OF AGING, WITH RELEVANCE FOR NATIVE AMERICAN TRAINEES; II. SUPPORT MENTORED PILOT RESEARCH, ESPECIALLY INVOLVING CHALLENGES IN HEALTH DISPARITIES AND DIVERSITY RELATED TO NATIVE AMERICANS; III. ENCOURAGE TRAINEES’ AND ALUMNI’S LONGER-TERM CAREER PLANNING THROUGH PERSONAL COACHING, MENTORING SESSIONS, AND PEER-TO-PEER ADVICE; IV. DISCUSS NIH REGULATORY REQUIREMENTS WITHIN THE CONTEXT OF TRIBAL SOVEREIGNTY; AND V. EVALUATE, IMPROVE, AND MONITOR THE NATIVE AMERICAN ADAR’S STRENGTHS AND AVOID WEAKNESSES WITH UNBIASED, QUANTITATIVE, INDEPENDENT MECHANISMS WHICH TRACK TRAINEES’ AND ALUMNI’S ACHIEVEMENTS TO ENSURE THAT THE PROGRAM IS A WISE, COST-EFFECTIVE INVESTMENT. IN SO DOING, WE WILL ENHANCE AND EXPAND THE RESEARCH CAREERS OF PROMISING TRAINEES, ESPECIALLY NATIVE AMERICANS, TO HELP ENSURE FULL DIVERSITY IN THE NIA AND NIH.

TRANSCRIPTIONAL REGULATION OF EARLY FOLLICULOGENESIS

HORMONES, IMMUNITY AND HIV RISK

NOVEL MECHANISMS OF PPARG IN ADIPOSE TISSUE DEVELOPMENT

NICHD MATERNAL FETAL MEDICINE UNITS NETWORK

NUTRITION AND THE GENETICS OF PREMATURITY

EVALUATING UNIQUE ASPECTS OF QUIESCENT OVARIAN CANCER CELL BIOLOGY FOR THERAPEUTIC TARGETS - MOST OVARIAN CANCER (OVCA) PATIENTS DEVELOP FATAL CHEMOTHERAPY-RESISTANT DISEASE. ELUCIDATING MECHANISMS OF CHEMORESISTANCE IN OVCA MAY IDENTIFY THERAPEUTIC TARGETS TO PREVENT OR TREAT RELAPSED OVCA. ONE UNDERSTUDIED MECHANISM OF CHEMOTHERAPY RESISTANCE IN OVCA IS QUIESCENCE. QUIESCENT CELLS ARE TRANSIENTLY NON-PROLIFERATING AND THUS REFRACTORY TO STANDARD THERAPIES WHICH TARGET RAPIDLY PROLIFERATING CELLS. THE OVER- ARCHING HYPOTHESIS OF THIS PROJECT IS THAT HYPOTHESIS IS THAT UNDERSTANDING THE BIOLOGY OF QUIESCENT OVCA CANCER CELLS WILL IDENTIFY CRITICAL NEW THERAPEUTIC TARGETS TO IMPROVE PATIENT OUTCOMES. WE HAVE USED MULTIPLE NOVEL APPROACHES TO IDENTIFY AND CHARACTERIZE THE TRANSCRIPTIONAL SIGNATURE OF QUIESCENT OVCA CELLS. THIS WORK INDICATES THAT QUIESCENT OVCA (QOVCA) CELLS HAVE SEVERAL UNIQUE CHARACTERISTICS INCLUDING: (I) A UNIQUE QUIESCENCE ASSOCIATED SECRETORY PHENOTYPE (QUASP) WHICH DRIVES CHEMOTHERAPY RESISTANCE IN NON- QUIESCENT CANCER CELLS, AND (II) ALTERED EXPRESSION OF SELECT COMPONENTS OF THE UBIQUITIN-PROTEOSOME SYSTEM (UPS) INCLUDING INDUCTION OF UBL7. INDEED, OUR PRELIMINARY DATA INDICATE THAT INDUCTION OF UBL7 IS SUFFICIENT TO DRIVE A QUIESCENT CELL PHENOTYPE, INCLUDING THE EXPRESSION OF THE QUASP. BIO-INFORMATIC ANALYSIS OF QUIESCENT OVCA CELL RNASEQ DATA IDENTIFIED THE SRF/MRTF TRANSCRIPTION PATHWAY AS BEING INVERSELY CORRELATED WITH THE OVCA QUIESCENT SIGNATURE. CONSISTENT WITH THIS, A SMALL MOLECULE INHIBITOR OF SRF/MRTF-MEDIATED TRANSCRIPTION, CCG081, (I) INDUCES UBL7, (II) DRIVES CELLS INTO A DENSE QUIESCENT STATE, AND (III), INDICATING A CRITICAL ROLE FOR THE UPS IN QUIESCENT CELL VIABILITY, CCG081 SENSITIZES OVCA CELLS TO PROTEASOME INHIBITORS. BASED ON THESE DISCOVERIES, WE PROPOSE: SA 1: TO CHARACTERIZE THE OVCA QUASP. WE HYPOTHESIZE THAT, CHARACTERIZING THE QUASP WILL IDENTIFY CRITICAL BIOLOGIC FACTORS RELATED TO QUIESCENCE. WE WILL IDENTIFY QUASP FACTORS, VALIDATE THE EXPRESSION OF QUASP FACTORS IN OVARIAN CANCER AND OTHER CANCER TYPES, AND USE KNOCKDOWN AND NEUTRALIZING ANTIBODIES TO EVALUATE THE FUNCTION OF THESE FACTORS IN QUIESCENT OVCA CELLS.SA 2: TO DETERMINE THE ROLE OF THE UPS AND UBL7 IN QUIESCENT CANCER CELLS. WE HYPOTHESIZE THAT UPS CHANGES CONTRIBUTE TO THE QUIESCENT CELL STATE AND ARE ESSENTIAL FOR QUIESCENT CELL VIABILITY. WE WILL IDENTIFY WHICH COMPONENTS OF THE UPS CONTRIBUTE TO THE QUIESCENT PHENOTYPE, INCLUDING EXPRESSION OF THE QUASP, AND DETERMINE IF THE PROTEOSOME IS ESSENTIAL TO MAINTAIN QUIESCENT OVCA CELL VIABILITY. FINALLY, WE WILL SA 3: EVALUATE THE IMPACT OF TARGETING THE PROTEOSOME QUIESCENT CELLS IN VIVO. WE HYPOTHESIZE THAT THE ABILITY TO PHARMACOLOGICALLY FORCE THESE RESIDUAL CELLS INTO A QUIESCENT STATE AND THEN ELIMINATE THESE QUIESCENT CELLS VIA PROTEOSOME INHIBITION WILL INCREASE CURE RATES. WE WILL EVALUATE THE THERAPEUTIC POTENTIAL OF COMBINED CCG081 AND FDA-APPROVED PROTEOSOME INHIBITORS AS CONSOLIDATIVE THERAPY AFTER CHEMOTHERAPY TO ERADICATE RESIDUAL QUIESCENT CELLS. IMPACT: WE WILL DEFINE THE REGULATORS OF OVCA CELL QUIESCENCE, PROVIDING THERAPEUTIC TARGETS ERADIATE TO IMPROVE PATIENT OUTCOMES.

PUBOVISCERAL MUSCLE ENTHESIS INJURY: A BIOINSPIRED APPROACH TO REPAIR - PROJECT SUMMARY EACH YEAR, AT LEAST 20% OF WOMEN WHO GIVE BIRTH VAGINALLY SUSTAIN AN AVULSION OF THE PUBOVISCERAL MUSCLE ENTHESIS (PVME) AT THE PUBIC BONE, SUBSTANTIALLY PREDISPOSING TO PELVIC ORGAN PROLAPSE (POP) AND ASSOCIATED DISORDERS LATER IN LIFE. POP, A CHRONIC DISEASE UNIQUE TO WOMEN, REPRESENTS A MAJOR PUBLIC HEALTH BURDEN SINCE 12.6% OF US WOMEN WILL UNDERGO A MAJOR SURGICAL REPAIR OF POP BY AGE 80, AT AN ESTIMATED COST OF > $10 BILLION ANNUALLY. CURRENTLY, OUR INABILITY TO REPAIR PVME AVULSIONS, EITHER AT THE TIME OF INJURY OR LATER IN LIFE WHEN POP HAS OCCURRED, SEVERELY UNDERMINES THE OUTCOMES OF CURRENT POP SURGERIES. PVME INJURIES ARE RARELY RECOGNIZED AT VAGINAL BIRTH, AND GIVEN THAT THERE IS NO VIABLE TREATMENT, THERE IS LITTLE INCENTIVE TO CHANGE THIS STANDARD OF CARE. LACK OF FUNDAMENTAL AND LONGITUDINAL DATA ON THE PATHOPHYSIOLOGIC EVENTS THAT FOLLOW PVME AVULSION AND THE RELATED BIOMECHANICAL CONSEQUENCES FURTHER HINDERS THE DESIGN OF INTERVENTIONS. BRIDGING THIS KNOWLEDGE GAP, THE CURRENT PROPOSAL WILL FIRST INVESTIGATE THE STRUCTURE AND FUNCTION OF NATIVE PVME AND THE PATHOPHYSIOLOGIC EVENTS FOLLOWING INJURY, SO AS TO INFORM THE DESIGN OF A COMPOSITE SCAFFOLD THAT ORCHESTRATES AN INTEGRATIVE REPAIR. WE HYPOTHESIZE THAT A SURGICALLY PLACED BIOINSPIRED COMPOSITE SCAFFOLD WITH PRE-ENGINEERED BIOMIMETIC SPATIAL CUES IN STRUCTURE AND COMPOSITION WILL ENABLE ENTHESIS REGENERATION THAT WILL BE SUPERIOR TO SUTURE REPAIR. TO TEST THIS, WE DEVELOP A COMPREHENSIVE FRAMEWORK FOR DEFINING PVME INJURY AND REPAIR BASED ON TRANSPERINEAL ULTRASOUND TO 1) IMPROVE THE IDENTIFICATION OF PATIENTS WHO WILL HAVE PERSISTENT LEVATOR AVULSION AND ARE CANDIDATES FOR REPAIR; AND 2) GUIDE THE DEVELOPMENT OF DESIGN PARAMETERS FOR AN EFFECTIVE REPAIR USING A BIOINSPIRED GRAFT. STATISTICAL SHAPE MODELS DERIVED FROM 3D MRI MODELS WILL BE USED AS A GOLD STANDARD TO INFORM THE DIAGNOSTIC INTERPRETATION OF CORRESPONDING SHAPE MODELS ESTABLISHED FROM TRANSPERINEAL ULTRASOUND (TPUS) IN WOMEN WITH AND WITHOUT PVME INJURY. THESE ANALYSES WILL BE FURTHER INFORMED BY FINITE ELEMENT SIMULATIONS PREDICTING FUNCTIONAL DEFICITS AFTER PVME INJURY AND SUBSEQUENT PARAMETRIC STUDIES OF ENTHESIS REPAIR TO ENABLE THE ESTABLISHMENT OF BASIC DESIGN CRITERIA FOR A SCAFFOLD BASED REPAIR. IN PARALLEL, WE PERFORM CELL CULTURE AND SMALL ANIMAL STUDIES (AIM 2) TO INVESTIGATE MATRIX ATTRIBUTES, CELL POPULATIONS, AND MOLECULAR AND MECHANICAL CUES INVOLVED IN ENTHESIS REPAIR TO FURTHER REFINE SCAFFOLD DESIGN AND DEFINE NEEDS FOR DURABLE REPAIR. WITH ITS HIGH CAPACITY FOR BIOMIMICRY, A NANOFIBER-BASED BILAYER SCAFFOLD WITH A MINERALIZED COMPONENT FOR OSTEOINTEGRATION AND A NONMINERALIZED PORTION FOR TENDON FORMATION ALREADY ESTABLISHED TO REGENERATE A FUNCTIONAL TENDON-BONE INTERFACE IN ROTATOR CUFF REPAIR WILL BE ADAPTED FOR PVME. FIBER DIAMETER, ALIGNMENT, AND MINERAL CONTENT WILL BE READILY OPTIMIZED IN AIM 2 TO GUIDE THE CELL RESPONSE AND DIRECT ENTHESIS HEALING. FINALLY, A NONHUMAN PRIMATE MODEL WILL BE EMPLOYED IN A PRECLINICAL STUDY THAT COMPARES SCAFFOLD TO SUTURE REPAIR AND UNINJURED ENTHESIS (AIM 3). WE FIRMLY BELIEVE THAT DEVELOPMENT OF THIS BIOINSPIRED COMPOSITE SCAFFOLD FOR PVME REPAIR WILL LEAD TO A PARADIGM SHIFT IN THE TREATMENT OF TRAUMATIC CHILDBIRTH TO THE BENEFIT OF WOMEN WORLD-WIDE.

THE FUNCTION OF EGFL6 IN OVARIAN CANCER CELL BIOLOGY, TUMOR INITIATION, AND THERAPY

EXPANDING THE FAMILY CHECK-UP IN EARLY CHILDHOOD TO PROMOTE CARDIOVASCULAR HEALTH OF MOTHERS AND YOUNG CHILDREN (ENRICH) - PROJECT SUMMARY THIS TWO-PHASED RANDOMIZED CONTROLLED TRIAL WILL EXAMINE THE IMPLEMENTATION AND EFFECTIVENESS OF A CARDIOVASCULAR HEALTH (CVH) INTERVENTION ON POSTPARTUM MOTHERS AND YOUNG CHILDREN THROUGH AGE 3. WE WILL ADAPT A CVH INTERVENTION INTO AN EVIDENCE-BASED HOME VISITING PROGRAM, FAMILY CHECK-UP (FCU) TO CREATE FCU-HEART. THROUGH A TYPE 1 HYBRID EFFECTIVENESS- IMPLEMENTATION DESIGN, THE FIRST PHASE RCT PILOT STUDY WILL TEST THE FEASIBILITY AND EFFECTIVENESS OF FCU-HEART (FCU-HEART, N=100; FCU, N=50) (AIM 1A AND 1B). A SECOND GOAL OF THE HYBRID STUDY IS TO UNDERSTAND THE REACH, ENGAGEMENT, AND CONTEXT FOR IMPLEMENTATION OF FCU-HEART AND GATHER INFORMATION FOR DEVELOPMENT OF THE MULTI-CENTER HOME VISITING MODEL TRIAL. THE SECOND PHASE OF OUR STUDY WILL COMPARE THE FCU-HEART TO STANDARD FCU OUTCOMES THROUGH A COLLABORATIVE, MULTICENTER RANDOMIZED TRIAL (AIMS 2 AND 3). OUR FCU-HEART PROGRAM IS INTENDED TO IMPROVE THE CVH OF HIGH-RISK MOTHERS (LOW-INCOME WITH CARDIOVASCULAR RISK DURING PREGNANCY—HYPERTENSION, DIABETES, OBESITY) COMPARED TO THE TRADITIONAL FCU AND OTHER HOME VISITING PROGRAMS BY INCORPORATING INDIVIDUALIZED, CULTURALLY COMPETENT INTERVENTIONS THAT TARGET DIET AND EXERCISE, BLOOD PRESSURE CONTROL, STRESS MANAGEMENT AND SELF-CARE, AND SMOKING CESSATION. THE INTERVENTION INCLUDES CARDIOVASCULAR ASSESSMENT AND FEEDBACK, FOLLOWED BY A TAILORED TREATMENT PROGRAM DELIVERED BY FAMILY COACHES IN 3-4 WEEK MODULES TO ESTABLISH GOALS AND TRACK PROGRESS. THESE SESSIONS WILL WORK TOWARDS OBTAINING POSITIVE CVH OUTCOMES AND EMPOWERING MOTHERS OF INFANTS TO ACHIEVE THEIR GOALS THROUGH EDUCATION AND A CONNECTION TO RESOURCES WHICH WE HYPOTHESIZE WILL ALSO PRESERVE CHILD CVH. PRIMARY ANALYSES WILL ASSESS THE IMPACT OF FCU-HEART ON MATERNAL AND CHILD CVH OUTCOMES AT CHILD AGES 1, 2, AND 3 YEARS COMPARED TO FCU ALONE. FURTHER, BASED ON THE HIGHER RATES OF CVH COMPLICATIONS AMONG BLACK WOMEN AND CHILDREN, WE WILL EXAMINE THE EFFECTS OF FCU-HEART VS FCU ALONE ON MATERNAL AND CHILD CVH RACIAL DISPARITIES AT THE 1-, 2-, AND 3-YEAR ASSESSMENTS (AIM 3). THIS APPLICATION HAS THE POTENTIAL TO IMPROVE THE CVH TRAJECTORIES OF POSTPARTUM MOTHERS AND YOUNG CHILDREN DURING A CRITICAL PERIOD OF THEIR DEVELOPMENT, PROVIDING LONG-LASTING HEALTH BENEFITS.

MECHANISMS OF PREECLAMPSIA RISK WITH OBESITY: ROLE OF ELEVATED ADMA

ORGANIZING AND REORGANIZING HUMAN TESTIS DEVELOPMENT IN VITRO - ABSTRACT THIS IS A MULTI-PI, MULTI-INSTITUTIONAL GRANT TO DEVELOP PHYSIOMIMETIC SYSTEMS THAT MIMIC HUMAN TESTIS DEVELOPMENT AND SPERMATOGENIC LINEAGE DEVELOPMENT, EX VIVO. CHEMOTHERAPY AND RADIATION TREATMENTS FOR CANCER OR GENDER AFFIRMING TREATMENTS FOR TRANSGENDER PATIENTS CAN CAUSE INFERTILITY. ADULT PATIENTS HAVE THE OPTION TO CRYOPRESERVE EGGS OR SPERM PRIOR TO TREATMENT THAT CAN BE THAWED IN THE FUTURE AND USED TO ACHIEVE PREGNANCY WITH STANDARD ASSISTED REPRODUCTIVE TECHNOLOGIES, INCLUDING IVF. THOSE OPTIONS ARE NOT AVAILABLE TO ALL ADULT PATIENTS OR TO PREPUBERTAL PATIENTS WHO ARE NOT ABLE TO PRODUCE MATURE EGGS OR SPERM. ALTHOUGH PREPUBERTAL BOYS OR TRANSGENDER GIRLS WHO ARE ON GENDER AFFIRMING TREATMENTS ARE NOT PRODUCING SPERM, THEY DO HAVE SPERMATOGONIAL STEM CELLS SSCS IN THEIR TESTES THAT HAVE THE POTENTIAL TO PRODUCE SPERM. THE MPIS IN CHICAGO AND PITTSBURGH HAVE BEEN CRYOPRESERVING IMMATURE TESTICULAR TISSUES FOR YOUNG PATIENTS FOR MORE THAN A DECADE WITH ANTICIPATION THAT THOSE TISSUES CAN BE THAWED IN THE FUTURE AND MATURED TO PRODUCE SPERM. EACH PATIENT DONATES A PORTION OF THEIR TISSUE TO RESEARCH TO DEVELOP NEXT GENERATION TECHNOLOGIES THAT WILL ALLOW THEM TO USE THEIR TISSUES FOR REPRODUCTION. WE WILL USE THOSE TISSUES TO GAIN FUNDAMENTAL INSIGHTS INTO HUMAN TESTIS DEVELOPMENT FROM NEWBORN TO ADULT STAGES OF LIFE. THIS WILL ESTABLISH BENCHMARKS TO EVALUATE OUR PROGRESS ENGINEERING THREE NOVEL TESTIS PHYSIOMIMETIC SYSTEMS THAT SUPPORT SPERMATOGENESIS, EX VIVO. AIM 1 WILL REPLICATE MOUSE TESTICULAR TISSUE ORGANOTYPIC CULTURE AT THE AIR/LIQUID INTERFACE USING A MICROFLUIDICS DEVICE AND A STATIC PDMS ROOF-TRANSWELL SYSTEM BEFORE TRANSLATING THE APPROACH TO HUMAN TESTIS TISSUES. AIM 2 WILL ESTABLISH MOUSE AND HUMAN TESTICULAR ORGANOIDS, WHICH WILL THEN BE INDUCED TO FUSE INTO ELONGATED SEMINIFEROUS TUBULE-LIKE STRUCTURES. AIM 3 WILL PRINT SEMINIFEROUS TUBULE LIKE SCAFFOLDS USING HUMAN TESTIS EXTRACELLULAR MATRIX (HTECM) AND PIG TESTIS ECM (PTECM) HYDROGELS AS BIOINK AND THEN SEED THE SCAFFOLDS WITH MOUSE AND HUMAN TESTICULAR SOMATIC CELLS AND GERM CELLS. THESE TESTICULAR PHYSIOMIMETIC SYSTEMS WILL PROVIDE FUNDAMENTAL INSIGHTS INTO HUMAN TESTICULAR SOMATIC CELL AND GERM CELL DEVELOPMENT AND ESTABLISH EXPERIMENTAL PLATFORMS TO TEST TOXICOLOGIC OR PHARMACEUTICAL COMPOUNDS OR DRUGS THAT PROMOTE OR PREVENT SPERM PRODUCTION. THE OVERARCHING OBJECTIVE IS TO MATURE HUMAN TESTICULAR TISSUES IN ONE OR MORE OF THESE PHYSIOMIMETIC SYSTEMS TO PRODUCE FERTILIZATION COMPETENT SPERM, EX VIVO.

PITTSBURGH PELVIC FLOOR RESEARCH PROGRAM

PITTSBURGH PELVIC FLOOR RESEARCH PROGRAM

USING MICROFLUIDIC SINGLE CELL CULTURE TO CHARACTERIZE CANCER CELL ASYMMETRIC DIVISION

PRETERM BIRTH IN NULLIPAROUS WOMEN: AN UNDERSTUDIED POPULATION AT GREAT RISK

PLACENTAL INJURY AND MICRORNA

DEVELOPMENT OF A URINE-BASED POINT-OF-CARE TEST FOR ADHERENCE TO ANTIRETROVIRAL DRUGS

THE ROLE OF EGFL6 IN TUMOR IMMUNITY - OVARIAN CANCER (OVCA) HAS AN EXTREMELY HIGH MORTALITY RATE, INDICATING A CLEAR NEED FOR NEW THERAPEUTIC APPROACHES. ONE SUCH APPROACH IS IMMUNE CHECKPOINT INHIBITOR (ICI) THERAPY. UNFORTUNATELY, DESPITE THE PRESENCE OF ANTI-TUMOR EFFECTOR CELLS IN MANY OVCA PATIENTS, ICI THERAPIES HAVE POOR RESPONSE RATES IN OVCA. ONE REASON FOR THIS MAY LARGE NUMBERS OF IMMUNOSUPPRESSIVE MYELOID-DERIVED SUPPRESSOR CELLS (MDSCS) AND TUMOR-ASSOCIATED MACROPHAGES (TAMS) PRESENT IN THE OVCA. BOTH MDSC AND TAM NEGATIVELY REGULATE IMMUNITY IN CANCER AND THERAPEUTIC APPROACHES WHICH CAN DISRUPT THE RECRUITMENT/FUNCTION OF THESE CELLS CAN ENHANCE ICI RESPONSE. A POTENTIAL THERAPEUTIC TARGET TO DISRUPT MDSC/TAM IS EGFL6. EGFL6 IS A DEVELOPMENTAL GROWTH FACTOR WHICH IS KNOWN TO REGULATE CELLULAR MIGRATION, PROLIFERATION, AND DIFFERENTIATION AND IS HIGHLY EXPRESSED IN OVCA. WE FOUND THAT MICE WHICH OVEREXPRESS EGFL6 HAVE INCREASED NUMBERS OF GRANULOCYTES AND MONOCYTES IN BOTH THE BONE MARROW (BM) AND SPLEEN. EGFL6 TREATMENT OF BM MYELOID CELLS WAS ASSOCIATED WITH AN INTEGRIN DEPENDENT INCREASE IN P-SYK, AND DIFFERENTIATION TO IL-10+ AND S100A9+ GRANULOCYTIC MDSC. MURINE TUMORS WHICH OVEREXPRESS EGFL6, COMPARED TO CONTROLS, (I) HAVE A SIGNIFICANT INCREASE IN MDSC ACCUMULATION AND M2- LIKE TAM, (III) EXPRESS CXCL2 AND CLEC5A, FACTORS ASSOCIATED WITH NEUTROPHIL EXTRACELLULAR TRAPS (NETS) FORMATION, AND (III) ARE REFRACTORY TO ICI THERAPY. WE THUS HYPOTHESIZE THAT EGFL6, VIA SYK ACTIVATION, PROMOTES AN IMMUNOSUPPRESSIVE TME BY INCREASING NUMBERS OF MDSC/TAM AND THEIR PRODUCTION OF NETS IN TUMORS. AS AN EXTENSION OF THIS, WE HYPOTHESIZE THAT INHIBITION OF EGFL6, WILL ENHANCE THE EFFICACY OF ICI THERAPY. TO TEST OUR HYPOTHESES, WE PROPOSE: SA1. TO EVALUATE THE REQUIREMENT FOR SYK IN EGFL6 SIGNALING ON MYELOID CELLS. AS SYK IS REQUIRED FOR INTEGRIN SIGNALING IN GRANULOCYTES, WE HYPOTHESIZE THAT TARGETED DISRUPTION OF SYK WILL PREVENT EGFL6- DEPENDENT GRANULOCYTE ACCUMULATION. USING SPECIFIC SYK INHIBITOR COMPOUNDS AND SYK-KO GRANULOCYTES/MONOCYTES, WE WILL DISSECT THE EGFL6-SYK REGULATORY AXIS. SA2. TO ANALYZE THE ROLE OF EGFL6 IN NETS FORMATION AND RESISTANCE TO ICI THERAPY. WE FOUND EGFL6 EXPRESSING TUMORS HAVE INCREASED LEVELS AND NETOSIS AND THAT EGFL6 INDUCES CXCL2 AND CLEC5A, FACTORS ASSOCIATED WITH NETOSIS. THIS OCCURS BOTH IN THE PRESENCE AND ABSENCE OF ICI THERAPY. WE HYPOTHESIZE THAT EGFL6, BY INDUCTION OF NETS, LIMITS THE ANTI-TUMOR IMMUNITY PROMOTING RESISTANCE TO ICI THERAPY. WE WILL USE CXCL2 AND CLEC5A MEDIATED INHIBITION/KO APPROACHES TO DEFINE THE MECHANISMS BY WHICH EGFL6 INDUCES NETOSIS AND THE IMPACT OF EGFL6 INDUCED NETOSIS ON ICI CYTOTOXIC IMMUNITY. SA 3. EVALUATE THE IMPACT OF EGFL6 NEUTRALIZING ANTIBODY ON THE EFFICACY OF ICI THERAPY AND ANTI-TUMOR IMMUNITY. WE WILL USE AN IMMUNE COMPETENT ICI RESPONSIVE MURINE OVCA MODEL TO EVALUATE THE ABILITY OF AN EGFL6 NEUTRALIZING ANTIBODY TO OVERCOME EGFL6 MEDIATED IMMUNE SUPPRESSION. COMBINED THESE STUDIES WILL CHARACTERIZE A NOVEL MECHANISM OF OVCA MEDIATED TUMOR IMMUNE SUPPRESSION AND VALIDATE EGFL6 ANTIBODY AS A NOVEL THERAPEUTIC APPROACH TO ENHANCE ICI THERAPY IN OVCA PATIENTS.

MUC1 ROLES IN OVARIAN CANCER PATHOGENESIS AND IMMUNE THERAPY

DEVELOPMENT OF NON-INVASIVE LIQUID BIOPSY SCREENING TOOL FOR PRETERM BIRTH CAUSES AND CONSEQUENCES - PROGRAM DIRECTOR/PRINCIPAL INVESTIGATOR (LAST, FIRST, MIDDLE): PETERS, DAVID, G. ABSTRACT THE OVERARCHING GOAL OF THIS STUDY IS TO DEVELOP EPIGENOMIC LIQUID BIOPSY METHODS FOR BOTH THE EARLY DETECTION AND ONGOING PREDICTION OF THE CLINICAL TRAJECTORIES THAT RESULT IN PRETERM BIRTH (PTB). PTB IS THE MOST IMPORTANT PROBLEM IN MODERN OBSTETRICS. DESPITE ONGOING EFFORTS TO UNDERSTAND ITS ETIOLOGIES, THERE ARE NO SCREENS THAT RELIABLY IDENTIFY AT-RISK EXPECTANT MOTHERS EARLY IN GESTATION. FURTHERMORE, IN THE CASE OF PREECLAMPSIA (PE), THE CLINICAL TRAJECTORY OF DISEASE, ONCE DIAGNOSED, IS DIFFICULT TO PREDICT. SIMILARLY, FOR FETUSES AFFECTED BY INTRAUTERINE GROWTH RESTRICTION (IUGR) IT IS IMPOSSIBLE TO IDENTIFY IN EARLY GESTATION THOSE THAT WILL HAVE THE POOREST OUTCOMES. BUILDING ON OUR PIONEERING WORK IN NON-INVASIVE PRENATAL TESTING (NIPT) WE PROPOSE TO DEVELOP A LIQUID BIOPSY SCREEN FOR PTB AND ANALYTICAL METHODS THAT WILL PREDICT THE CLINICAL TRAJECTORIES OF PE AND IUGR. LIQUID BIOPSY OF CELL-FREE DNA (CFDNA) IS A POWERFUL TOOL FOR NON-INVASIVE DIAGNOSIS AND PHENOTYPING OF HUMAN DISEASE. CFDNA CONTAINS A WEALTH OF BIOLOGICALLY IMPORTANT INFORMATION, IF ONE HAS THE ANALYTICAL TOOLS TO EXPLOIT IT. FOR EXAMPLE, METHYLATION SIGNATURES ON CFDNA FRAGMENTS IN MATERNAL PLASMA CONTAIN INFORMATION RELATING TO THEIR TISSUE(S) OF ORIGIN, AS WELL AS INDICATORS OF EPIGENOMIC DYSREGULATION ASSOCIATED WITH PATHOLOGICAL CHANGES WITHIN THOSE TISSUES. WE HAVE DEVELOPED ANALYTICAL METHODS THAT CAN DETECT DNA METHYLATION CHANGES IN MATERNAL AND FETAL TISSUES MANY WEEKS BEFORE THE ONSET OF PTB. THE CASCADE OF EVENTS THAT CULMINATE IN PTB HAS SEVERAL POSSIBLE UNDERLYING PATHOPHYSIOLOGICAL PATHWAYS. THESE PATHWAYS MAY BE INITIATED WEEKS TO MONTHS BEFORE CLINICALLY APPARENT PRETERM LABOR OR PRETERM RUPTURE OF MEMBRANES. WE PROPOSE TO DEVELOP TWO KINDS OF "EARLY WARNINGS". ONE WILL PREDICT THE TRAJECTORIES OF PREGNANCIES, PARTICULARLY PREGNANCIES THAT EXPERIENCE MILD OR SEVERE PREECLAMPSIA (PE) (AIM 1) OR IUGR (AIM 2). THESE PREDICTIONS WILL BE MADE AFTER A CLINICAL DIAGNOSIS AND ARE INTENDED TO HELP WITH CLINICAL MANAGEMENT OF THE PREGNANCY. THE OTHER WILL BE A SCREEN, ADMINISTERED BETWEEN WEEKS 10 AND 13, FOR PREGNANCIES THAT ARE LIKELY TO END IN PRETERM BIRTH (AIM 3).

EXPANDING THE FAMILY CHECK-UP IN EARLY CHILDHOOD TO PROMOTE CARDIOVASCULAR HEALTH OF MOTHERS AND YOUNG CHILDREN (ENRICH) - PROJECT SUMMARY THIS TWO-PHASED RANDOMIZED CONTROLLED TRIAL WILL EXAMINE THE IMPLEMENTATION AND EFFECTIVENESS OF A CARDIOVASCULAR HEALTH (CVH) INTERVENTION ON POSTPARTUM MOTHERS AND YOUNG CHILDREN THROUGH AGE 3. WE WILL ADAPT A CVH INTERVENTION INTO AN EVIDENCE-BASED HOME VISITING PROGRAM, FAMILY CHECK-UP (FCU) TO CREATE FCU-HEART. THROUGH A TYPE 1 HYBRID EFFECTIVENESS- IMPLEMENTATION DESIGN, THE FIRST PHASE RCT PILOT STUDY WILL TEST THE FEASIBILITY AND EFFECTIVENESS OF FCU-HEART (FCU-HEART, N=100; FCU, N=50) (AIM 1A AND 1B). A SECOND GOAL OF THE HYBRID STUDY IS TO UNDERSTAND THE REACH, ENGAGEMENT, AND CONTEXT FOR IMPLEMENTATION OF FCU-HEART AND GATHER INFORMATION FOR DEVELOPMENT OF THE MULTI-CENTER HOME VISITING MODEL TRIAL. THE SECOND PHASE OF OUR STUDY WILL COMPARE THE FCU-HEART TO STANDARD FCU OUTCOMES THROUGH A COLLABORATIVE, MULTICENTER RANDOMIZED TRIAL (AIMS 2 AND 3). OUR FCU-HEART PROGRAM IS INTENDED TO IMPROVE THE CVH OF HIGH-RISK MOTHERS (LOW-INCOME WITH CARDIOVASCULAR RISK DURING PREGNANCY—HYPERTENSION, DIABETES, OBESITY) COMPARED TO THE TRADITIONAL FCU AND OTHER HOME VISITING PROGRAMS BY INCORPORATING INDIVIDUALIZED, CULTURALLY COMPETENT INTERVENTIONS THAT TARGET DIET AND EXERCISE, BLOOD PRESSURE CONTROL, STRESS MANAGEMENT AND SELF-CARE, AND SMOKING CESSATION. THE INTERVENTION INCLUDES CARDIOVASCULAR ASSESSMENT AND FEEDBACK, FOLLOWED BY A TAILORED TREATMENT PROGRAM DELIVERED BY FAMILY COACHES IN 3-4 WEEK MODULES TO ESTABLISH GOALS AND TRACK PROGRESS. THESE SESSIONS WILL WORK TOWARDS OBTAINING POSITIVE CVH OUTCOMES AND EMPOWERING MOTHERS OF INFANTS TO ACHIEVE THEIR GOALS THROUGH EDUCATION AND A CONNECTION TO RESOURCES WHICH WE HYPOTHESIZE WILL ALSO PRESERVE CHILD CVH. PRIMARY ANALYSES WILL ASSESS THE IMPACT OF FCU-HEART ON MATERNAL AND CHILD CVH OUTCOMES AT CHILD AGES 1, 2, AND 3 YEARS COMPARED TO FCU ALONE. FURTHER, BASED ON THE HIGHER RATES OF CVH COMPLICATIONS AMONG BLACK WOMEN AND CHILDREN, WE WILL EXAMINE THE EFFECTS OF FCU-HEART VS FCU ALONE ON MATERNAL AND CHILD CVH RACIAL DISPARITIES AT THE 1-, 2-, AND 3-YEAR ASSESSMENTS (AIM 3). THIS APPLICATION HAS THE POTENTIAL TO IMPROVE THE CVH TRAJECTORIES OF POSTPARTUM MOTHERS AND YOUNG CHILDREN DURING A CRITICAL PERIOD OF THEIR DEVELOPMENT, PROVIDING LONG-LASTING HEALTH BENEFITS.

BUILDING INTERDISCIPLINARY RESEARCH CAREERS IN WOMEN'S HEALTH IN PITTSBURGH - PROJECT SUMMARY IN THIS RENEWAL APPLICATION, WE DESCRIBE AN ENHANCED EDUCATIONAL FRAMEWORK FOR THE TRAINING, NURTURING, AND SUPPORT OF TALENTED UNIVERSITY OF PITTSBURGH (PITT) FACULTY SCHOLARS POISED TO EMBARK ON RESEARCH CAREERS IN WOMEN’S HEALTH ACROSS THE LIFESPAN. WE HAVE BUILT OUR PROGRAM ON AN UNPARALLELED FOUNDATION IN REPRODUCTIVE SCIENCES AND WOMEN’S HEALTH RESEARCH LED BY MAGEE-WOMENS RESEARCH INSTITUTE (MWRI). LOCATED AT THE CENTER OF PITT’S CAMPUS, MWRI IS IMMEDIATELY ADJACENT TO MAGEE-WOMENS HOSPITAL OF THE UNIVERSITY OF PITTSBURGH MEDICAL CENTER (UPMC), ONE OF THE NATION’S MOST ROBUST INTEGRATED HEALTHCARE SYSTEMS. OUR 71 PRIMARY MWRI RESEARCHERS ARE FULLY ENGAGED IN BASIC, TRANSLATIONAL, CLINICAL, HEALTH SERVICES, AND COMMUNITY- ORIENTED RESEARCH, SUPPORTED BY PITT’S SIX HEALTH SCIENCES AND ENGINEERING SCHOOLS. WITH MWRI AS THE PROGRAMMATIC HUB OF BIRCWH@PITT, WE HAVE MARKEDLY STRENGTHENED OUR WOMEN’S HEALTH NETWORK AND CREATED NEW AND EXCITING INVESTIGATIVE NODES WITHIN PITT’S CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTE (CTSI). WE EMBARKED ON NEW INITIATIVES TO SUPPORT AND ENHANCE TRAINING ON SOCIAL AND MORAL DETERMINANTS OF HEALTH IN DIVERSE POPULATIONS, DEVELOPED NEW EDUCATIONAL OPPORTUNITIES, STRENGTHENED INCLUSIVE RESEARCH WITHIN CTSI, WITH A VANGUARD EMPHASIS ON WOMEN’S HEALTH ACROSS THE LIFESPAN. WE HAVE DEEPENED OUR TRAINING IN THE INCORPORATION OF SEX AND GENDER AS BIOLOGICAL VARIABLES AND EXPANDED OUR SPECIAL ENRICHMENT TOOLS, DESIGNED TO SPARK EACH SCHOLAR’S IMAGINATION IN NEW INQUIRES AND CAREER PATHS. WE HAVE DEVELOPED INNOVATIVE TOOLS THAT BETTER CONNECT THE PROMISE OF SCIENTIFIC DISCOVERIES WITH PEOPLE AND COMMUNITIES. OUR NOVEL MODEL OF COMMUNITY PARTNERSHIP BRINGS RESEARCHERS AND COMMUNITY MEMBERS TOGETHER AS ALLIES IN THE SCIENTIFIC PURSUIT. WE HAVE TAKEN OUR ENGAGEMENT OF UNDERREPRESENTED MINORITIES TO A HIGHER LEVEL, AT BOTH THE TRAINEE AND ADVISORY COMMITTEE LEVEL. TOGETHER, OUR INNOVATIVE PLATFORMS ENABLE US TO FOCUS ON OUR LONG-TERM OBJECTIVES OF EDUCATION, INTELLECTUAL STIMULATION, HANDS-ON TRAINING, INTENSE CAREER DEVELOPMENT TOWARD ACADEMIC INDEPENDENCE, PROMOTION OF NEW SYNERGIES, AND A FULL REALIZATION OF COLLABORATIVE, DYNAMIC, AND MEANINGFUL ENGAGEMENT. TO ACCOMMODATE AN EXPECTED HETEROGENEITY IN SCHOLARS’ ACADEMIC BACKGROUNDS AND CAREER GOALS, WE HAVE CRAFTED INDIVIDUALLY TAILORED DEVELOPMENT PLANS OF 2–5 YEARS, ADJUSTED TO ACCOMMODATE THE EXPERTISE AND TRAINING OF THE ANTICIPATED FIVE OR SIX SCHOLARS. A TEAM OF MENTORS WITH VARIED YET COMPLEMENTARY SKILLS IS FITTED TO SUPPORT EACH SCHOLAR. RESOURCES GARNERED THROUGH OUR PROGRAM ARE SHARED WITH OTHER TRAINEES AT MWRI, ACROSS PITT’S HEALTH SCIENCES SCHOOLS, AND AT THE LATINX-ABUNDANT PONCE HEALTH SCIENCES UNIVERSITY IN PUERTO RICO. TOGETHER, BIRCWH@PITT EMPHASIZES IMAGINATIVE, INCLUSIVE THINKING, CROSS-FERTILIZATION, AND COLLABORATION THAT BRIDGES BASIC AND CLINICAL SCIENCES AND SERVES TO PROPEL OUR SCHOLARS TO SUCCESSFUL CAREERS IN IMPACTFUL WOMEN’S HEALTH RESEARCH.

APTAMER MICROBICIDE DEVELOPMENT PROGRAM (MDP)

SPERMATOGONIAL STEM CELL TRANSPLANTATION AND CULTURE IN PATIENTS - ABSTRACT MEDICAL TREATMENTS FOR CANCER OR OTHER CONDITIONS CAN CAUSE INFERTILITY. SPERM CRYOPRESERVATION IS AN EFFECTIVE OPTION FOR ADULT MEN TO PRESERVE THEIR FERTILITY. THIS OPTION, HOWEVER, IS NOT AVAILABLE TO PREPUBERTAL BOYS WHO ARE NOT YET PRODUCING SPERM. FOR OVER 20 YEARS, CENTERS AROUND THE WORLD HAVE BEEN CRYOPRESERVING IMMATURE TESTICULAR TISSUES, WHICH CONTAIN SPERMATOGONIAL STEM CELLS, FOR BOYS IN ANTICIPATION THAT THE TISSUES OR CELLS CAN BE MATURED IN THE FUTURE TO PRODUCE SPERM. SOME OF THOSE SURVIVORS ARE NOW RETURNING TO USE THEIR TISSUES FOR REPRODUCTION. SSC TRANSPLANTATION AND TESTICULAR TISSUE GRAFTING ARE MATURE TECHNOLOGIES THAT ARE READY FOR TRANSLATION TO THE HUMAN CLINIC. AT THE UNIVERSITY OF PITTSBURGH MEDICAL CENTER, WE ARE APPROVED TO DEPLOY THESE TECHNOLOGIES FOR PATIENTS WHO PREVIOUSLY CRYOPRESERVED THEIR TESTICULAR TISSUES. IN THE PROPOSED RESEARCH, WE WILL TEST THE SAFETY AND FEASIBILITY OF TRANSPLANTING HUMAN SSCS (HSSCS) OR GRAFTING TESTICULAR TISSUES BACK INTO HUMAN PATIENTS. WE NOTE, HOWEVER, THAT TECHNICAL CHALLENGES EXIST THAT LIMIT TRANSPLANT EFFICIENCY OR THE DEPLOYMENT OF THESE TECHNOLOGIES TO ALL PATIENTS. FIRST, AUTOLOGOUS TRANSPLANTATION IN PATIENTS WITH TESTICULAR OR BLOOD-BORNE CANCERS OR NEUROBLASTOMAS MAY RISK RE-INTRODUCING MALIGNANT CELLS. SECOND, TESTIS BIOPSIES FROM YOUNG BOYS ARE SMALL AND MAY CONTAIN A SMALL NUMBER OF SSCS. THERE IS A BROAD CONSENSUS THAT WE WILL NEED TO PROPAGATE HSSCS EX VIVO FOR ROBUST REGENERATION OF SPERMATOGENESIS UPON TRANSPLANTATION. LONG-TERM CULTURES THAT LEAD TO SSC PROPAGATION ARE WELL ESTABLISHED IN MICE, BUT ITS TRANSLATION TO HSSCS HAS BEEN LIMITED. THE PROPOSED RESEARCH WILL DEVELOP MULTI-PARAMETER SORTING STRATEGIES TO ENRICH HUMAN TESTIS CELL FRACTIONS WITH HSSC TRANSPLANTATION WHILE REMOVING CONTAMINATING SOMATIC CELLS THAT CAN OVERGROW CULTURES AND MALIGNANT CELLS THAT WOULD BE UNSAFE TO TRANSPLANT BACK INTO THE PATIENT. WE WILL TEST THE HYPOTHESIS THAT SORTED HUMAN TESTIS CELL FRACTIONS WITH THE GREATEST TRANSPLANTATION POTENTIAL ALSO HAVE THE BEST CULTURE INITIATING POTENTIAL AS SEEN IN MICE. IN ADDITION, WE WILL TEST THE IMPACT OF DONOR AGE ON HSSC CULTURE STARTS AS WELL AS THE IMPACT OF GROWTH FACTORS OR OTHER COMPOUNDS, OXYGEN CONCENTRATION, FEEDER CELLS AND EXTRACELLULAR MATRIX SUBSTRATES (ECM). OUR MULTIDISCIPLINARY TEAM HAS PATIENTS WHO ARE READY FOR FIRST IN HUMAN TRANSPLANT PROCEDURES, TESTICULAR TISSUES FROM ALL AGES OF DEVELOPMENT, BIOINFORMATIC DATA THAT SUGGEST POTENTIAL LIGANDS TO TEST IN HSSC CULTURE AND DECELLULARIZED PIG AND HUMAN TESTIS ECM SUBSTRATES. COLLECTIVELY, OUR EFFORTS WILL TEST AND IMPROVE THE SAFETY AND FEASIBILITY OF TESTICULAR CELL/TISSUE TRANSPLANT PROCEDURES IN PATIENTS AND ESTABLISH ROBUST, REPRODUCIBLE METHODS TO MAINTAIN AND EXPAND HSSCS IN CULTURE.

ELUCIDATING THE ROLE OF THE HYALURONAN ON PGC DEVELOPMENT AND OVARIAN RESERVE ESTABLISHMENT - ABSTRACT IN MAMMALS GENERALLY, INCLUDING HUMANS, THE OVARY CEASES ITS FUNCTIONS LITTLE MORE THAN HALFWAY THROUGH A FEMALE’S LIFESPAN. THIS IS STRIKINGLY DIFFERENT FROM THE CHANGES THAT OCCUR IN OTHER ORGANS, LEADING TO A VERY LONG POST-REPRODUCTIVE PERIOD IN HUMANS. FEMALE REPRODUCTIVE AGING IS CHARACTERIZED BY A LOSS OF FOLLICLES; FOLLICLES ARE THE FUNCTIONAL UNITS OF THE OVARY, CONSISTING OF OOCYTES SURROUNDED BY COMPANION GRANULOSA CELLS. ALL THE OOCYTES/FOLLICLES THAT THE OVARY WILL EVER HAVE WILL HAVE BEEN GENERATED IN UTERO OR AT A VERY EARLY POSTNATAL AGE. THE STUDY OF OVARIAN RESERVE REGULATION HAS BEEN VERY GERM CELL CENTRIC, RELEGATING TO A QUITE SECONDARY ROLE THE OVARIAN STROMA AND THE MICROENVIRONMENT (INCLUDING SOMATIC CELLS AND THE EXTRACELLULAR MATRIX). IN FACT, THE MICROENVIRONMENT IN WHICH CELLS GROW AND DEVELOP INFORMS FUNCTION. RECENT PUBLICATIONS HAVE SHOWN THAT THE OVARIAN STROMA BECOMES INFLAMMATORY, FIBROTIC, AND STIFF WITH ADVANCED REPRODUCTIVE AGE. THESE PHENOTYPES ARE MECHANISTICALLY LINKED TO CHANGES IN THE HYALURONAN (HA) MATRIX, A UBIQUITOUS AND POLYDISPERSE EXTRACELLULAR GLYCOSAMINOGLYCAN THAT REGULATES TISSUE HOMEOSTASIS. IN ITS HIGH-MOLECULAR-WEIGHT (HMW) FORM, HA BINDS WATER AND PROMOTES HYDRATION AND HAS ANTI-INFLAMMATORY PROPERTIES. IN CONTRAST, LOW-MOLECULAR-WEIGHT (LMW) HA TENDS TO HAVE PRO-INFLAMMATORY PROPERTIES. HIGH LEVELS OF HA ARE ASSOCIATED WITH STEM CELL PROLIFERATION AND PROTECTION FROM DIFFERENTIATION DURING EARLY EMBRYOGENESIS. THE NAKED MOLE-RAT (HETEROCEPHALUS GLABER, NMR) IS A UNIQUE RODENT SPECIES WHICH LIVES UP TO FOUR DECADES AND MAINTAINS REPRODUCTIVE FUNCTION THROUGHOUT ITS ENTIRE LIFESPAN. THIS EXTREME LONGEVITY IS ATTRIBUTABLE IN PART TO THE PRODUCTION OF LARGE AMOUNTS OF VERY-HIGH-MOLECULAR-WEIGHT HYALURONAN (VHMW-HA). VHMW-HA IS PRODUCED IN NMRS BY A UNIQUELY MODIFIED VERSION OF THE HYALURONAN SYNTHASE 2 GENE (HAS2). IN THE PROPOSED RESEARCH, WE WILL TEST THE OVERARCHING HYPOTHESIS THAT THE STROMAL MICROENVIRONMENT OF THE FETAL OVARY, INCLUDING AN HA-RICH MATRIX, REGULATES THE ESTABLISHMENT AND MAINTENANCE OF THE OVARIAN RESERVE AND REPRODUCTIVE LONGEVITY.

IMPROVING FERTILITY PRESERVATION IN BOYS WITH CANCER

REGULATION OF TROPHOBLAST DIFFERENTIATION AND FUNCTION

URINARY INCONTINENCE TREATMENT NETWORK

IMPACT OF COLLABORATIVE CARE FOR PREGNANT PERSONS WITH OPIOID USE DISORDER IN LOW-RESOURCE OBSTETRIC SETTINGS - OPIOID USE DISORDER (OUD) DURING PREGNANCY IS A MAJOR CONTRIBUTOR TO MATERNAL MORBIDITY AND MORTALITY IN THE UNITED STATES. PREGNANT, POSTPARTUM, AND PARENTING PERSON (PPPP) WITH OUD FACE NUMEROUS, COMPLEX CHALLENGES THAT CREATE BARRIERS TO TREATMENT ENGAGEMENT IN PREGNANCY AND SUSTAINED TREATMENT AFTER DELIVERY. WHILE MEDICATION FOR OUD (MOUD) USE SUBSTANTIALLY REDUCES THE RISK OF OVERDOSE AND PRETERM BIRTH, MANY PPPP WITH OUD DO NOT INITIATE OR SUSTAIN MOUD TREATMENT. FURTHER, GENDER-RELATED CO-MORBIDITIES INCLUDING HIGH RATES OF TRAUMA AND EXPOSURE TO VIOLENCE, MULTI-DIMENSIONAL ABUSE AND COERCION FROM PARTNERS, AND UNDERTREATED MENTAL HEALTH CONDITIONS CONTRIBUTE TO AN INCREASED RISK OF RETURN TO USE, OVERDOSE, AND DEATH IN THE FIRST YEAR POSTPARTUM. IN THIS CONTEXT, COLLABORATIVE CARE MODELS (CCM) HAVE EMERGED AS AN INNOVATIVE AND COMPREHENSIVE WAY TO ADDRESS THE COMPLEX NEEDS OF PPPP WITH OUD. CCMS ARE DESIGNED TO INTEGRATE CARE FROM MULTIDISCIPLINARY HEALTHCARE, PEER, AND SOCIAL SERVICES PROVIDERS TO ADDRESS THE SOCIAL, BEHAVIORAL, AND PHYSICAL HEALTH NEEDS OF PATIENTS IN ADDITION TO PROVIDING MOUD. TYPICALLY, CCMS ARE LOCATED IN ACADEMIC MEDICAL CENTERS DUE TO FINANCIAL AND ORGANIZATIONAL FACTORS. AS SUCH, THE FEASIBILITY, EFFECTIVENESS, AND SUSTAINABILITY OF CCMS FOR PPPP WITH OUD LIVING LOW-RESOURCE AND RURAL SETTINGS IS UNKNOWN – DESPITE THE FACT THAT THESE SETTINGS OFTEN HAVE A HIGH BURDEN OF OUD-RELATED MORBIDITY. IN THIS APPLICATION, WE SEEK TO ADAPT A CCM FOR COMMUNITY-BASED, LOW-RESOURCE OBSTETRIC SETTINGS AND TO TEST THE EFFECTS OF THIS ADAPTED CCM ON HEALTH OUTCOMES AMONG PPPP WITH OUD AND THEIR FAMILIES. TO ACHIEVE THIS GOAL, WE WILL CONDUCT A NON- RANDOMIZED, TYPE 1 HYBRID IMPLEMENTATION-EFFECTIVENESS STUDY ACROSS 3 COMMUNITY-BASED, LOW-RESOURCE OBSTETRIC SITES IN NORTHWEST PA, A REGION WITH RATES OF MATERNAL OPIOID-RELATED DIAGNOSES 4 TIMES HIGHER THAN NATIONAL AVERAGES. OUR CENTRAL HYPOTHESIS IS THAT PERSON-CENTERED, RECOVERY SUPPORTS, PROVIDED IN THE CCM WILL INCREASE MOUD INITIATION AND CONTINUATION, DECREASE OVERDOSE AND REDUCE CHILD REMOVAL RATES AMONG PPPP WITH OUD. SPECIFICALLY, IN THE R61 PHASE, WE WILL: 1) CONDUCT AN INTERVENTION ADAPTATION PROJECT TO ADAPT THE PWRC CCM FOR RURAL AND LOW-RESOURCE OBSTETRIC SETTINGS; AND 2) CREATE A COMMON DATA MODEL TO HARMONIZE VARIABLES ACROSS DATA SOURCES AND DATA COLLECTION PROCESSES ACROSS STUDY SITES. IN THE R33 PHASE, WE WILL: 1) EVALUATE THE EFFECTS OF THE ADAPTED PWRC CCM ON OUTCOMES AMONG PPPP WITH OUD; 2) DETERMINE IF IMPROVEMENTS IN PERSON-CENTERED, RECOVERY SUPPORTS MEDIATE THE RELATIONSHIP BETWEEN PWRC COMMUNITY AND OUTCOMES USING CAUSAL MEDIATION METHODS; AND 3) IDENTIFY PWRC COMMUNITY ADAPTATIONS THAT ARE ASSOCIATED WITH INCREASED MOUD ACCESS, IMPROVED OUTCOMES AND THAT FACILITATE SUSTAINABILITY AND SCALABILITY. RESEARCH FINDINGS WILL: 1) PROVIDE HIGH-QUALITY EVIDENCE ON HOW CCMS AFFECT SERVICE DELIVERY AND HEALTH OUTCOMES FOR PPPP WITH OUD, 2) INFORM STAKEHOLDERS ABOUT WAYS TO ADAPT CCMS FOR LOW-RESOURCE AND RURAL HEALTHCARE SETTINGS, AND 3) INFORM POLICYMAKERS ABOUT THE ADAPTATIONS NECESSARY TO REPLICATE THESE MODELS WIDELY.

CONSERVED AND UNIQUE FEATURES REGULATING MEIOTIC CROSSOVER FORMATION - PROJECT SUMMARY ALL EUKARYOTES ON THE PLANET EVOLVED THE ABILITY TO FORM HAPLOID GAMETES THROUGH THE SPECIALIZED CELL DIVISION PROCESS OF MEIOSIS. CENTRAL TO MEIOSIS IS CROSSOVER (CO) FORMATION, THE EXCHANGE OF DNA BETWEEN HOMOLOGOUS CHROMOSOMES - A PROCESS THAT BOTH INCREASES DIVERSITY AND ENSURES PROPER SEGREGATION OF THE HOMOLOGS. IRONICALLY, COS INITIATE WITH THE FORMATION OF DOUBLE-STRAND BREAKS (DSBS) CONSIDERED THE MOST DANGEROUS DNA LESIONS BECAUSE MIS- OR UNREPAIRED BREAKS CAN LEAD TO CHROMOSOME ABERRATIONS INCLUDING TRANSLOCATIONS AND INVERSIONS, AMONG OTHERS. HOWEVER, IF MEIOTIC DSBS ARE NOT FORMED, CHROMOSOMES SEGREGATE RANDOMLY AT MEIOSIS, RESULTING IN ANEUPLOID GAMETES, AND SUBSEQUENT EMBRYONIC LETHALITY OR BIRTH ABNORMALITIES UPON FERTILIZATION. THUS, MEIOTIC BREAK FORMATION MUST BE TIGHTLY REGULATED TO ENSURE THAT NEITHER TOO FEW NOR TOO MANY LESIONS ARE MADE. DSBS ARE CATALYZED BY THE ENDONUCLEASE SPO11 IN COLLABORATION WITH ACCESSORY FACTORS THAT REGULATE NUMBER, TIMING AND PLACEMENT OF DSBS. DESPITE THE UBIQUITY OF DSB FORMATION FOR MEIOSIS, WE KNOW VERY LITTLE ABOUT HOW THE DIFFERENT COMPONENTS OF THE CORE MACHINERY CONTRIBUTE TO THESE REGULATORY FUNCTIONS, IN PART BECAUSE GERMLINE GENES ARE AMONG THE FASTEST EVOLVING IN OUR GENOME. THIS PROPOSAL ADDRESSES THIS CRITICAL GAP IN OUR UNDERSTANDING BY INTERROGATING THE INTERACTIONS BETWEEN, AND REGULATION OF, THE NEMATODE DSB MACHINERY. OUR PRIOR STUDIES FOUND THAT DSB-1 INTERACTS WITH BOTH SPO-11 AND HIM-5 PROVIDES A MECHANISM TO BRING THE BREAK MACHINERY TO THE CHROMOSOME AXIS WHERE STRAND EXCHANGE IS EXECUTED. THIS GRANT COMBINES STRUCTURAL MODELING, BIOCHEMISTRY, GENETICS AND COMPARATIVE EVOLUTIONARY CELL APPROACHES IN 3 SPECIFIC AIMS. IN AIM 1 WE PROPOSE TO PERFORM FUNCTIONAL ANALYSES OF THE SPO-11 AND DSB-1 PROTEINS AND THE CONTRIBUTIONS OF DIFFERENT DOMAINS TO THE VARIOUS REGULATORY ASPECTS OF DSB FORMATION. WE WILL TEST THE HYPOTHESIS SUGGESTED BY OUR PRELIMINARY DATA THAT SPO-11 AUTOREGULATES ITS OWN ACTIVITY. WE WILL ALSO CREATE NEW TOOLS TO INTERROGATE SPO-11 BINDING PARTNERS IN VIVO. OUR PRELIMINARY STUDIES HAVE ALSO REVEALED THAT THE HIM-5 EXHIBITS A TIGHTLY REGULATED NUCLEAR MOBILIZATION THAT IS FUNCTIONALLY RELEVANT. WE HYPOTHESIZE THAT NUCLEAR RETENTION REPRESENTS A PREVIOUSLY UNRECOGNIZED WAY TO CONTROL THE PROPER TIMING AND REPAIR OF DSBS. IN AIM 2, WE WILL FOLLOW UP ON THESE NOVEL OBSERVATIONS AND ADDRESS THE FUNCTIONAL SIGNIFICANCE OF HIM-5 SUB-CELLULAR LOCALIZATION WITH DSB-1 AND ITS REGULATION BY DSB SIGNALING. IN AIM 3, WE WILL DEPLOY KNOCKDOWN AND GENE SWAPS TO INTERROGATE THE CONSERVATION OF THE DSB MOLECULAR MACHINERY BETWEEN C. ELEGANS AND C. BRIGGSAE, NEMATODES THAT HAVE MAINTAINED STRONG SYNTENY AND RECOMBINATION MAPS DESPITE 100MY OF INDEPENDENT EVOLUTION. WE HYPOTHESIZE THAT COMPARISONS BETWEEN THE CONSERVED DSBS FACTORS WILL SHED LIGHT BOTH ON THE CORE PARTS OF THE DSB MACHINERY THAT MAINTAIN TIGHT CO CONTROL AND ON THE FLEXIBILITY OF THESE FACTOR TO ADAPT TO EVOLUTIONARY FORCES. OVERALL, THIS STUDY WILL REVEAL FUNDAMENTAL MECHANISTIC INSIGHTS INTO THE REGULATION AND EVOLUTION OF MEIOTIC DSB FORMATION.

INCLUDE CLINICAL RESEARCHER TRAINING (ICRT) - THIS NEW R25 PROGRAM, RESPONSIVE TO PAR-22-195, PLAYS A CRUCIAL ROLE IN THE INCLUDE PROJECT. EACH YEAR, WE RECRUIT, TRAIN, MENTOR, AND PROVIDE CAREER ADVICE TO COHORTS OF 16 POST-GRADUATE PARTICIPANTS DEDICATED TO MASTERING DOWN SYNDROME (DS) CLINICAL RESEARCH. DESPITE THE SWIFT GROWTH OF INCLUDE, THERE ARE STILL TOO FEW LABORATORIES LED BY DOWN SYNDROME EXPERT SCIENTISTS AND TOO FEW NEW CLINICAL TRAINEES WITH EXPERTISE IN DOWN SYNDROME. IN FULL COMPLIANCE WITH NOT-OD-25-090 (NOTICE OF CIVIL RIGHTS TERM AND CONDITION OF AWARD), THIS PROGRAM IS AVAILABLE FOR ALL QUALIFIED AMERICAN CITIZENS AND PERMANENT RESIDENTS. UNDER THE MULTIPLE PI DIRECTION OF: ANN COHEN, PHD (PITT); BENJAMIN HANDEN, PHD (PITT); ELIZABETH HEAD, PHD (IRVINE); ADAM RESNICK, MD PHD (CHOP); JONATHAN SANTORO, MD (USC-KECK) AND GERALD SCHATTEN, PHD, CONTACT PI (PITT), WITH CO-I CALVIN SIMERLY, PHD (PITT), ICRT IS OVERSEEN BY AN EXTERNAL SCIENTIFIC ADVISORY BOARD. THEY, ALONG WITH THE FACULTY, PROVIDE HANDS-ON, FACE-TO-FACE TRAINING IN DS CLINICAL RESEARCH. MENTORING AND CAREER GUIDANCE, INCLUDING BALANCED LIFE CHOICES, ARE CONSIDERED BOTH DURING THE COURSE, WITH ON-GOING PERSONAL CAREER GUIDANCE AT ANNUAL REUNIONS. THE FIVE SPECIFIC AIMS ARE: I. OFFER ANNUAL ICRT ADVANCED HANDS-ON CLINICAL RESEARCH LAB COURSES COVERING DS THROUGH THE ENTIRE LIFESPAN PROVIDING CONCEPTUAL EDUCATION AND CLINICAL RESEARCH LABS AND DISCUSSIONS. CANDIDATES APPLY ON-LINE DESCRIBING THEIR DS RESEARCH CAREER TRAJECTORIES AND 16 PARTICIPANTS ARE SELECTED ANNUALLY. COMPREHENSIVE TRAINING ON FUNDAMENTALS AND METHODOLOGIES NECESSARY FOR FLOURISHING CAREERS. PARTICIPANTS IMPLEMENT CAREER PLANNING WITH SENIOR AND JUNIOR FACULTY, PEER-TO-PEER AND PERSONALIZED COACHING. II. PROVIDE ONGOING POST-COURSE MENTORING AT ANNUAL COURSE REUNIONS, HELD AT INCLUDE-SPONSORED CONFERENCES AND MONTHLY ICRT ONLINE SESSIONS. PARTICIPANTS ARE ENCOURAGED TO ARTICULATE THEIR OWN LONGER-TERM CAREER TRAJECTORIES AND EXPLORE THEIR CAREER CHOICES. III. CULTIVATE AND ENHANCE INTRA-INCLUDE COLLABORATIONS AND CROSS-INCLUDE TRAINING FOR ALL INCLUDE SCIENTISTS AT COURSES AND REUNIONS. THESE CREATE A DYNAMIC, ROBUST AND MEANINGFUL INCLUDE COMMUNITY, AMONG COLLEAGUES AND FRIENDS. IV. DEMYSTIFY THE CHANGING REGULATORY OVERSIGHT REQUIREMENTS IN RESPONSIBLE CONDUCT FOR RESEARCH (RCR) TO ENSURE FULL COMPLIANCE WITH NIH AND INSTITUTIONAL GUIDANCE, REGULATIONS AND LAW. CREATING SAFE SUPPORTIVE RESEARCH ENVIRONMENTS (ALONG WITH A FORMAL SAFETY PLAN ARE PRESENTED. THIS IS SO THAT PARTICIPANTS MAY BEGIN THEIR OWN RESEARCH PROGRAMS IN THE MOST EFFECTIVE, TIMELY, AND RESPONSIBLE MANNER. V. PROVIDE UNBIASED, QUANTITATIVE INDEPENDENT EVALUATIONS TO TRACK PARTICIPANTS’ CAREERS, COMPREHENSIVELY AND LONGITUDINALLY, TO ENSURE THAT ICRT IS A WISE, EFFECTIVE INVESTMENT. ICRT WILL MEET AND EXCEED THE PAR’S MANDATE OF TRAINING THE NEXT GENERATION OF DS CLINICAL RESEARCHERS, 80 ADDITIONAL CLINICAL INVESTIGATORS, AND THEREBY IMPROVING THE QUALITY OF LIFE AND HEALTH SPAN OF THOSE WITH DOWN SYNDROME AS WELL AS ALL AMERICANS.

DEVELOPMENT OF A BIOADHESIVE VAGINAL FILM FOR EXTENDED RELEASE OF MPT ANTIBODIES - PROJECT SUMMARY PRODUCTS WHICH OFFER PROTECTION FROM UNINTENDED PREGNANCY AND SEXUALLY TRANSMITTED DISEASE INFECTION ARE DESIRED BY WOMEN. THIS PROJECT WILL DEVELOP AN ANTIBODY-BASED EXTENDED RELEASE (ER) MULTIPURPOSE TECHNOLOGY (MPT) VAGINAL FILM THAT COMBINES A CONTRACEPTIVE MONOCLONAL ANTIBODY (MAB) AND MABS AGAINST HIV AND HSV. THE ER MPT FILM DEVELOPED WILL PROVIDE CONTRACEPTION AND ANTIVIRAL PROTECTION FOR 7 DAYS FOLLOWING A SINGLE INTRAVAGINAL ADMINISTRATION. THIS VERSATILE EXTENDED RELEASE MPT FILM PLATFORM IS INTENDED TO PROVIDE A DISCREET, LOW COST AND CONVENIENT ALTERNATIVE TO WOMEN AT HIGH RISK OF HIV/HSV INFECTION AND UNINTENDED PREGNANCY. IN SEPARATE PHASE 1 CLINICAL STUDIES FAST RELEASE FILMS CONTAINING EITHER A HUMAN CONTRACEPTIVE ANTIBODY (HCA) (ZB06) OR MABS AGAINST HIV AND HSV (MB66) SHOWED VAGINAL APPLICATION OF THE MABS TO BE SAFE AND WELL TOLERATED. ANTIVIRAL AND CONTRACEPTIVE EFFICACY WAS ALSO DEMONSTRATED THROUGH EX VIVO CHALLENGE OF VAGINAL SAMPLES WITH EITHER HIV, HSV, OR SPERM. DEVELOPMENT OF A FILM WHICH COMBINES THESE ACTIVES IN AN EXTENDED- RELEASE PLATFORM WOULD PROVIDE A DESIRABLE OPTION FOR WOMEN SEEKING PROTECTION. RECENT DATA FROM OUR LAB SHOWS THAT VAGINAL FILMS CAN BE DESIGNED TO SUSTAIN DELIVERY OF ACTIVES EVEN IN THE CONTEXT OF MENSES AND SEXUAL INTERCOURSE. USING THIS KNOWLEDGE AND OUR EXPERTISE IN THE DEVELOPMENT OF INTRAVAGINAL FILMS, THIS PROPOSAL WILL DEVELOP A FILM PLATFORM FOR SUSTAINED DELIVERY OF HCA AND ANTIVIRAL MABS FOR AT LEAST 1 WEEK. OUR GROUP RECENTLY ENGINEERED MULTIVALENT VARIANTS OF THESE ANTIBODIES AND HAVE DEMONSTRATED THAT MULTIVALENT HCA HAS GREATLY ENHANCED CONTRACEPTIVE ACTIVITY; WE WILL TEST THE ACTIVITY OF MULTIVALENT ANTI-HIV AND HSV MABS IN THE R61 PHASE OF THIS PROJECT AND STUDY THE STABILITY AND RELEASE OF MULTIVALENT MABS FROM ER FILMS. BASED ON THE OUTCOME OF THESE EXPERIMENTS, WE WILL COMBINE MULTIVALENT OR IGG1 FORMS OF HCA AND ANTIVIRAL MABS IN AN ER VAGINAL MPT FILM PRODUCT WITHIN THE R33 PHASE OF THIS PROJECT. THE LEAD PROTOTYPE ER MPT FILM WILL BE FULLY CHARACTERIZED, AND SAFETY, ANTIVIRAL/CONTRACEPTIVE ACTIVITY AND LARGE-SCALE MANUFACTURING FEASIBILITY WILL BE ESTABLISHED. SUCCESSFUL COMPLETION OF THIS PROJECT WILL PRODUCE A VERSATILE, LOW COST, AND EXTENDED RELEASE VAGINAL MPT FILM FOR CO-DELIVERY OF HIGHLY POTENT CONTRACEPTIVE, ANTI-HIV, AND ANTI-HSV MABS WHICH IS POSITIONED FOR ADVANCEMENT TO CLINICAL EVALUATION. THIS WORK WILL GENERATE A NOVEL EXTENDED RELEASE MPT FILM PLATFORM THAT CAN BE APPLIED TO OTHER DRUG COMBINATIONS.

PERTURBATION OF MAMMARY IMMUNOGLOBULINS DURING MATERNAL ANTIBIOTIC ADMINISTRATION - PROJECT SUMMARY PRESCRIBED IN UP TO 40% OF PREGNANCIES, ANTIBIOTICS REPRESENT THE MOST COMMONLY USED CLASS OF MEDICATION DURING PREGNANCY. ALTHOUGH THIS PRACTICE IS OFTEN NECESSARY FOR MATERNAL HEALTH, ACCUMULATING EVIDENCE SUGGESTS THAT ANTIBIOTIC EXPOSURE MAY HAVE UNINTENDED CONSEQUENCES FOR THE MOTHER-INFANT DYAD. EPIDEMIOLOGIC STUDIES ASSOCIATE MATERNAL ANTIBIOTIC EXPOSURE, ESPECIALLY IN THE ABSENCE OF INFECTION, WITH INCREASED RISK OF NEONATAL COMPLICATIONS INCLUDING LATE-ONSET SEPSIS (LOS) AND NECROTIZING ENTEROCOLITIS (NEC), YET THE MECHANISMS DRIVING THESE ASSOCIATIONS REMAIN POORLY UNDERSTOOD. SECRETORY IGA (SIGA) IN MILK IS AN ESSENTIAL COMPONENT OF NEONATAL MUCOSAL IMMUNITY, SHAPING EARLY GUT MICROBIAL COLONIZATION AND PROVIDING PROTECTION AGAINST ENTERIC PATHOGENS. THE MECHANISMS BY WHICH MATERNAL PHYSIOLOGY REGULATES THE ABUNDANCE AND MICROBIAL SPECIFICITY OF THESE ANTIBODIES IN MILK REMAIN POORLY UNDERSTOOD. IN ANIMAL MODELS, THE MATERNAL GUT–MAMMARY AXIS GOVERNS THE GENERATION OF MILK IGA: IGA-COMMITTED LYMPHOCYTES FROM THE MATERNAL INTESTINE MIGRATE TO THE MAMMARY GLAND DURING ADVANCING PREGNANCY VIA CCL- 28/CCR10 SIGNALING. OUR PRELIMINARY DATA SUGGEST THAT MATERNAL ANTIBIOTIC EXPOSURE DISRUPTS THIS PROCESS LEADING TO A DECREASE IN MILK IGA. HOWEVER, THE TIMING AND EXTENT OF ANTIBODY DYSBIOSIS ARE UNDEFINED; THE DOWNSTREAM EFFECTS ON NEONATAL INTESTINAL HEALTH ARE UNKNOWN; AND THE UNDERLYING MECHANISMS—WHETHER DUE TO ALTERED MICROBIAL STIMULATION, IMPAIRED RECRUITMENT OF IGA⁺ CELLS TO THE MAMMARY GLAND, OR BOTH—REMAIN TO BE ELUCIDATED. OUR CENTRAL HYPOTHESIS IS THAT MATERNAL ANTIBIOTIC EXPOSURE REDUCES PATHOGEN-REACTIVE IGA IN MILK BY IMPAIRING GUT-TO-MAMMARY IMMUNE CELL TRAFFICKING THEREBY COMPROMISING NEONATAL MUCOSAL IMMUNITY AND INCREASING INFECTION SUSCEPTIBILITY. WE WILL ADDRESS THIS HYPOTHESIS THROUGH THREE INTEGRATED AIMS: (1) DETERMINE THE MAGNITUDE AND DURATION OF ANTIBIOTIC-MEDIATED MAMMARY ANTIBODY DYSBIOSIS IN WOMEN WHO DELIVER PRETERM AND AT TERM; (2) IDENTIFY MICROBIAL TARGETS OF MAMMARY ANTIBODIES DIMINISHED BY MATERNAL ANTIBIOTIC EXPOSURE AND (3 DETERMINE THE ROLE OF MATERNAL ANTIBIOTICS IN THE DISRUPTION OF MAMMARY RESIDENT IGA+ PLASMA CELLS IN ANIMAL MODELS. THIS INTEGRATIVE HUMAN AND ANIMAL STUDY WILL UNCOVER CRITICAL MECHANISMS BY WHICH MATERNAL ANTIBIOTIC USE ALTERS THE MATERNAL-INFANT IMMUNE AXIS. THE RESULTS WILL PROVIDE MECHANISTIC INSIGHT INTO THE RISKS ASSOCIATED WITH PERINATAL ANTIBIOTIC EXPOSURE AND INFORM CLINICAL STRATEGIES TO MITIGATE RISK TO NEONATAL HEALTH.

REPRODUCTIVE DEVELOPMENT FROM GONADS TO FETUSES

DISEASE HETEROGENEITY AND IMMUNE BIOMARKERS IN PRECLINICAL MOUSE MODELS OF OVARIAN CARCINOGENESIS

LIM HOMEODOMAIN REGULATED GENETIC PATHWAYS IN OOGENESIS AND OVARIAN FAILURE

NIMA-LIKE KINASE NEK1 AS A REGULATOR OF MAMMALIAN GAMETOGENESIS

THE FUNCTION OF NFAT3 IN OVARIAN CANCER CELL QUIESCENCE AND CHEMOTHERAPY RESISTANCE

MICROBIAL REGULATION OF TYPE 2 IMMUNITY IN OVARIAN TISSUE REMODELING AND FIBROSIS - PROJECT SUMMARY EARLY MENOPAUSE AND ACCELERATED REPRODUCTIVE AGING AFFECT MILLIONS OF WOMEN WORLDWIDE, DRAMATICALLY INCREASING RISKS FOR CARDIOVASCULAR DISEASE, BONE FRACTURES, AND PREMATURE DEATH. THIS BURDEN INTENSIFIES AS SOCIETAL TRENDS TOWARD DELAYED CHILDBEARING CREATE UNPRECEDENTED BARRIERS TO CONCEPTION, FERTILITY, AND SYSTEMIC HEALTH. CHALLENGING THE LONGSTANDING PARADIGM THAT REPRODUCTIVE DECLINE REPRESENTS INEVITABLE FOLLICLE DEPLETION, THIS RESEARCH IDENTIFIES OVARIAN TISSUE FIBROSIS AS AN ACTIVE, ENVIRONMENTALLY MODIFIABLE PROCESS DRIVEN BY DYSREGULATED IMMUNE SIGNALING. OUR STUDIES REVEAL THAT GUT MICROBIOTA ESTABLISHED DURING CRITICAL EARLY-LIFE WINDOWS PROGRAM IMMUNE CIRCUITS THAT DETERMINE WHETHER OVARIAN AGING FOLLOWS PROTECTIVE OR PATHOLOGICAL TRAJECTORIES. MICE LACKING A MICROBIOTA SHOW PREMATURE REPRODUCTIVE AGING CHARACTERIZED BY A DIMINISHED OVARIAN RESERVE, COMPROMISED FERTILITY, EXCESSIVE INTERLEUKIN-33 (IL-33) EXPRESSION, EXPANSION OF TYPE 2 IMMUNE CELLS, AND PATHOLOGICAL COLLAGEN DEPOSITION, WHILE MICROBIAL COLONIZATION AT CRITICAL PERIODS RESCUES THESE PHENOTYPES. USING SINGLE-CELL IMMUNE PROFILING, WE IDENTIFY THE SPECIFIC IMMUNE POPULATIONS DRIVING IL-33-MEDIATED TISSUE REMODELING IN OVARIES. THE CENTRAL HYPOTHESIS IS THAT MICROBIAL-DERIVED SIGNALS CALIBRATE IL-33 SIGNALING TO PREVENT PATHOLOGICAL TYPE 2 IMMUNE ACTIVATION, THEREBY MAINTAINING TISSUE HOMEOSTASIS AND PRESERVING REPRODUCTIVE FUNCTION. THREE SPECIFIC AIMS WILL: (1) DETERMINE WHETHER STROMAL OR OOCYTE IL-33 DRIVES FIBROSIS; (2) DEFINE THE IMMUNE CASCADE MEDIATING IL-33-DRIVEN FIBROSIS; AND (3) VALIDATE MICROBIOTA-TARGETED INTERVENTIONS. THIS RESEARCH ESTABLISHES FUNDAMENTAL MECHANISMS BY WHICH ENVIRONMENTAL FACTORS PROGRAM IMMUNE CIRCUITS THAT GOVERN TISSUE AGING, PROVIDING THE FIRST EVIDENCE THAT REPRODUCTIVE AGING IS MODIFIABLE RATHER THAN PREDETERMINED. EXPECTED OUTCOMES INCLUDE IDENTIFICATION OF SPECIFIC BACTERIAL TAXA AND METABOLITES THAT PREVENT OVARIAN FIBROSIS, MECHANISTIC UNDERSTANDING OF IMMUNE-STROMAL INTERACTIONS DRIVING TISSUE REMODELING, AND TRANSLATABLE DIETARY INTERVENTIONS FOR CLINICAL IMPLEMENTATION. BY DEMONSTRATING THAT REPRODUCTIVE AGING CAN BE PREVENTED THROUGH TARGETED INTERVENTIONS DURING CRITICAL DEVELOPMENTAL WINDOWS, THIS WORK FUNDAMENTALLY REFRAMES APPROACHES TO WOMEN'S HEALTH FROM TREATMENT-FOCUSED TO PREVENTION-FOCUSED, OFFERING EVIDENCE-BASED STRATEGIES TO EXTEND REPRODUCTIVE HEALTHSPAN AND REDUCE THE SUBSTANTIAL DISEASE BURDEN ASSOCIATED WITH PREMATURE MENOPAUSE.

UNIVERSITY OF PITTSBURGH/MAGEE-WOMENS RESEARCH INSTITUTE WOMEN'S REPRODUCTIVE HEALTH RESEARCH ACROSS THE LIFESPAN (PITT-MWRI WRHR) - BACKGROUND: THE UNIVERSITY OF PITTSBURGH DEPARTMENT OF OBSTETRICS, GYNECOLOGY AND REPRODUCTIVE SCIENCES (OBGYN) AND MAGEE-WOMENS RESEARCH INSTITUTE (PITT-MWRI) PROPOSE TO LEAD A CAREER DEVELOPMENT PROGRAM ENTITLED WOMEN’S REPRODUCTIVE HEALTH RESEARCH ACROSS THE LIFESPAN (PITT-MWRI WRHR). PITT-MWRI IS DEEPLY COMMITTED TO TRAINING THE NEXT GENERATION OF PHYSICIAN-SCIENTISTS IN REPRODUCTIVE BIOLOGY AND WOMEN’S HEALTH. AS ONE OF THE RESEARCH LEADERS IN OUR FIELD, WE UNDERSTAND THE SIGNIFICANCE OF SCIENTIFIC DISCOVERY, AND THE NEED TO TRANSLATE THE RESULTS OF RESEARCH INTO KNOWLEDGE AND SKILLS FOR CLINICIANS, AND ULTIMATELY, INTO IMPROVEMENTS IN REPRODUCTIVE HEALTH, WOMEN’S HEALTH AND THE HEALTH OF THEIR OFFSPRING. OUR FUNDAMENTAL GOALS ARE TO PROVIDE ADVANCED TRAINING FOR TALENTED PITT OBGYN PHYSICIAN SCHOLARS IN IMPACTFUL INTERDISCIPLINARY RESEARCH ACROSS THE LIFESPAN OF WOMEN, AND MENTOR THEM AS THEY DEVELOP A STRONG SCHOLARLY FOUNDATION FOR A PRODUCTIVE AND SUSTAINABLE CAREER IN THE FIELD OF WOMEN’S REPRODUCTIVE HEALTH. OUR PROGRAM SPANS TRAINING IN BASIC, TRANSLATIONAL, CLINICAL, HEALTH SERVICES, AND COMMUNITY RESEARCH AND FOCUSES ON PATHOGENESIS AND PERSONALIZED DIAGNOSTICS, THERAPEUTICS AND PREVENTION FOR WOMEN OF ALL AGES. OUR GOALS ARE ALIGNED WITH THE EUNICE SHRIVER KENNEDY NICHD STRATEGIC GOALS AND OBJECTIVES, CROSS-CUTTING TOPICS AND ASPIRATIONAL GOALS. WE STRONGLY BELIEVE THAT REPRODUCTIVE HEALTH RESEARCH IS ESSENTIAL TO PROPEL PROGRESS IN CARE FOR WOMEN. FEW OBGYN DEPARTMENTS HAVE THE CRITICAL MASS OF REPRODUCTIVE BIOLOGY AND WOMEN’S HEALTH RESEARCHERS, THE MENTORING ENVIRONMENT AND THE INFRASTRUCTURE TO DISTINCTIVELY TARGET TRAINING FOR OBGYN PHYSICIAN SCIENTISTS. PITT-MWRI EXCELS IN ALL THESE AREAS. WE HAVE AN OUTSTANDING TRACK RECORD OF TRAINING, SUPPORTING AND RETAINING PREVIOUS WRHR SCHOLARS WHO ARE BROADLY RECOGNIZED AS LEADERS IN OUR FIELD. GIVEN THE BREADTH OF SCIENTIFIC SKILLS AMONG OUR OBGYN PRIMARY MENTORS, ESTABLISHED COLLABORATIONS WITH OUTSTANDING MENTORS ACROSS THE UNIVERSITY OF PITTSBURGH, OUR TRAINING PROGRAM THAT EMPHASIZES MULTIDISCIPLINARY MENTORING, CLASSROOM-BASED EDUCATION, TEAM SCIENCE AND GRANT WRITING, AND OUR LARGE PIPELINE OF OBGYN TRAINEES, OUR PITT-MWRI TRAINING PROGRAM WILL ENABLE EACH GRADUATING SCHOLAR TO EMBARK ON A SUCCESSFUL CAREER AS A PHYSICIAN-SCIENTIST POISED TO CONTRIBUTE TO THE IMPROVEMENT OF WOMEN’S HEALTH.

GENETIC BASIS OF OLIGOZOOSPERMIA IN INFERTILE MALES

IMMUNOSUPPRESSIVE FACTORS CONTRIBUTING TO IMMUNOTHERAPY RESISTANCE IN ENDOMETRIAL CANCER WITH DEFICIENT MISMATCH REPAIR SYSTEM

A RANDOMIZED PILOT AND FEASIBILITY STUDY OF A CULTURE-DIRECTED APPROACH TO URINARY TRACT INFECTION SYMPTOMS IN OLDER WOMEN: A MIXED METHODS EVALUATION - THE REDUCTION TRIAL - PROJECT ABSTRACT URINARY TRACT INFECTIONS (UTIS) ACCOUNT FOR SIGNIFICANT MORBIDITY ON BOTH AN INDIVIDUAL AND SOCIETAL LEVEL. UTIS ARE ESPECIALLY COMMON IN OLDER WOMEN AND A SUBSET ARE PRONE TO RECURRENT UTIS (RUTIS). CURRENT UNDERSTANDING OF THE NATURAL PROGRESSION OF PATIENT REPORTED UTIS IN OLDER WOMEN WITH RUTI IS LIMITED DUE TO LOW LEVELS OF INCLUSION IN PREVIOUS RANDOMIZED CONTROLLED TRIALS ON INITIAL NON-ANTIBIOTIC STRATEGIES. FOR AIM 1: WE SEEK TO EVALUATE THE FEASIBILITY OF RECRUITING ELIGIBLE PARTICIPANTS INTO A RANDOMIZED TRIAL OF A CULTURE-DIRECTED VERSUS EMPIRIC ANTIBIOTIC STRATEGY FOR PATIENT-REPORTED UTI SYMPTOMS IN OLDER WOMEN AND THE ADHERENCE TO STUDY PROCEDURES. WE WILL EXPLORE THE SAFETY OF A CULTURE-DIRECTED UTI TREATMENT STRATEGY AND PRELIMINARY SECONDARY OUTCOMES OF ASSIGNED TREATMENTS. FOR AIM 2: WE WILL INVESTIGATE PREVIOUS UTI EXPERIENCES AND ACCEPTABILITY OF TRIAL DESIGN/FUTURE RECRUITMENT EFFORTS VIA FOCUS GROUPS WITH WOMEN THAT ARE RECRUITED FOR THE PILOT TRIAL AND ALSO AMONG KEY COMMUNITY STAKEHOLDERS. FOR AIM 3, WE WILL ASSESS FACILITATORS AND BARRIERS WITH TRIAL IMPLEMENTATION AND RECRUITMENT THROUGH SEMI-STRUCTURED INTERVIEWS AMONG BOTH PARTICIPATING AND REPRESENTATIVE NON-PARTICIPATING PROVIDERS. WE PLAN TO RECRUIT OLDER WOMEN WITH RUTI THROUGH BOTH OUR CLINICAL PRACTICE AND THE UNIVERSITY OF PITTSBURGH’S CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTE (CTSI) PITT+ME® RESEARCH REGISTRY. WHEN SYMPTOMATIC FOR UTI, A TOTAL OF 70 WOMEN WILL BE ENROLLED AND RANDOMIZED TO EITHER A CULTURE-DIRECTED OR EMPIRIC ANTIBIOTIC STRATEGY. THOSE IN THE EMPIRIC ARM WILL BE PRESCRIBED ANTIBIOTICS FOLLOWING A STANDARD PROTOCOL AND THOSE IN THE CULTURE-DIRECTED ARM WILL HAVE ANTIBIOTICS PRESCRIBED BASED ON URINE CULTURE AND SENSITIVITY RESULTS THAT RETURN IN ~48-72 HOURS. AT BASELINE, SUBJECTS WILL COMPLETE DEMOGRAPHIC AND SYMPTOM QUESTIONNAIRES. SUBJECTS WILL BE FOLLOWED WHEN URINE CULTURE RESULTS ARE AVAILABLE AND THEN WEEKLY UNTIL THEY ARE 28 DAYS FROM SYMPTOM ONSET (WITH ELECTRONIC SURVEY AND PHONE CALL). FOLLOW-UP QUESTIONS WILL INVESTIGATE SYMPTOM RESOLUTION, ANTIBIOTIC SIDE EFFECTS, AND ANY TREATMENT FOR PROGRESSION OF SYMPTOMS (EITHER PYELONEPHRITIS OR UROSEPSIS). SUBJECTS WILL HAVE CONTACT INFORMATION TO A MEMBER OF OUR TEAM THAT IS AVAILABLE 24/7. A TOTAL OF 30 WOMEN (10 WHO COMPLETE STUDY, 10 WHO DECLINED PARTICIPATION AND 10 COMMUNITY STAKEHOLDERS) WILL BE INTERVIEWED THROUGH FOCUS GROUPS TO ENSURE THE PATIENT-VOICE IS TAKEN INTO CONSIDERATION ON FUTURE TRIAL PLANNING. WE WILL ADDITIONALLY RECRUIT PROVIDERS (10 OF THOSE WHO PARTICIPATED IN RECRUITMENT AND 10 NON-RECRUITING PROVIDERS) TO COMPLETE SEMI-STRUCTURED, QUALITATIVE INTERVIEWS ON THEIR TRIAL EXPERIENCES. OUR MIXED-METHODS PILOT STUDY WILL GENERATE THE REQUISITE PRELIMINARY FEASIBILITY, ACCEPTABILITY, EFFICACY/PROOF OF CONCEPT, AND SAFETY DATA TO INFORM THE DESIGN OF A DEFINITIVE RANDOMIZED TRIAL OF A CULTURE-DIRECTED VERSUS EMPIRIC ANTIBIOTIC STRATEGY FOR THE TREATMENT OF PATIENT REPORTED UTI IN OLDER WOMEN WITH RUTI AS WE SEEK TO DRIVE CHANGE IN CURRENT PRESCRIBING PRACTICES IN THIS POPULATION.

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IMMUNE AND DEVELOPMENTAL ACTIONS OF THE MATERNAL MICROBIAL METABOLITES ON THE HYPOTHALAMUS

DEVELOPMENT OF A BIOADHESIVE VAGINAL FILM FOR EXTENDED RELEASE OF MPT ANTIBODIES - PROJECT SUMMARY PRODUCTS WHICH OFFER PROTECTION FROM UNINTENDED PREGNANCY AND SEXUALLY TRANSMITTED DISEASE INFECTION ARE DESIRED BY WOMEN. THIS PROJECT WILL DEVELOP AN ANTIBODY-BASED EXTENDED RELEASE (ER) MULTIPURPOSE TECHNOLOGY (MPT) VAGINAL FILM THAT COMBINES A CONTRACEPTIVE MONOCLONAL ANTIBODY (MAB) AND MABS AGAINST HIV AND HSV. THE ER MPT FILM DEVELOPED WILL PROVIDE CONTRACEPTION AND ANTIVIRAL PROTECTION FOR 7 DAYS FOLLOWING A SINGLE INTRAVAGINAL ADMINISTRATION. THIS VERSATILE EXTENDED RELEASE MPT FILM PLATFORM IS INTENDED TO PROVIDE A DISCREET, LOW COST AND CONVENIENT ALTERNATIVE TO WOMEN AT HIGH RISK OF HIV/HSV INFECTION AND UNINTENDED PREGNANCY. IN SEPARATE PHASE 1 CLINICAL STUDIES FAST RELEASE FILMS CONTAINING EITHER A HUMAN CONTRACEPTIVE ANTIBODY (HCA) (ZB06) OR MABS AGAINST HIV AND HSV (MB66) SHOWED VAGINAL APPLICATION OF THE MABS TO BE SAFE AND WELL TOLERATED. ANTIVIRAL AND CONTRACEPTIVE EFFICACY WAS ALSO DEMONSTRATED THROUGH EX VIVO CHALLENGE OF VAGINAL SAMPLES WITH EITHER HIV, HSV, OR SPERM. DEVELOPMENT OF A FILM WHICH COMBINES THESE ACTIVES IN AN EXTENDED- RELEASE PLATFORM WOULD PROVIDE A DESIRABLE OPTION FOR WOMEN SEEKING PROTECTION. RECENT DATA FROM OUR LAB SHOWS THAT VAGINAL FILMS CAN BE DESIGNED TO SUSTAIN DELIVERY OF ACTIVES EVEN IN THE CONTEXT OF MENSES AND SEXUAL INTERCOURSE. USING THIS KNOWLEDGE AND OUR EXPERTISE IN THE DEVELOPMENT OF INTRAVAGINAL FILMS, THIS PROPOSAL WILL DEVELOP A FILM PLATFORM FOR SUSTAINED DELIVERY OF HCA AND ANTIVIRAL MABS FOR AT LEAST 1 WEEK. OUR GROUP RECENTLY ENGINEERED MULTIVALENT VARIANTS OF THESE ANTIBODIES AND HAVE DEMONSTRATED THAT MULTIVALENT HCA HAS GREATLY ENHANCED CONTRACEPTIVE ACTIVITY; WE WILL TEST THE ACTIVITY OF MULTIVALENT ANTI-HIV AND HSV MABS IN THE R61 PHASE OF THIS PROJECT AND STUDY THE STABILITY AND RELEASE OF MULTIVALENT MABS FROM ER FILMS. BASED ON THE OUTCOME OF THESE EXPERIMENTS, WE WILL COMBINE MULTIVALENT OR IGG1 FORMS OF HCA AND ANTIVIRAL MABS IN AN ER VAGINAL MPT FILM PRODUCT WITHIN THE R33 PHASE OF THIS PROJECT. THE LEAD PROTOTYPE ER MPT FILM WILL BE FULLY CHARACTERIZED, AND SAFETY, ANTIVIRAL/CONTRACEPTIVE ACTIVITY AND LARGE-SCALE MANUFACTURING FEASIBILITY WILL BE ESTABLISHED. SUCCESSFUL COMPLETION OF THIS PROJECT WILL PRODUCE A VERSATILE, LOW COST, AND EXTENDED RELEASE VAGINAL MPT FILM FOR CO-DELIVERY OF HIGHLY POTENT CONTRACEPTIVE, ANTI-HIV, AND ANTI-HSV MABS WHICH IS POSITIONED FOR ADVANCEMENT TO CLINICAL EVALUATION. THIS WORK WILL GENERATE A NOVEL EXTENDED RELEASE MPT FILM PLATFORM THAT CAN BE APPLIED TO OTHER DRUG COMBINATIONS.

METABOLIC ANALYSIS FOR TREATMENT CHOICE IN GESTATIONAL DIABETES MELLITUS

PRECONCEPTION CONTRIBUTORS TO SEVERE MATERNAL MORBIDITY IN BLACK AND WHITE WOMEN

LEICA STELLARIS CONFOCAL TO POWER WOMEN'S HEALTH RESEARCH - PROJECT SUMMARY THIS SHARED INSTRUMENTATION GRANT IS FOR FUNDS TO PURCHASE A LEICA STELLARIS CONFOCAL MICROSCOPE TO BE HOUSED IN THE MAGEE-WOMENS RESEARCH INSTITUTE. THE MWRI CONFOCAL CORE SERVES THE 70 BASIC- AND CLINICAL-RESEARCH FACULTY WHO ARE FULL OR AFFILIATE MEMBERS OF MWRI. CURRENTLY, THE MWRI CORE IS COMPRISED OF A 10-YEAR-OLD NIKON A1R WITH PMT DETECTORS AND RESONANT SCANNING AND A NEARLY 20-YEAR-OLD LEICA SP2 CONFOCAL. THE FORMER HAS BEEN MAINTAINED CONTINUOUSLY UNDER A SERVICE CONTRACT AND WAS UPGRADED TO STEADY-STATE LASERS IN 2015. THE SP2, ON THE OTHER HAND, IS AT THE END OF ITS VIABLE LIFETIME: IT CANNOT BE UPGRADED; IT NO LONGER HAS A FUNCTIONING DAPI LASER; VENDOR SERVICE CONTRACTS HAVE BEEN DISCONTINUED; AND REPAIR PARTS ARE DIFFICULT TO ATTAIN. THIS APPLICATION REQUESTS FUNDS TO REPLACE THE OBSOLETE SP2 SYSTEM WITH LEICA'S NEWEST CONFOCAL, STELLARIS, WHICH WAS RELEASED THIS SPRING. OVER THE PAST TEN YEARS, INNOVATIONS IN CONFOCAL MICROSCOPY HAVE IMPROVED SENSITIVITY AND RESOLUTION, DECREASED BLEACHING, AND EXPANDED FLUORESCENT RANGE. THE NEW INSTRUMENTATION WILL ALLOW NIH-FUNDED RESEARCHERS TO USE STATE-OF-THE ART IMAGING APPROACHES TO ADDRESS A MYRIAD OF ISSUES RELATED TO WOMEN'S AND REPRODUCTIVE HEALTH, INCLUDING OVARIAN CANCER ETIOLOGY, MEIOTIC CROSSOVER REGULATION, PELVIC FLOOR DISORDERS, AND PLACENTA DYSFUNCTION, AMONG OTHERS. CRITICALLY, THE NEW SYSTEM WILL ALLOW USERS TO ACHIEVE SUB-DIFFRACTION IMAGING THAT IS BECOMING A STANDARD IN THE FIELD AND WILL ENHANCE THE LIVE-IMAGING CAPABILITIES OF THE MWRI CORE. THE RECENT HIRING OF FACULTY WITH CONFOCAL-INTENSIVE PROJECTS, TOGETHER WITH EXPANDED NEED OF OUR USER BASE, HAVE MADE IT DIFFICULT TO SUPPORT THE CONFOCAL NEEDS OF THE MWRI CONSTITUENCY WITH OUR CURRENT, OUTDATED MACHINE.

BUPRENORPHINE ASSIGNMENT IN PREGNANCY: OBJECTIVE CRITERIA

STEROID HORMONE PATHWAYS REGULATING BPH AND LUTS - AGING IS A MAJOR RISK FACTOR FOR BENIGN PROSTATE HYPERPLASIA (BPH), A PROGRESSIVE DISEASE THAT OCCURS WITH INCREASING PREVALENCE AS MEN AGE, AFFECTING 70% OF MEN IN THEIR SIXTIES AND 90% OF MEN IN THEIR EIGHTIES. QUALITY OF LIFE IS SEVERELY IMPACTED BY BPH, WHICH LEADS TO BLADDER OUTLET OBSTRUCTION AND LOWER URINARY TRACT SYMPTOMS (LUTS) PRESENTING AS REDUCED FLOW THROUGH THE PROSTATIC URETHRA AND INCOMPLETE BLADDER EMPTYING RESULTING IN MORE FREQUENT URINATION, ESPECIALLY AT NIGHT (NOCTURIA). MOLECULAR MECHANISMS RESPONSIBLE FOR BPH/LUTS ARE UNCLEAR, WHICH HAS DELAYED TREATMENT DEVELOPMENT. AGE-RELATED CHANGES IN RELATIVE SERUM TESTOSTERONE (T) AND ESTRADIOL (E2) LEVELS ARE ASSOCIATED WITH BPH/LUTS. T AND E2 ARE MAJOR CONTRIBUTORS TO BPH/LUTS INITIATION AND PROGRESSION THAT ACT THROUGH 1) NUCLEAR RECEPTORS TO REGULATE GENE EXPRESSION (CLASSICAL SIGNALING PATHWAY) OR 2) MEMBRANE RECEPTORS THAT RAPIDLY ACTIVATE KINASE CASCADES AND ALTER CELLULAR PROCESSES (NONCLASSICAL SIGNALING). OUR PRELIMINARY STUDIES IDENTIFY A NEW PARADIGM TO EXPLAIN SUSTAINED PROSTATIC SMOOTH MUSCLE CONTRACTION THAT CAUSES RESTRICTION OF URINE FLOW AND LUTS. USING 3 MODELS OF BPH/LUTS WITH AGED LEVELS OF T AND E2, WE FOUND CONSISTENT ALTERED EXPRESSION OF PROTEIN PHOSPHATASE 1 REGULATORS (PPP1R) THAT DECREASE OR ARE PREDICTED TO DECREASE ACTIVITY OF MYOSIN LIGHT CHAIN PHOSPHATASE (MLCP) REQUIRED FOR PROSTATIC SMOOTH MUSCLE (SM) RELAXATION AND BLADDER VOIDING. THIS IMPORTANT ADVANCE IDENTIFIES PPP1R PROTEINS AND OTHER SM RELAXATION REGULATORS AS TARGETS FOR THERAPIES TO REVERSE AGING ASSOCIATED BPH/LUTS. IN AIM 1, WE WILL IDENTIFY PPP1R PROTEINS AND OTHER MEMBERS OF THE RELAXATION PROMOTING PATHWAY THAT ARE DIFFERENTIALLY REGULATED IN AGED MOUSE PROSTATE MODELS AND HUMAN BPH TISSUES/CELL CULTURES. IN AIM 2, WE WILL IDENTIFY THE T- AND E2-MEDIATED PATHWAYS REQUIRED TO INITIATE AND SUSTAIN BPH AND LUTS BY USING OUR TRANSGENIC MICE HAVING ONLY CLASSICAL OR ONLY NONCLASSICAL E2 SIGNALING OR ONLY CLASSICAL T SIGNALING. OUR RESULTS WILL PROVIDE A MECHANISTIC EXPLANATION FOR SUSTAINED SM CONTRACTION AROUND THE PROSTATIC URETHRA, RESTRICTION OF URINE FLOW AND LUTS INCLUDING VOIDING DYSFUNCTION THAT OCCURS WITH AGING-RELATED ALTERED HORMONE LEVELS. OUR FINDINGS WILL IDENTIFY PATHWAYS AND PROCESSES REQUIRED FOR BPH/LUTS PROGRESSION AND IDENTIFY NEW TARGETS FOR LUTS THERAPIES.

EVALUATING THE ASSOCIATION BETWEEN SURGERY AND SUBSEQUENT COGNITIVE FUNCTION, EVERYDAY FUNCTIONING, AND INDEPENDENCE - PROJECT ABSTRACT THE PURPOSE OF THIS K23 CAREER DEVELOPMENT AWARD IS TO SUPPORT DR. ACKENBOM'S LONG TERM CAREER GOAL OF BECOMING AN INDEPENDENT SURGEON-SCIENTIST ADVANCING KNOWLEDGE ON COGNITIVE IMPAIRMENT AFTER SURGERY USED TO IMPROVE SURGICAL OUTCOMES AND QUALITY OF LIFE FOR OLDER PATIENTS. RECOGNIZING POSTOPERATIVE NEUROCOGNITIVE DISORDER (PNCD), PREVIOUSLY TERMED POSTOPERATIVE COGNITIVE DYSFUNCTION (POCD), IN SURGICAL PATIENTS IS ESSENTIAL AS IT IS ASSOCIATED WITH DELAYED POSTOPERATIVE RECOVERY, GREATER LOSS OF INDEPENDENCE, INCREASED MORBIDITY, MORTALITY, AND SUBSTANTIAL HEALTH CARE COSTS. IN THE UNITED STATES, APPROXIMATELY 35% OF ALL SURGERIES ARE PERFORMED ON ADULTS =65 YEARS, AND WITH THE INCREASE IN THE AGING POPULATION, THE NUMBER OF SURGERIES AND THUS PNCD INCIDENCE IS EXPECTED TO RISE. PNCD/POCD IS CHARACTERIZED AS A LARGELY TRANSIENT DETERIORATION OF CONCENTRATION, INFORMATION PROCESSING, AND MEMORY OFTEN LASTING DAYS TO MONTHS, BUT THERE ARE STUDIES REPORTING COGNITIVE IMPAIRMENT AFTER SURGERY LASTING YEARS. COGNITIVE IMPAIRMENT OCCURRING MORE THAN 12 MONTHS AFTER SURGERY IS CONCERNING FOR AN ONGOING DIAGNOSIS OF MILD COGNITIVE IMPAIRMENT OR OTHER COGNITIVE DIAGNOSES, INCLUSIVE OF ALZHEIMER'S DISEASE AND RELATED DEMENTIAS (ADRD).THERE IS A CRITICAL RESEARCH NEED TO EXAMINE THE LONGITUDINAL COURSE OF COGNITIVE IMPAIRMENT AFTER SURGERY AND ITS INFLUENCE ON EVERYDAY FUNCTIONING, INDEPENDENCE, AND QUALITY OF LIFE AS IT IS NOT WELL UNDERSTOOD. WE PROPOSE A STUDY USING LINKED 2011-2017 DATA FROM THE NATIONAL HEALTH AND AGING TRENDS STUDY (NHATS), A POPULATION-BASED STUDY FOCUSED ON LATE-LIFE FUNCTIONING OVER TIME, WITH MEDICARE CLAIMS DATA, INCLUSIVE OF SURGICAL DATA VARIABLES AS WELL AS BUILDING UPON A SURGICAL PATIENT COHORT WITH AVAILABLE DETAILED NEUROPSYCHOLOGICAL TESTING RESULTS TO ADDRESS THE FOLLOWING AIMS: 1) COMPARE CHANGE IN COGNITIVE PERFORMANCE OF PERSONS =65 YEARS WHO UNDERWENT MAJOR NONCARDIAC ELECTIVE SURGERY AND THOSE WHO DID NOT, 2) COMPARE CHANGE IN EVERYDAY FUNCTIONING IN PERSONS =65 YEARS WHO UNDERWENT MAJOR NONCARDIAC ELECTIVE SURGERY AND THOSE WHO DID NOT, 3) ASSESS CHANGE IN COGNITIVE PERFORMANCE AND DIAGNOSIS TWO YEARS AFTER PROLAPSE SURGERY IN WOMEN =70 YEARS PREVIOUSLY ENROLLED IN ACKENBOM ET. AL STUDY ASSESSING PNCD. THE TRAINING AIMS IN THIS PROPOSAL ARE: 1) TO BUILD ON FOUNDATIONAL KNOWLEDGE IN MEASUREMENT OF A RANGE OF COGNITIVE ABILITIES IN CLINICAL RESEARCH SETTINGS AND 2) TO ENHANCE MY KNOWLEDGE AND UNDERSTANDING IN RESEARCH AND CLINICAL DIAGNOSIS AND MANAGEMENT OF COGNITIVE IMPAIRMENT DISORDERS IN GENERAL AND IN PARTICULAR, ADRD, TO INCORPORATE INTO FUTURE STUDY DESIGNS INVOLVING COGNITIVE EVALUATION IN PERIOPERATIVE SETTINGS. THIS STUDY WILL DETERMINE APPROPRIATE EFFECT SIZES IN PREPARATION FOR FUTURE STUDIES TO CONDUCT AN EXTENDED ASSESSMENT OF COGNITIVE PERFORMANCE AND COGNITIVE DIAGNOSES, INCLUDING PNCD AND INCIDENT DEMENTIA, AFTER UNDERGOING MAJOR NONCARDIAC ELECTIVE SURGERY IN PERSONS =70 YEARS OVER A 5-YEAR PERIOD. FURTHER, ACHIEVEMENT OF THESE TRAINING AIMS WILL PROPEL DR. ACKENBOM IN HER TRANSITION TO INDEPENDENCE AS A CLINICAL RESEARCHER IN THIS IMPORTANT AREA OF STUDY.

TRAINING IN BASIC AND CLINICAL PHARMACOLOGY IN PREGNANCY

CHD7-DEPENDENT REGULATION OF MIGRATION AND MORPHOGENESIS - PROJECT SUMMARY CHARGE SYNDROME IS A CONGENITAL, MULTISYSTEMIC, DEVELOPMENTAL DISORDER CAUSED BY LOSS-OF-FUNCTION MUTATIONS IN THE CHROMODOMAIN HELICASE DNA-BINDING PROTEIN 7 (CHD7). CHARGE IS CLASSIFIED AS A NEUROCRISTOPATHY, WITH DEFECTS IN NEURAL CREST CELL (NCC) SPECIFICATION, MIGRATION AND DIFFERENTIATION CONTRIBUTING TO MANY OF ITS CHARACTERISTIC DEVELOPMENTAL ANOMALIES. HOWEVER, PATIENTS ALSO FREQUENTLY PRESENT WITH RENAL, GENITAL, AND CARDIAC DEFECTS, SUGGESTING THAT CHD7 FUNCTIONS MORE BROADLY IN EMBRYOGENESIS BEYOND NCC DERIVATIVES. CHD7 IS ALSO MUTATED IN KALLMANN SYNDROME, A GENETIC DISORDER CHARACTERIZED BY HYPOGONADISM AND ANOSMIA, AND OCCASIONALLY, KIDNEY ABNORMALITIES. ALTHOUGH RENAL ANOMALIES ARE COMMON IN CHARGE, KALLMANN, AND RELATED DISORDERS, THE MOLECULAR MECHANISMS BY WHICH CHD7 AND ITS DOWNSTREAM EFFECTORS CONTRIBUTE TO KIDNEY PATHOGENESIS REMAIN LARGELY UNDEFINED. KIDNEY DEVELOPMENT RELIES ON COORDINATED CELL MOVEMENTS AND ECM REMODELING; DISRUPTIONS IN THIS PROCESS CAN LEAD TO STRUCTURAL ABNORMALITIES OF THE KIDNEY AND URINARY TRACT, AS SEEN IN CHARGE PATIENTS. IN THIS PROPOSAL, WE USE A CROSS-SPECIES APPROACH TO REVEAL NEW INSIGHTS INTO CHD7’S ROLE IN KIDNEY DEVELOPMENT. WE USE THE NEMATODE C. ELEGANS AS A DISCOVERY TOOL FOR GENES AND DOWNSTREAM PATHWAYS REGULATED BY CHD-7 AND THE FROG X. LAEVIS TO STUDY THE IMPACT ON THE DEVELOPING KIDNEY. WE RECENTLY OBSERVED THAT CHD-7 MUTANT WORMS HAVE A HIGHLY PENETRANT DEFECT IN SOMATIC GONAD MORPHOGENESIS. LIKE THE VERTEBRATE KIDNEY, THE WORM SOMATIC GONAD IS SHAPED BY COMPLEX INTERACTIONS BETWEEN THE UNDERLYING ECM AND THE MIGRATING TISSUE. WE PREVIOUSLY SHOWED THAT CHD7 REGULATES TGFΒ PATHWAYS AFFECTING CRITICAL DEVELOPMENTAL PROCESSES THROUGH ECM MODULATION IN BOTH WORM AND FROG MODELS. IN AIM 1, WE EXPLORE HOW ECM DYSFUNCTION PROMOTES CHD7-ASSOCIATED PATHOLOGIES BY CHARACTERIZATION OF THE IMPACTS OF CHD7 LOSS ON BOTH WORM SOMATIC GONAD AND X. LAEVIS PRONEPHROS MORPHOGENESIS AND ASSOCIATED CHANGES IN BM COMPOSITION IN BOTH SPECIES. IN AIM 2, WE FOLLOW UP ON PUTATIVE DOWNSTREAM TARGETS OF CHD-7. OUR ANALYSES REVEALED THAT CHD-7 BINDS TO THE REGULATORY REGION OF MIR-34, A MICRORNA WHOSE LOSS PHENOCOPIES CHD-7 DEFICIENCY IN GONAD MIGRATION, LONGEVITY, AND DAUER FORMATION IN WORMS. IN HUMANS, MEMBERS OF THE MIR-34/449 FAMILY ARE LOCATED WITHIN TWO GENOMIC REGIONS DELETED IN CHARGE-RELATED SYNDROMES, SUGGESTING THAT THIS MIRNA FAMILY IS AN EVOLUTIONARILY CONSERVED DOWNSTREAM TARGET OF CHD7, A HYPOTHESIS WE TEST IN AIM 2.

THE NON-INVASIVE EARLY DETECTION OF ENDOMETRIOSIS - ABSTRACT ENDOMETRIOSIS IS A DEBILITATING DISEASE INVOLVING THE GROWTH OF ENDOMETRIAL GLANDS AND STROMA OUTSIDE THE UTERUS. THE PRIMARY SYMPTOMS ARE PELVIC PAIN AND INFERTILITY. NEARLY HALF OF AFFECTED WOMEN HAVE CHRONIC PELVIC PAIN, AND IN 70% OF THOSE, THE PAIN OCCURS DURING MENSTRUATION. PAIN WITH SEX (“DYSPAREUNIA”) AND INFERTILITY OCCUR IN CLOSE TO HALF OF WOMEN AFFECTED BY ENDOMETRIOSIS. LESS COMMON SYMPTOMS INCLUDE URINARY OR BOWEL SYMPTOMS. ABOUT 25% OF WOMEN HAVE NO SYMPTOMS. ENDOMETRIOSIS CAN HAVE BOTH SOCIAL AND PSYCHOLOGICAL EFFECTS. CURRENTLY, DEFINITIVE DIAGNOSIS IS ACHIEVED BY SURGICAL BIOPSY. BECAUSE OF THE INVASIVE NATURE OF THIS METHOD, THE DIAGNOSIS AND TREATMENT OF ENDOMETRIOSIS IS CONSIDERABLY DELAYED, WITH AVERAGE TIME FROM SYMPTOM ONSET TO DIAGNOSIS BEING 10 YEARS. THE CONSEQUENCE OF THIS SIGNIFICANT DELAY IS PROLONGED AND PROGRESSIVE PAIN, A RISK OF INFERTILITY AND CONSIDERABLE SOCIAL/ECONOMIC IMPACT. THE PURPOSE OF THIS STUDY IS TO DEVELOP NON-INVASIVE SCREENING METHODS FOR THE EARLY DETECTION OF ENDOMETRIOSIS. SPECIFICALLY, WE WILL TARGET DNA METHYLATION SIGNATURES CARRIED BY CIRCULATING FRAGMENTS OF EXTRACELLULAR DNA, REFERRED TO HEREIN AS CELL-FREE DNA (CFDNA). THESE FRAGMENTS, WHICH ARE DETECTED IN A VARIETY OF FLUID RESERVOIRS INCLUDING BLOOD PLASMA, CONVEY EPIGENOMIC INFORMATION BOTH ABOUT THEIR CELL TYPE OF ORIGIN AND ITS PATHOLOGICAL STATE. OUR OVER-ARCHING HYPOTHESIS IS THAT ALTERED DNA METHYLATION SIGNATURES IN THE UTERINE TISSUE OF ENDOMETRIOSIS PATIENTS ARE DETECTABLE VIA ANALYSIS OF PLASMA-DERIVED CFDNA. IN THIS STUDY WE WILL BUILD A FOUNDATION OF PRELIMINARY DATA TOWARDS THE DEVELOPMENT OF METHODS FOR THE EARLY NON-INVASIVE DETECTION OF ENDOMETRIOSIS.

ICR-INDEPENDENT ESTABLISHMENT OF DOMAIN IMPRINTING

TARGETING MACROPHAGE TO IMPROVE THE OUTCOMES OF UROGYNECOLOGIC MESHES IN DIABETIC WOMEN

DEVELOPMENT OF A SMARTPHONE-BASED DEVICE TO DETECT FLUID OVERLOAD AMONG POSTPARTUM WOMEN WITH HYPERTENSIVE DISORDERS OF PREGNANCY - PROJECT ABSTRACT HYPERTENSIVE DISORDERS OF PREGNANCY CONTRIBUTE TO A SIGNIFICANT PROPORTION OF MATERNAL MORBIDITY AND MORTALITY AND ARE THE MOST COMMON REASON FOR HOSPITAL READMISSION POSTPARTUM. WHILE TREATMENT OF HYPERTENSION IS THE CORNERSTONE OF POSTPARTUM MANAGEMENT, EMERGING EVIDENCE SUGGESTS THAT IMPLEMENTATION OF ROBUST REMOTE BLOOD PRESSURE MONITORING AND TREATMENT PROGRAMS ALONE DO NOT REDUCE MATERNAL MORBIDITY OR HOSPITAL READMISSIONS RELATED TO POSTPARTUM FLUID OVERLOAD AND HEART FAILURE SYMPTOMS. THE ABILITY TO PREDICT WHICH WOMEN WILL DEVELOP THESE COMPLICATIONS AND PURSUE MORE AGGRESSIVE TREATMENT WITH DIURESIS PRIOR TO HOSPITAL DISCHARGE OR IN THE FIRST WEEK POSTPARTUM IS LIMITED. THE OVERALL GOAL OF THIS LINE OF RESEARCH IS TO DEVELOP AND IMPLEMENT A CONVENIENT CONGESTION PREDICTION DEVICE FOR HOME USE IN CONJUNCTION WITH HOME BLOOD PRESSURE MONITORING IN A POSTPARTUM POPULATION FOLLOWING A HYPERTENSIVE DISORDER OF PREGNANCY. IN THIS APPLICATION, THE OBJECTIVE IS TO DEVELOP AND TEST A SMARTPHONE-BASED DEVICE TO PREDICT FLUID OVERLOAD IN PATIENTS WITH PREECLAMPSIA THROUGH THREE SPECIFIC AIMS: 1) TO BUILD MULTIPLE SMARTPHONE-BASED DEVICES TO ASSESS VOLUME STATUS VIA A CONGESTION PREDICTION INDEX IN POSTPARTUM WOMEN WITH PREECLAMPSIA, 2) TO COLLECT PATIENT TRAINING DATA WITH THE DEVICES, OPTIMIZE THEIR ACCURACY IN ASSESSING VOLUME STATUS, AND IDENTIFY AND CREATE THE FINAL REAL-TIME DEVICE AND 3) TO VALIDATE THE FINAL DEVICE PROSPECTIVELY IN RESPONSE TO KNOWN FLUID CHANGES AMONG A NEW COHORT OF POSTPARTUM WOMEN WITH PREECLAMPSIA. THE RESEARCH PROPOSED IN THIS APPLICATION IS INNOVATIVE IN ITS NOVEL ADAPTATION OF EVIDENCE-BASED APPROACHES TO FLUID ASSESSMENT IN HEART FAILURE PATIENTS TO AN UNDERSTUDIED POSTPARTUM POPULATION WITH SIGNIFICANT MORBIDITY, ITS USE OF A SMARTPHONE FORM FACTOR AND THE DESIGN AND THE PROPOSED TESTING OF MULTIPLE DEVICES TO OPTIMIZE EFFECTIVENESS AND CONVENIENCE. THIS PROPOSAL IS SIGNIFICANT AS IT WILL PROVIDE AN OPPORTUNITY TO DEVELOP AND ASSESS THE FEASIBILITY OF SMARTPHONE- BASED ASSESSMENT OF FLUID STATUS AMONG POSTPARTUM WOMEN WITH PREECLAMPSIA. EFFECTIVE INTERVENTIONS TO IMPROVE POSTPARTUM HYPERTENSION CARE COUPLED WITH INNOVATIVE REMOTE STRATEGIES HAVE BROAD IMPLICATIONS FOR IMPROVING MATERNAL MORBIDITY AND REDUCING DISPARITIES IN CARE. OUR FINDINGS WILL PROVIDE A VALUABLE FRAMEWORK TO INFORM A FUTURE RANDOMIZED TRIAL OF REMOTE ASSESSMENT AND MANAGEMENT OF FLUID STATUS IN THE POSTPARTUM PERIOD. SUCCESSFUL COMPLETION OF THIS LINE OF RESEARCH WOULD REPRESENT A TRANSFORMATION IN POSTPARTUM MANAGEMENT OF WOMEN WITH PREECLAMPSIA AND HAVE A DIRECT IMPACT TO IMPROVE HYPERTENSION AND CARDIOVASCULAR-RELATED MATERNAL MORBIDITY AND MORTALITY.

A PHASE 1 PK AND SAFETY STUDY OF VELPATASVIR/SOFOSBUVIR FOR CHRONIC HEPATITIS C INFECTION IN PREGNANT WOMEN

A PHASE 1 PHARMACOKINETIC TRIAL OF LEDIPASVIR/SOFOSBUVIR (LDV/SOF) FIXED DOSE COMBINATION IN PREGNANT WOMEN WITH CHRONIC HEPATITIS C VIRUS INFECTION

GENOMIC SIGNATURES OF X-LINKED AND AUTOSOMAL CANDIDATE-GENES IN AZOOSPERMIA

THE REGULATORY CODE GOVERNING PLACENTA-SPECIFIC EXPRESSION OF THE CHROMOSOME 19 MIRNA CLUSTER

THE ROLE OF OXYSTEROLS IN PLACENTAL BIOLOGY

FLUORESCENTLY TAGGED C. ELEGANS TO PROBE MEIOTIC RECOMBINATION

GENOMIC INTEGRITY OF THE X CHROMOSOME & OVARY-SPECIFIC AUTOSOMAL GENES

SMALL RNAS AT THE PLACENTAL MATERNAL COMMUNICATION INTERFACE

KNOCKOUT/KNOCKIN RATS USING ZINC FINGER NUCLEASES AND HOMOLOGOUS RECOMBINATION

GENETICS OF HUMAN OVARIAN FAILURE

MULTI-OMICS & AI-BASED IMAGING TO IDENTIFY BIOMARKERS OF MOLECULAR TARGETS FOR BREAST CANCER PREVENTION - HIGH MAMMOGRAPHIC BREAST DENSITY (MBD) PRESENTS TWO CHALLENGES: (1) IT IS ASSOCIATED WITH A 2-TO 6-FOLD INCREASE IN BREAST CANCER (BRCA) RISK, AND (2) IT SIGNIFICANTLY DECREASES MAMMOGRAM SENSITIVITY. SINCE MOST WOMEN HAVE HIGH MBD, IDENTIFYING MODIFIABLE FACTORS CONTRIBUTING TO MBD IS CRITICAL FOR REDUCING BRCA RISK, IMPROVING EARLY DETECTION, AND INCREASING SURVIVAL FROM SCREEN-DETECTED BREAST CANCERS. HOWEVER, FACTORS LEADING TO HIGH MBD REMAIN POORLY UNDERSTOOD. WE AIM TO IDENTIFY MODIFIABLE FACTORS INFLUENCING MBD THAT CAN BE TARGETED FOR NOVEL THERAPEUTICS TO PREVENT BRCA. GUT BACTERIA, WHICH CAN BE MODIFIED BY DIET AND ORAL AGENTS, MAY BE ONE SUCH FACTOR. GUT BACTERIA AND THEIR METABOLITES IMPACT NUMEROUS PROCESSES LINKED TO BRCA AND MBD, INCLUDING ESTROGEN PRODUCTION, INFLAMMATION, AND IMMUNE RESPONSES. EMERGING STUDIES SUGGEST AN ASSOCIATION BETWEEN THE GUT MICROBIOME (GM) AND BRCA AND BETWEEN THE GM AND HOST FACTORS RELATED TO BRCA AND MBD. HOWEVER, THE GM-MBD RELATIONSHIP REMAINS UNCLEAR. OUR PRELIMINARY DATA SUGGEST THAT GUT BACTERIA METABOLITES ARE ASSOCIATED WITH MBD AND THAT THERE ARE SIGNIFICANT DIFFERENCES IN THE GM BETWEEN WOMEN WITH HIGH VS. LOW MBD. HOWEVER, THE SPECIFIC BACTERIA RESPONSIBLE FOR OUR OBSERVATIONS ARE UNKNOWN. MOREOVER, NO STUDIES HAVE EXAMINED THE JOINT ROLES OF THE GUT MICROBIOME AND SYSTEMIC METABOLOME IN MBD. OUR STUDY ADDRESSES THIS GAP. WE HYPOTHESIZE THAT GUT BACTERIA AND THEIR METABOLITES PREDICT MBD. WE PROPOSE IDENTIFYING SPECIFIC GUT BACTERIA SPECIES, METABOLITES, AND METABOLIC PATHWAYS ASSOCIATED WITH MBD TO PROVIDE INSIGHT INTO WAYS TO REDUCE MBD, DECREASE BRCA RISK, INCREASE MAMMOGRAM SENSITIVITY, AND ULTIMATELY IMPROVE BRCA SURVIVAL. WE WILL USE NOVEL, AUTOMATED AI-BASED IMAGE ANALYSIS SOFTWARE TO QUANTIFY AND CLASSIFY MBD IN A COHORT OF WOMEN WITH NO HISTORY OF CANCER. WE WILL USE 16S RRNA GENE AMPLIFICATION SEQUENCING AND METAGENOMIC WHOLE-GENOME SHOTGUN SEQUENCING TO QUANTIFY SPECIES-LEVEL TAXA IN FECAL SAMPLES. LINEAR DISCRIMINANT ANALYSIS EFFECT SIZE (LEFSE) WILL IDENTIFY TAXA ABUNDANCE DIFFERENCES BETWEEN LOW VS HIGH MBD GROUPS (AIM 1). METABOLITES WILL BE QUANTIFIED IN BANKED SERUM SAMPLES USING MASS SPECTROMETRY AND COMPARED BETWEEN MBD GROUPS (AIM 2). METABOLITES AND METABOLIC ENRICHMENT ANALYSES WILL ALSO HELP FURTHER IDENTIFY BIOLOGICALLY ACTIVE AND MEANINGFUL BACTERIA SPECIES ASSOCIATED WITH MBD. WE WILL IDENTIFY GUT BACTERIA PREDICTIVE OF MBD, FACILITATING THE DEVELOPMENT OF PERSONALIZED BRCA SURVEILLANCE AND PREVENTION CARE. WE WILL ALSO IDENTIFY GUT BACTERIA THAT CAN SERVE AS INTERVENTION TARGETS TO REDUCE MBD. OUR TEAM WILL THEN BE WELL- POSITIONED TO CONDUCT HUMAN TRIALS TO ASSESS HOW ALTERING GUT BACTERIA COMPOSITION IMPACTS MBD. WE WILL ALSO BE WELL-POSITIONED TO PURSUE FUNCTIONAL STUDIES ILLUMINATING THE MECHANISMS BY WHICH GUT BACTERIA INFLUENCE MBD, THUS FURTHER IDENTIFYING PREVENTION TARGETS. RESPONDING TO PAR-22-216, OURS IS A HYPOTHESIS-DRIVEN, CORRELATIVE TRANSLATIONAL EXPLORATORY R21 STUDY GROUNDED IN LAB-BASED RESEARCH THAT WILL USE HIGH-DIMENSIONAL DATA AND AI TO IDENTIFY (1) BIOMARKERS PREDICTIVE OF MBD, AND (2) POTENTIAL TARGETS AND AGENTS TO REDUCE MBD.

NEW FERTILITY PRESERVING OPTION FOR MALE CANCER SURVIVORS

GLYCOCALYX IN PREGNANCY AND THE PREECLAMPSIA SYNDROME

MULTI-OMIC PREDICTIVE MARKERS FOR OVARIAN CANCER THERAPY RESPONSE AND OUTCOMES - EPITHELIAL OVARIAN CANCER (EOC) IS THE MOST LETHAL GYNECOLOGIC MALIGNANCY, WITH MORE THAN 20,000 NEWLY- DIAGNOSED CASES AND OVER 13,000 DEATHS IN THE UNITED STATES EACH YEAR. UNFORTUNATELY, THERE HAS BEEN LITTLE CHANGE IN SURVIVAL SINCE PLATINUM-BASED THERAPIES WERE INTRODUCED OVER 30 YEARS AGO. BECAUSE THE SEARCH FOR NEWER, MORE EFFECTIVE AGENTS HAS NOT BEEN FRUITFUL, AGGRESSIVE SURGERY PLUS PLATINUM-BASED CHEMOTHERAPY REMAINS THE STANDARD FIRST-LINE TREATMENT OF THE DISEASE. HOWEVER, INDIVIDUAL RESPONSE TO PLATINUM THERAPY IS HIGHLY VARIABLE AND UNPREDICTABLE. EVENTUALLY, MOST WOMEN DEVELOP AND SUCCUMB TO PLATINUM-RESISTANT DISEASE. NO WAY EXISTS TO IDENTIFY WHO WILL RESPOND POORLY TO PLATINUM-BASED THERAPY; NOR ARE THERE ANY CLINICALLY-VALIDATED INTERVENTIONS TO IMPROVE THERAPY RESPONSE. BIOMARKERS THAT CAN PREDICT THERAPY RESPONSE, PROVIDE AN EARLY INDICATION OF EFFICACY, SUPPORT PATIENT TREATMENT STRATIFICATION, AND SUGGEST INTERVENTIONS TO IMPROVE THERAPY RESPONSE AND SURVIVAL ARE URGENTLY NEEDED. BASIC CANCER RESEARCH DISCOVERIES IN EOC AND OTHER SOLID TUMORS SUGGEST THAT GUT BACTERIA IMPACT HOW A WOMAN RESPONDS TO PLATINUM-BASED THERAPY BY INFLUENCING THE LOCAL TUMOR MICROENVIRONMENT (TME). THUS, GUT BACTERIA MAY SERVE AS PREDICTIVE BIOMARKERS OF THERAPY RESPONSE AND OUTCOME. HOWEVER, THERE HAVE BEEN NO HUMAN STUDIES OF GUT BACTERIA AND EOC THERAPY RESPONSE, NOR ON THE INTERACTIONS AMONG GUT BACTERIA, TME IMMUNITY, AND TREATMENT RESPONSE AND OUTCOME. OUR PRELIMINARY FINDINGS IN WOMEN WITH NEWLY-DIAGNOSED EOC SUPPORT THE ANIMAL MODEL DATA. BACKED BY THE LABORATORY RESEARCH DATA AND BASED ON OUR PRELIMINARY FINDINGS IN AN EOC POPULATION, WE PROPOSE TO DEVELOP PREDICTIVE MICROBIOME-BASED BIOMARKERS THAT WILL LEAD TO BETTER PATIENT STRATIFICATION. IN AIM 1, WE WILL ASSESS THE GUT MICROBIOME AND SYSTEMIC METABOLOME IN 104 NEWLY DIAGNOSED EOC CASES TO IDENTIFY GUT BACTERIA PREDICTIVE OF RESPONSE AND OUTCOME TO PLATINUM-BASED THERAPY. IN AIM 2 WE WILL USE IMMUNE-PROFILING ASSAYS TO ASSESS TME IMMUNE INFILTRATES AND IMMUNE GENE EXPRESSION IN OUR COHORT. WE WILL THEN USE THE HIGH- DIMENSIONAL GENOMIC, METABOLOMIC AND TRANSCRIPTOMIC DATA GENERATED FROM AIMS 1 AND 2 TO IDENTIFY FAVORABLE AND UNFAVORABLE GUT MICROBIOMES ASSOCIATED WITH THERAPY RESPONSE, OUTCOMES, AND LOCAL TUMOR IMMUNITY. WE WILL ALSO IDENTIFY GUT BACTERIA THAT CAN SERVE AS INTERVENTION TARGETS TO IMPROVE THERAPY EFFICACY OR BLOCK CANCER PROGRESSION. OUR TEAM WILL THEN BE WELL POSITIONED TO CONDUCT HUMAN TRIALS TO ASSESS THE EFFECTS OF ALTERING GUT BACTERIA COMPOSITION ON EOC OUTCOMES. WE WILL ALSO BE WELL POSITIONED TO PURSUE MECHANISTIC STUDIES TO ILLUMINATE HOW GUT BACTERIA IMPACT THERAPY RESPONSE AND OUTCOME, THUS FURTHER IDENTIFYING TREATMENT TARGETS. THIS PROPOSAL USES EXISTING BIOSPECIMENS FROM PREVIOUSLY-FUNDED NCI PROJECTS TOGETHER WITH CLINICAL ANNOTATING DATA TO GENERATE HIGH-DIMENSIONAL, MULTI-OMIC DATA IN ORDER TO DEVELOP PREDICTIVE AND PROGNOSTIC BIOMARKERS FOR PATIENT SELECTION OR STRATIFICATION.

PROFESSIONAL AND CULTURAL EXCHANGES - ONE-TIME GRANT COMPETITION

FACILITATING HCV TREATMENT THROUGH TAILORED PRENATAL CARE FOR HCV INFECTED, SUBSTANCE USING PREGNANT WOMEN

REHABILITATIVE AND REGENERATIVE MEDICINE FOR MINORITY HEALTH & HEALTH DISPARITIES

RELATIONSHIP BETWEEN ADOLESCENT WEIGHT, SEXUAL BEHAVIOR AND REPRODUCTIVE OUTCOMES

A NOVEL PLATFORM FOR OVARIAN CANCER DIAGNOSIS AND SCREENING

FY2014 YOUTH LEADERSHIP & TEACHER PROFESSIONAL DEVELOPMENT PROGRAM WITH BOSNIA & HERZEGOVINA

YOUTH LEADERSHIP PROGRAM

YOUTH LEADERSHIP PROGRAM (YLP): SOUTH ASIA

A BIORELEVANT DISSOLUTION METHODS FOR PARTICULATE DOSAGE FORMS IN THE PERIODONTAL POCKET

HEALTHY BEYOND PREGNANCY: LEVERAGING BEHAVIOR ECONOMICS TO IMPROVE POSTPARTUM CARE

UNDERSTANDING THE BELIEFS, CONCERNS, AND NEEDS OF PREGNANT PATIENTS WHO USE MARIJUANA AND OF THE OBSTETRICS PROVIDERS CARING FOR THEM

IMPACT OF MENOPAUSE ON VAGINAL CONNECTIVE TISSUE SUPPORT

PLACENTAL INJURY AND ADAPTATION

A PROSPECTIVE EXAMINATION OF PERIOPERATIVE NEUROCOGNITIVE DISORDERS IN OLDER WOMEN UNDERGOING UROGYNECOLOGIC SURGERY

ELASTOMERIC AUXETIC UROGENITAL MESHES: EXPLORING ALTERNATIVES TO KNITTED POLYPROPYLENE

HSV-2 SHEDDING: ROLE OF HORMONAL CONTRACEPTION AND BV

YOUTH LEADERSHIP PROGRAM

PATIENT-PROVIDER COMMUNICATION ON PARTNER VIOLENCE

ELUCIDATING THE ROLE OF THE HYALURONAN MATRICES ON THE ESTABLISHMENT OF OVARIAN RESERVE AND AGING - ABSTRACT IN MAMMALS GENERALLY, INCLUDING HUMANS, THE OVARY CEASES ITS FUNCTIONS LITTLE MORE THAN HALFWAY THROUGH A FEMALE'S LIFESPAN. THIS IS STRIKINGLY DIFFERENT FROM THE CHANGES THAT OCCUR IN OTHER ORGANS, LEADING TO A VERY LONG POST-REPRODUCTIVE PERIOD IN HUMANS. FEMALE REPRODUCTIVE AGING IS CHARACTERIZED BY A LOSS OF FOLLICLES; FOLLICLES ARE THE FUNCTIONAL UNITS OF THE OVARY, CONSISTING OF OOCYTES SURROUNDED BY COMPANION GRANULOSA CELLS. ALL THE OOCYTES/FOLLICLES THAT THE OVARY WILL EVER HAVE WILL HAVE BEEN GENERATED IN UTERO OR AT A VERY EARLY POSTNATAL AGE. THE STUDY OF OVARIAN RESERVE REGULATION HAS BEEN VERY GERM CELL CENTRIC, RELEGATING TO A QUITE SECONDARY ROLE THE OVARIAN STROMA AND THE MICROENVIRONMENT (INCLUDING SOMATIC CELLS AND THE EXTRACELLULAR MATRIX). IN FACT, THE MICROENVIRONMENT IN WHICH CELLS GROW AND DEVELOP INFORMS FUNCTION. RECENT PUBLICATIONS HAVE SHOWN THAT THE OVARIAN STROMA BECOMES INFLAMMATORY, FIBROTIC, AND STIFF WITH ADVANCED REPRODUCTIVE AGE. THESE PHENOTYPES ARE MECHANISTICALLY LINKED TO CHANGES IN THE HYALURONAN (HA) MATRIX, A UBIQUITOUS AND POLYDISPERSE EXTRACELLULAR GLYCOSAMINOGLYCAN THAT REGULATES TISSUE HOMEOSTASIS. IN ITS HIGH-MOLECULAR-WEIGHT (HMW) FORM, HA BINDS WATER AND PROMOTES HYDRATION AND HAS ANTI-INFLAMMATORY PROPERTIES. IN CONTRAST, LOW-MOLECULAR-WEIGHT (LMW) HA TENDS TO HAVE PRO-INFLAMMATORY PROPERTIES. HIGH LEVELS OF HA ARE ASSOCIATED WITH STEM CELL PROLIFERATION AND PROTECTION FROM DIFFERENTIATION DURING EARLY EMBRYOGENESIS. THE NAKED MOLE-RAT (HETEROCEPHALUS GLABER, NMR) IS A UNIQUE RODENT SPECIES WHICH LIVES UP TO FOUR DECADES AND MAINTAINS REPRODUCTIVE FUNCTION THROUGHOUT ITS ENTIRE LIFESPAN. THIS EXTREME LONGEVITY IS ATTRIBUTABLE IN PART TO THE PRODUCTION OF LARGE AMOUNTS OF VERY-HIGH-MOLECULAR-WEIGHT HYALURONAN (VHMW-HA). VHMW-HA IS PRODUCED IN NMRS BY A UNIQUELY MODIFIED VERSION OF THE HYALURONAN SYNTHASE 2 GENE (HAS2). IN THE PROPOSED RESEARCH, WE WILL TEST THE OVERARCHING HYPOTHESIS THAT THE STROMAL MICROENVIRONMENT OF THE FETAL OVARY, INCLUDING AN HA-RICH MATRIX, REGULATES THE ESTABLISHMENT AND MAINTENANCE OF THE OVARIAN RESERVE AND REPRODUCTIVE LONGEVITY.

TRANSCRIPTIONAL REGULATORY NETWORKS IN SPERMATOGONIAL STEM CELLS

PREGNANCY AS A WINDOW TO FUTURE CARDIOVASCULAR HEALTH

MECHANISMS OF ADIPOCYTE DEATH

FRONTIERS IN HUMAN EMBRYONIC STEM CELLS

GLYCOCALYX SYNDECAN-1 IN TROPHOBLAST LIPID TRANSPORT

THE ROLE OF HORMAD1 IN GERM CELL DEVELOPMENT AND MEIOSIS

LET US LIVE HEALTHY

LET US LIVE HEALTHY, PART 2

AAV GENE THERAPY TO RESTORE FERTILITY IN MAMMALIAN SERTOLI CELL DYSFUNCTION MODELS - ABSTRACT: INFERTILITY IMPACTS 48 MILLION COUPLES WORLDWIDE AND 50% OF CASES ARE DUE TO A MALE FACTOR. NON-OBSTRUCTIVE AZOOSPERMIA (NOA) IS THE ABSENCE OF SPERM DUE TO SPERMATOGENIC FAILURE. SOME CASES ARE DUE TO KNOWN CONDITIONS (KLINEFELTER’S SYNDROME, Y CHROMOSOME MICRODELETIONS, AND HYPOGONADISM) BUT MANY CASES ARE IDIOPATHIC (UNEXPLAINED). RECENT IDENTIFICATION OF NOVEL MONOGENIC CAUSES OF NOA SPARKS THE POSSIBILITY OF GENE THERAPY AS A POTENTIAL TREATMENT OPTION. THERE ARE ETHICAL, LEGAL AND SOCIETAL CONCERNS ABOUT GENE THERAPY APPROACHES THAT WOULD MODIFY THE GERMLINE AND POTENTIALLY BE PASSED TO PROGENY. THEREFORE, DEVELOPMENT OF GENE THERAPY APPROACHES FOR MALE INFERTILITY SHOULD CONSIDER THE RISK OF GERMLINE MODIFICATION AND TRANSMISSION. SERTOLI CELLS ARE THE ONLY TESTICULAR SOMATIC CELLS THAT ARE INSIDE THE SEMINIFEROUS TUBULES AND IN DIRECT CONTACT WITH THE GERM CELLS AND SERTOLI CELL MUTATIONS CAN LEAD TO NOA IN BOTH MICE AND HUMANS. I WILL TEST THE FEASIBILITY AND SAFETY OF IN VIVO SERTOLI CELL GENE THERAPY IN MOUSE MODELS OF HUMAN NOA. ADENO-ASSOCIATED VIRUS (AAV) IS AN OPTIMAL VECTOR FOR SERTOLI CELL GENE THERAPY BECAUSE THERE ARE MANY AAV SEROTYPES WITH CELL TYPE SPECIFICITY OF INFECTION, IT CAN HAVE LONG LASTING EXPRESSION, IT HAS LOW TOXICITY IN THE TESTIS, AND DOES NOT TYPICALLY INTEGRATE INTO THE GENOME. AAV HAS BEEN USED TO INTRODUCE A CORRECTIVE KITL GENE INTO SERTOLI CELLS OF KITL-/- MICE THAT HAVE AN NOA PHENOTYPE, RESTORING SPERMATOGENESIS. IN HUMANS, MUTATIONS IN THE KITL GENE DO NOT CAUSE INFERTILITY. UNDER SEPARATE FUNDING, OUR GROUP HAS BEEN PERFORMING WHOLE GENOME OR WHOLE EXOME SEQUENCING TO IDENTIFY GENETIC VARIANTS IN MEN WITH NOA. I HAVE SCREENED THOSE DATA TO IDENTIFY NOA-ASSOCIATED VARIANTS IN MAP7 AND CLCN2 THAT ARE EXPRESSED BY SERTOLI CELLS AND CAUSE NOA WHEN KNOCKED OUT IN MICE. I WILL USE CRISPR/CAS9 GENE EDITING TO INTRODUCE THE PATIENT VARIANTS INTO THE ORTHOLOGOUS REGIONS OF THE MOUSE GENOME TO CREATE NEW MOUSE MODELS OF HUMAN NOA. I WILL USE THESE MODELS TO TEST THE HYPOTHESIS THAT, FERTILITY CAN BE SAFELY RESTORED BY AAV-MEDIATED SERTOLI CELL GENE THERAPY AND THAT THIS CAN BE ACCOMPLISHED WITHOUT GERMLINE MODIFICATION OR TRANSMISSION TO PROGENY. TO FACILITATE THE TRANSLATION OF THIS TECHNOLOGY TOWARD THE HUMAN CLINIC, I WILL UTILIZE A NOVEL HUMAN TESTIS ORGAN CULTURE TECHNIQUE TO IDENTIFY AAV SEROTYPES THAT EXHIBIT SERTOLI CELL SPECIFIC INFECTION IN HUMAN TESTICULAR TISSUE. COMPLETION OF MY PROJECT WILL DEMONSTRATE THE SAFETY AND FEASIBILITY OF SERTOLI CELL GENE THERAPY USING AAV VECTORS. I WILL UNCOVER NEW KNOWLEDGE INTO GENETIC CAUSES OF SERTOLI CELL DYSFUNCTION AND PROPOSE A TECHNIQUE THAT CAN TEST OTHER ASPECTS OF AAV USE IN HUMAN TISSUE. OVERALL, THE COMPLETION OF THIS GRANT WILL GREATLY INCREASE MY TECHNICAL RESEARCH SKILLS IN GENE THERAPY AND MALE INFERTILITY IN A BENCH TO BEDSIDE RESEARCH PIPELINE. THIS WILL PROVIDE A STRONG FOUNDATION OF KNOWLEDGE AND SKILLS TO PREPARE ME FOR A CAREER AS A FACULTY AND INDEPENDENT RESEARCHER IN ACADEMIA.

YOUTH LEADERSHIP PROGRAM

YOUTH LEADERSHIP PROGRAM

MECHANISMS MODULATING THE ASSOCIATION BETWEEN THE ENG PATHWAY AND PREECLAMPSIA

YOUTH LEADERSHIP PROGRAM

HEALTH CARE AND OTHER FACILITIES

DEVELOPMENT OF NOVEL TESTICULAR TISSUE ORGAN CULTURE SYSTEMS TO INDUCE IN VITRO SPERMATOGENESIS

THE SLEEP EXPERIENCE OF MOTHERS WITH HOSPITALIZED PRETERM INFANTS AND SUBSEQUENT BREAST MILK PROFILES

HIGH RESOLUTION TRANSCRIPTOME ANALYSIS OF THE PRIMATE TESTIS

OVARIAN CANCER: PREVENTION OF THE DISEASE AND ITS RECURRENCE

39TH ANNUAL SCIENTIFIC MEETING OF THE INFECTIOUS DISEASES SOCIETY FOR OBSTETRICS