Palo Alto Veterans Institute For Research

PREDICTING RESILIENCE IN THE HUMAN MICROBIOME

ACCELERATED TREATMENT FOR CO-OCCURRING INSOMNIA, NIGHTMARES, AND PTSD

PROGENITOR CELLS FOR HIGH ENDOTHELIUM IN THE IMMUNE RESPONSE

A CRITICAL ROLE FOR THE MICROVASCULATURE IN AIRWAY TRANSPLANTATION

FUNCTIONAL AND MOLECULAR DISSECTION OF MUTANT CALRETICULIN IN MYELOPROLIFERATIVE NEOPLASMS

NEURAL IMMUNOREGULATION OF POST-TRAUMATIC AUTOIMMUNITY

DEVELOPMENT OF AN AGONIST OF THE TGF-BETA SIGNALING PATHWAY TO TREAT ALZHEIMER'S

ANTIMICROBIAL RESISTANCE AND HORIZONTAL GENE TRANSFER IN THE HUMAN GUT MICROBIOME IN RESPONSE TO AN ANTIBIOTIC

AN INTEGRATED DIAGNOSTIC BIOCHIP FOR POINT OF CARE PATHOGEN IDENTIFICATION

A BIOORTHOGONAL APPROACH TO STUDY MAMMALIAN AGING

A NEW MUSCLE-BRAIN AXIS UNDERLYING THE COGNITIVE BENEFITS OF PHYSICAL ACTIVITY

INTESTINAL LYMPHOCYTE TRAFFICKING

HYPOSALIVATION AND THE HUMAN ORAL MICROBIOME

IMPROVING AND SUSTAINING DELIVERY OF CPT FOR PTSD IN MENTAL HEALTH SYSTEMS

APPLYING HYPERTENSION CLINICAL TRIALS TO REAL WORLD ADULTS WITH CKD - PROJECT SUMMARY / ABSTRACT HYPERTENSION AFFECTS MORE THAN 80% OF ADULTS WITH CHRONIC KIDNEY DISEASE (CKD), AND ITS TREATMENT IS A CORNERSTONE OF CKD MANAGEMENT. CLINICAL GUIDELINES VARY IN THEIR RECOMMENDATIONS FOR BLOOD PRESSURE TARGETS IN CKD, REFLECTING UNCERTAINTIES IN THE INTERPRETATION OF THE SYSTOLIC BLOOD PRESSURE INTERVENTION TRIAL (SPRINT) AND ITS EXTRAPOLATION TO ADULTS WITH CKD, PARTICULARLY THOSE WITH ADVANCED CKD. ALTHOUGH EVIDENCE FROM RANDOMIZED TRIALS HAS STRONG INTERNAL VALIDITY, IT MAY NOT REFLECT THE RISK BENEFIT PROFILE OF PATIENT POPULATIONS THAT WILL RECEIVE TREATMENT IN PRACTICE. OUR OVERARCHING GOAL IS TO EVALUATE THE COMPARATIVE RISKS AND BENEFITS OF INTENSIVE VERSUS STANDARD BLOOD PRESSURE TARGETS IN REAL WORLD ADULTS WITH CKD. OUR SECONDARY GOAL IS TO DEMONSTRATE THE FEASIBILITY AND UTILITY OF NOVEL ANALYTICAL APPROACHES THAT EXTEND CAUSAL EFFECTS FROM RANDOMIZED TRIAL EFFECTS TO BROADER POPULATIONS. WE WILL ACCOMPLISH THESE GOALS BY LEVERAGING ELECTRONIC HEALTH RECORD DATA FROM TWO LARGE HEALTH CARE SYSTEMS ENCOMPASSING 13 MILLION ENROLLEES - THE VETERANS HEALTH ADMINISTRATION AND KAISER PERMANENTE OF SOUTHERN CALIFORNIA. TO INFORM OUR REAL-WORLD ESTIMATES, WE WILL INTEGRATE INDIVIDUAL-LEVEL DATA FROM FOUR DIVERSE HYPERTENSION TRIALS ON 20,000 PARTICIPANTS. IN AIM 1, WE WILL ESTIMATE AVERAGE TREATMENT EFFECTS OF INTENSIVE VERSUS STANDARD BLOOD PRESSURE TARGETS AMONG SPRINT-ELIGIBLE REAL WORLD ADULTS WITH CKD. IN AIM 2, WE WILL DEVELOP AND VALIDATE MODELS FOR INDIVIDUALIZED PREDICTION OF INTENSIVE BLOOD PRESSURE TREATMENT EFFECTS, AND ILLUSTRATE THE APPLICATION IN REAL WORLD CKD POPULATIONS. IN AIM 3, WE WILL EMULATE A SEQUENTIAL CLINICAL TRIAL OF BLOOD PRESSURE MEDICATION INTENSIFICATION USING ELECTRONIC HEALTH RECORDS IN PERSONS WITH CKD. OUR STUDY IS IMPORTANT BECAUSE HYPERTENSION TREATMENT AFFECTS NEARLY ALL ADULTS WITH CKD AND KEY EVIDENCE GAPS MAY LEAD TO SUBOPTIMAL MANAGEMENT IN THIS HIGH-RISK POPULATION. IT IS INNOVATIVE BECAUSE IT WILL PROVIDE NEW EVIDENCE ABOUT THE IMPLICATIONS OF INTENSIVE BLOOD PRESSURE TARGETS AND NEW ANALYTIC APPROACHES TO SUPPORT CLINICAL DECISIONS WITH REAL WORLD DATA.

PHAGOCYTOSIS AND NOX2 IN LIVER FIBROGENESIS

PROTEIN HOMEOSTASIS AND PROTEOTOXICITY MECHANISMS

TARGETING CEREBROVASCULAR TGF SIGNALING IN ALZHEIMER'S DISEASE

NOTCH SIGNALING AND SATELLITE CELL ACTIVATION

PARTICIPATORY SYSTEM DYNAMICS VS AUDIT AND FEEDBACK: A CLUSTER RANDOMIZED TRIAL OF MECHANISMS OF IMPLEMENTATION CHANGE TO EXPAND REACH OF EVIDENCE-BASED ADDICTION AND MENTAL HEALTH CARE

VIRAL GASTROENTERITIS: BASIS OF PROTECTION AND VIRULENCE

INTESTINAL LYMPHOCYTE TRAFFICKING

RACIAL AND ETHNIC DISPARITIES IN HEPATOCELLULAR CARCINOMA SURVEILLANCE AMONG PATIENTS WITH CIRRHOSIS ACROSS FIVE SAFETY NET ORGANIZATIONS - BACKGROUND: IMPLEMENTING TIMELY AND CONSISTENT HEPATOCELLULAR CARCINOMA (HCC) SCREENING AMONG CIRRHOSIS PATIENTS IMPROVES EARLY TUMOR DETECTION, TREATMENT OPTIONS, AND OVERALL SURVIVAL. GUIDELINE- CONCORDANT HCC SCREENING RATES ARE SUBOPTIMAL, PARTICULARLY AMONG ETHNIC MINORITIES AND NON-ENGLISH SPEAKING IMMIGRANT POPULATIONS. THE UNDERLYING MECHANISTIC DRIVERS OF THESE DISPARITIES IN HCC SCREENING AMONG ETHNIC MINORITIES AND UNDERSERVED POPULATIONS IS NOT CLEAR, AND NO STUDIES HAVE COMPREHENSIVELY EVALUATED THE MEDIATING ROLES OF PATIENT, PROVIDER, AND SYSTEM LEVEL FACTORS IN CONTRIBUTING TO THESE DISPARITIES. GOALS: TO UNDERSTAND MECHANISMS OF DISPARITIES IN HCC SCREENING AMONG ETHNIC MINORITY AND UNDERSERVED POPULATIONS AND HOW COVID-19 PANDEMIC-RELATED DISRUPTIONS IN HEALTHCARE DELIVERY HAVE EXACERBATED THESE DISPARITIES, WE PROPOSE THREE SPECIFIC AIMS: 1) EXAMINE RACIAL AND ETHNIC DISPARITIES IN HCC SCREENING AMONG CIRRHOSIS PATIENTS IN THE PRE-COVID-19, COVID-19, AND POST-COVID-19 RECOVERY PERIODS; 2) IDENTIFY PROVIDER- SPECIFIC FACTORS (E.G. KNOWLEDGE, ATTITUDES, PRACTICE PATTERNS, PERCEIVED BARRIERS, BIASES AND STEREOTYPES TOWARDS ETHNIC MINORITIES, PANDEMIC-RELATED PRACTICE ADAPTATIONS) CONTRIBUTING TO HCC SCREENING DISPARITIES; AND 3) CONDUCT MULTI-LEVEL MEDIATIONAL ANALYSES TO IDENTIFY PATIENT, PROVIDER, AND SYSTEM LEVEL FACTORS THAT CONTRIBUTE TO ETHNIC DISPARITIES IN HCC SCREENING, AFFECTING TUMOR STAGE AT DIAGNOSIS, RECEIPT OF TREATMENT, AND SURVIVAL. METHODS: CONTEMPORANEOUS LONGITUDINAL REAL-WORLD OBSERVATIONAL DATA ON 10,500 CIRRHOSIS PATIENTS LINKED TO PROVIDER SURVEY DATA FROM 300 PRIMARY CARE AND GASTROENTEROLOGY ACROSS FIVE SAFETY NET HEALTH SYSTEMS REPRESENTING BROAD GEOGRAPHIC AND ETHNIC DIVERSITY WILL BE USED. PATIENT-LEVEL AND SYSTEM-LEVEL FACTORS WILL BE RETROSPECTIVELY EXTRACTED FROM ELECTRONIC HEALTH RECORDS AT EACH SITE, AND PROVIDER-LEVEL FACTORS WILL BE ASSESSED USING A PREVIOUSLY VALIDATED SURVEY-BASED APPROACH. INNOVATIVE MULTI-LEVEL MEDIATION ANALYTIC METHODS THAT INCORPORATE PATIENT, PROVIDER, AND SYSTEM LEVEL FACTORS WILL BE UTILIZED TO EVALUATE MECHANISMS OF DISPARITIES IN HCC SCREENING AMONG ETHNIC MINORITIES AND NON-ENGLISH SPEAKING IMMIGRANTS. TO MITIGATE CONFOUNDING FOUND IN OBSERVATIONAL ANALYSES, INNOVATIVE CASUAL INFERENCE TECHNIQUES WILL BE APPLIED. SIGNIFICANCE: DESPITE THE HIGH BURDEN OF HCC AMONG ETHNIC MINORITIES AND NON-ENGLISH SPEAKING IMMIGRANTS AND THE OBSERVED LOWER RATES OF HCC SCREENING AMONG THESE POPULATIONS, IT REMAINS UNCLEAR WHAT THE DRIVERS OF THESE DISPARITIES ARE. TO OUR KNOWLEDGE, NO STUDIES EXIST THAT COMPREHENSIVELY EVALUATE THE COMPLEX INTERPLAY BETWEEN PATIENT, PROVIDER, AND SYSTEM LEVEL FACTORS THAT MEDIATE ETHNIC DISPARITIES IN RECEIPT OF HCC SCREENING AS IS PROPOSED BY OUR NOVEL STUDY. LESSONS LEARNED FROM THE SYNERGY OF OUR STUDY AIMS WILL IDENTIFY POTENTIALLY MODIFIABLE FACTORS THAT CAN BE USED TO DESIGN A FUTURE MULTI-LEVEL PROSPECTIVE INTERVENTIONAL CLINICAL TRIAL TO IMPROVE HCC SCREENING AND HCC OUTCOMES IN CIRRHOSIS PATIENTS, PARTICULARLY AMONG ETHNIC MINORITIES AND UNDERSERVED SAFETY-NET POPULATIONS.

B LYMPHOCYTE-MEDIATED AUTOIMMUNITY IN PAIN AFTER TRAUMA

LEVERAGING ROUTINE CLINICAL MATERIALS AND MOBILE TECHNOLOGY TO ASSESS CBT QUALITY

DEVELOPMENT OF A RISK FACTOR SCREEN FOR MENTAL HEALTH PROBLEMS AFTER SUDDEN ILLNESS OR INJURY

REGULATORY T CELLS AND PULMONARY HYPERTENSION - PROJECT SUMMARY / ABSTRACT CLINICAL AND PRECLINICAL STUDIES INDICATE THAT AUTOIMMUNITY AND CHRONIC INFLAMMATION, RESULTING FROM ABNORMALITIES IN REGULATORY T CELLS (TREGS), CONTRIBUTE TO THE DEVELOPMENT AND PROGRESSION OF PULMONARY ARTERIAL HYPERTENSION (PAH). TREG DYSFUNCTION AFFECTS MALES AND FEMALES DIFFERENTLY AND MAY ARISE BECAUSE OF PATHOGENIC GENE VARIANTS AND AN INFLAMED TISSUE MICROENVIRONMENT. TREG INFUSION, AS A CELL-BASED THERAPY, RESTORES IMMUNE REGULATION, REDUCES VASCULAR INFLAMMATION, AND PREVENTS ANIMALS FROM DEVELOPING PAH. IN A NOVEL TRANSGENIC RAT MODEL OF HEREDITARY PAH, MONOALLELIC MUTATIONS IN BONE MORPHOGENETIC PROTEIN RECEPTOR 2 (BMPR2) AND LUNG INFLAMMATION ELICIT SEVERE DISEASE. IN THESE BMPR2 MUTANT ANIMALS, AS WELL AS THE ATHYMIC RAT MODEL OF DISEASE, THE PREDISPOSITION TO PAH MAY RELATE TO ABNORMAL TREG DEVELOPMENT AND FUNCTION. INFUSION OF GENETICALLY- CORRECTED (BMPR2 WILDTYPE) TREGS INTO BMPR2 MUTANT ANIMALS, OR INJECTION OF TREGS INTO ATHYMIC RATS, RESTORES IMMUNE REGULATION, PREVENTS VASCULAR REMODELING AND AMELIORATES PAH. A NUMBER OF TREG-INFUSION CLINICAL TRIALS ARE BEING TESTED FOR AUTOIMMUNE AND INFLAMMATORY CONDITIONS AND HAVE SHOWN EARLY PROMISE. GIVEN THE FUTURE POTENTIAL OF TREG THERAPY IN TREATING HUMAN PAH, THIS PROPOSAL TESTS THE HYPOTHESIS THAT GENETIC AND ENVIRONMENTAL CUES TRIGGER TREG ABNORMALITIES THAT EXACERBATE PAH AND THAT RESTORATION OF TREG FUNCTION MAY BE SUFFICIENT TO REVERSE SEVERE DISEASE. THIS PROPOSAL INVESTIGATES HOW GENETIC (BMPR2 MUTATIONS) AND ENVIRONMENTAL (PULMONARY INFLAMMATION) RISK FACTORS CONTRIBUTE TO TREG DERANGEMENTS AND A PREDISPOSITION TO PAH, AND HOW TREG INFUSION CAN LIMIT VASCULAR INJURY AND REVERSE PAH. PROPOSED STUDIES ADDRESS A PREVIOUSLY UNDOCUMENTED ROLE OF BMPR2 SIGNALING IN ADAPTIVE IMMUNE CELLS (I.E., TREGS). SPECIFIC AIM 1 EVALUATES THE MECHANISMS BY WHICH TREG IMMUNITY IN PAH IS AFFECTED BY BMPR2 MUTATIONS, CHRONIC LUNG INFLAMMATION AND SEX-RELATED FACTORS. SPECIFIC AIM 1 HAS TWO SUBAIMS WHICH STUDY THYMIC TREG DEVELOPMENT (AIM 1A) AND PULMONARY TREG PHENOTYPE AND FUNCTION (AIM 1B) IN PAH. BY UNDERSTANDING HOW TREG INFUSION QUELLS LUNG INFLAMMATION AND PREVENTS VASCULAR INJURY, SPECIFIC AIM 2 DEVELOPS PROTOCOLS TO USE EX VIVO-EXPANDED TREGS TO TREAT ESTABLISHED PAH. SPECIFIC AIM 2 HAS THREE SUBAIMS WHICH FIRST PROPOSES TO LABEL AND TRACK INFUSED TREGS AFTER ADOPTIVE TRANSFER (AIM 2A), THEN TO ASSESS TREG PROTECTIVE EFFECTS ON PULMONARY ARTERIAL VASCULAR CELLS (AIM 2B), AND, FINALLY, TO TEST THE EFFICACY OF VARIOUS TREG INFUSION STRATEGIES IN REVERSING ADVANCED PAH (AIM 2C).THESE STUDIES HELP UNIFY THE CONCEPTS OF GENETIC VULNERABILITY AND IMMUNE DYSREGULATION AS RELATED RISK FACTORS PREDISPOSING TO PAH, WHICH MAY OFFER CLEAR DIRECTIONS FOR FUTURE THERAPEUTIC AVENUES, MOST ESPECIALLY TREG IMMUNOTHERAPY.

REGULATION OF ROTAVIRUS REPLICATION, VIRULENCE, AND HOST RANGE RESTRICTION BY THE INNATE IMMUNE SYSTEM

INCREASING ACCESS TO EVIDENCED-BASED PTSD TREATMENT IN THE MILITARY: BEHAVIORAL HEALTH TECHNICIAN-DELIVERED WRITTEN EXPOSURE THERAPY

VIRTUALLY SUPERVISED EXERCISE FOR KIDNEY TRANSPLANT CANDIDATES - KIDNEY TRANSPLANTATION (KT) IS THE BEST TREATMENT FOR KIDNEY FAILURE; HOWEVER, DUE TO THE SHORTAGE OF ORGANS, MOST KT CANDIDATES MUST WAIT YEARS—SOMETIMES OVER A DECADE--TO RECEIVE A TRANSPLANT. KIDNEY FAILURE CAUSES MUSCLE WASTING. SO WHILE WAITING AND PERSEVERING WITH DIALYSIS TREATMENTS, KT CANDIDATES LOSE MUSCLE AND THUS PHYSICAL FUNCTION. BY THE TIME THEY UNDERGO TRANSPLANTATION, 47% OF KT CANDIDATES HAVE TROUBLE WALKING, BALANCING, AND/OR GETTING OUT OF A CHAIR. THESE LOSSES LEAD TO POOR POST-TRANSPLANT OUTCOMES, LONGER WAIT TIMES, OR EVEN WAITLIST REMOVAL. SUCH OUTCOMES ARE DEVASTATING FOR BOTH PATIENTS AND TRANSPLANT CENTERS, AND SADLY ARE NOT RARE. FURTHERMORE, SUCH EVENTS EXCESSIVELY IMPACT PERSONS OF BLACK, HISPANIC, OR ASIAN HERITAGE, WHO ARE MORE LIKELY TO DEVELOP KIDNEY FAILURE. WE KNOW WHAT REVERSES THESE LOSSES—EXERCISE. IDEALLY, TRANSPLANT CENTERS WOULD PROACTIVELY PRESCRIBE A PRE-TRANSPLANT EXERCISE PROGRAM. BUT UPTAKE OF EXERCISE INTERVENTIONS INTO KT CANDIDATE CARE REMAINS MINIMAL. THIS IS BECAUSE WE CONTINUE TO HAVE A KNOWLEDGE GAP ABOUT WHAT IS THE MOST EFFECTIVE WAY TO DELIVER AN EXERCISE INTERVENTION TO KT CANDIDATES. PATIENTS HAVE STATED THEY PREFER A HOME-BASED EXERCISE INTERVENTION, AS THIS FORMAT OVERCOMES THE BARRIER OF THE DIALYSIS SCHEDULE. YET PRIOR HOME-BASED INTERVENTIONS HAVE BEEN LIMITED BY LOW ADHERENCE, REDUCING IMPACT OF THE INTERVENTION. SUPERVISION BY AN INSTRUCTOR CAN INCREASE ADHERENCE BY ADDING THE ELEMENT OF ACCOUNTABILITY. BUT MOST HOME-BASED INTERVENTIONS HAVE BEEN UNSUPERVISED DUE TO COST. WITH THE ADOPTION OF VIRTUALLY DELIVERED HEALTH CARE, A NEW OPTION HAS EMERGED: VIRTUALLY SUPERVISED HOME-BASED EXERCISE INTERVENTIONS. USING A VIRTUAL MEETING PLATFORM, PERSONS CAN EXERCISE WHILE BEING SUPERVISED BY AN INSTRUCTOR ONLINE. FOR KT CANDIDATES, WHO COPE WITH THE INTENSE TIME AND TRAVEL REQUIREMENTS OF DIALYSIS, VIRTUALLY SUPERVISED EXERCISE MAY BE THE BEST OPTION TO EFFICIENTLY AND EFFECTIVELY IMPROVE THEIR PHYSICAL FUNCTION. OUR GOAL IS AN EFFECTIVE AND SCALABLE EXERCISE INTERVENTION THAT CAN BE USED BY TRANSPLANT CENTERS TO PREVENT THE LOSS OF PHYSICAL FUNCTION IN KT CANDIDATES. WE HAVE DEVELOPED AN INNOVATIVE CLINIC FOR KT CANDIDATES WHO ARE WITHIN TWO YEARS OF LIKELY TRANSPLANT, IDEAL FOR INSTILLING HEALTH BEHAVIOR CHANGE. LEVERAGING THIS CLINIC, WE WILL CONDUCT A 24-WEEK RANDOMIZED CONTROLLED TRIAL IN 80 KT CANDIDATES TO EVALUATE THE IMPACT OF A VIRTUALLY SUPERVISED HOME-BASED EXERCISE INTERVENTION USING A DELAYED INTERVENTION DESIGN. PARTICIPANTS WILL INITIALLY RECEIVE VIRTUALLY SUPERVISED EXERCISE OR HEALTH EDUCATION FOR 12 WEEKS, WHICH WILL BE THE PRIMARY ENDPOINT. AT THE END OF THE INITIAL 12-WEEK PERIOD, WE WILL EVALUATE THE IMPACT OF THE INTERVENTION ON PHYSICAL FUNCTION (AIM 1), DEPRESSIVE SYMPTOMS, AND FATIGUE (AIM 2). BOTH ARMS WILL THEN RECEIVE THE EXERCISE INTERVENTION IN THE SECOND 12 WEEKS TO ASSESS ADHERENCE AND ACCEPTABILITY (AIM 3). OUR END PRODUCT WILL BE AN INTERVENTION THAT CAN BE USED WIDELY TO IMPROVE THE PHYSICAL FUNCTION OF KT CANDIDATES, SUSTAINING THEIR HOPE AND WISH FOR A FUTURE FREE OF KIDNEY FAILURE.

HISTONE DEACETYLATION SIGNALING IN AGING AND CANCER PATHWAYS - OUR BROAD RESEARCH GOAL IS TO UNDERSTAND CHROMATIN REGULATORY MECHANISMS IN NUCLEAR AND EPIGENETIC PROGRAMS AND HOW THESE MECHANISMS ARE DEREGULATED IN AGING AND DISEASE. A FUNDAMENTAL MECHANISM FOR REGULATING CHROMATIN INVOLVES THE REVERSIBLE MODIFICATION OF HISTONES BY CHEMICAL MOIETIES SUCH AS ACETYL-, METHYL-, AND PHOSPHO-GROUPS. THESE DIFFERENT HISTONE MARKS ARE LINKED TO DISCRETE CHROMATIN STATES AND REGULATE THE ACCESSIBILITY OF DNA TO TRANSACTING FACTORS. IN BUDDING YEAST, HISTONE DEACETYLATION BY THE CHROMATIN SILENCING FACTOR SIR2 PREVENTS GENOMIC INSTABILITY AND AGING, AND IN MAMMALS, DE-REGULATION OF HISTONE ACETYLATION IS LINKED TO CELLULAR SENESCENCE AND AGING-RELATED PATHOLOGIES FROM NEURODEGENERATION TO CANCER. HERE, WE FOCUS ON SIRT7, A CHROMATIN REGULATORY, LYSINE DEACETYLASE ENZYME IN THE SIR2 FAMILY OF AGING-REGULATORY FACTORS. THIS PROJECT WILL STUDY NEW ROLES OF SIRT7-DEPENDENT HISTONE DEACETYLATION IN CHROMATIN REGULATORY MECHANISMS THAT ARE DEREGULATED IN AGING AND AGE-ASSOCIATED CANCER BIOLOGY. INACTIVATION OF SIRT7 IN MICE LEADS TO GENOMIC INSTABILITY, SHORTENED LIFESPAN AND AGING-RELATED PHENOTYPES, AND PRELIMINARY STUDIES SUGGEST THAT INCREASED SIRT7 PROTECTS AGAINST AGING PATHOLOGIES IN MICE. HOWEVER, SIRT7 CAN ALSO SUSTAIN ONCOGENIC TRANSCRIPTIONAL PROGRAMMING IN CANCER CELLS. THUS, UNCOVERING DISTINCT PATHWAYS OF SIRT7 CHROMATIN REGULATION, MAY BE IMPORTANT TO DISSECT PLEIOTROPIC FUNCTIONS OF SIRT7 IN AGING AND CANCER PATHWAYS. RECENTLY, WE IDENTIFIED A NOVEL SUBSTRATE OF SIRT7, ACETYLATED LYSINE K36 OF HISTONE H3 (H3K36AC), WHICH IS DRAMATICALLY HYPER-ACETYLATED UPON SIRT7-INACTIVATION. H3K36AC IS IMPLICATED IN CHROMATIN REMODELING AND DNA DAMAGE RESPONSES IN YEAST, BUT ITS REGULATION AND FUNCTIONS IN MAMMALIAN BIOLOGY ARE LARGELY OBSCURE. IN PRELIMINARY STUDIES WE FOUND THAT THE INCREASED H3K36 ACETYLATION IN SIRT7- DEFICIENT CELLS IS COUPLED TO DECREASED DI-METHYLATION AT THIS RESIDUE (H3K36ME2), A CHROMATIN MODIFICATION THAT HAS IMPORTANT ROLES IN GENE ACTIVATION, DNA METHYLATION AND ONCOGENIC TRANSFORMATION. MOREOVER, SIRT7 INTERACTS PHYSICALLY WITH THE ONCOPROTEIN NSD2, THE ENZYME THAT GENERATES THE BULK OF H3K36ME2 IN MANY CELL TYPES. HERE, WE WILL INVESTIGATE A NEW MODEL THAT SIRT7 CLEARS ACETYLATION AT H3K36 FROM LARGE SWATHS OF CHROMATIN TO HELP PRIME NSD2-CATALYZED METHYLATION AT H3K36. IN AIM 1, WE EXPLORE THE CONNECTION OF SIRT7 AND NSD2 IN AGING-RELATED PROCESSES USING GENOMIC, CELLULAR AND MOUSE SYSTEMS, AND IN AIM 2, WE TEST THE ROLE OF SIRT7-H3K36-NSD2 METHYLATION AXIS IN DRIVING LUNG CARCINOMA IN VIVO, USING PRE-CLINICAL MOUSE AND HUMAN CANCER MODELS. BY UNCOVERING DISTINCT PATHWAYS OF SIRT7 CHROMATIN REGULATION, THIS PROJECT MAY SUGGST STRATEGIES TO SELECTIVELY ENHANCE FUNCTIONS OF SIRT7 THAT ARE PROTECTIVE IN AGING WITHOUT PROMOTING ONCOGENIC SIRT7 ACTIVITIES. TOGETHER, THESE STUDIES SHOULD PROVIDE INSIGHTS INTO FUNDAMENTAL CHROMATIN MECHANISMS IN AGING AND CANCER BIOLOGY.

A NEW FRAMEWORK FOR UNDERSTANDING THE MECHANISMS OF DIASTOLIC DYSFUNCTION

A CRITICAL ROLE FOR LEUKOTRIENE B4 IN LYMPHEDEMA

A CRITICAL ROLE FOR HYPOXIA-INDUCIBLE FACTORS IN LYMPHEDEMA - PROJECT SUMMARY / ABSTRACT LYMPHEDEMA IS A CHRONIC AND DEBILITATING CONDITION CURRENTLY WITHOUT APPROVED MEDICAL THERAPIES. LYMPHATIC DRAINAGE INSUFFICIENCY, CAUSED BY INFLAMMATION AND LYMPHATIC ENDOTHELIAL CELL (LEC) DYSFUNCTION, IS THE MAIN FACTOR PROMOTING THE PROGRESSION OF LYMPHEDEMA. LEC-DERIVED HYPOXIA-INDUCIBLE FACTOR (HIF)-2A IS REQUIRED FOR PROPER LYMPHATIC DEVELOPMENT AND HOMEOSTASIS; THE DECLINE OF LEC HIF-2A, OBSERVED IN LYMPHEDEMA, MAY BE DIRECTLY INVOLVED WITH DISEASE PROGRESSION. IN EXPERIMENTAL MODELS, REDUCING HIF-2A EXPRESSION AGGRAVATES LYMPHATIC DRAINAGE INSUFFICIENCY AND EXACERBATES ACCUMULATING INTERSTITIAL FLUID. ANTI-INFLAMMATORY KETOPROFEN THERAPY WAS RECENTLY SHOWN TO BE EFFECTIVE IN LYMPHEDEMA, AND TREATED PATIENTS SHOW INCREASED LEC HIF-2A EXPRESSION IN THEIR SKIN BIOPSIES. THE STUDIES PROPOSED IN THIS GRANT ARE DESIGNED TO ADDRESS FUNDAMENTAL QUESTIONS ABOUT WHY LEC HIF-2A IS DECREASED IN LYMPHEDEMA AND HOW THIS REDUCTION INFLUENCES LYMPHATIC DRAINAGE. THE GRANT HYPOTHESIS IS THAT SUPPRESSED LEC HIF-2A EXPRESSION, CAUSED BY INFLAMMATORY MEDIATORS, IMPAIRS LYMPHATIC DRAINAGE BY PROMOTING LEC PHENOTYPIC TRANSFORMATION AND ABNORMAL CELLULAR ENERGETICS. SPECIFIC AIM 1 IS TO EXPLORE THE MECHANISMS BY WHICH INFLAMMATION INHIBITS LEC HIF-2A EXPRESSION AND MAP HIF-2A-REGULATED GENE NETWORKS IN LECS. AIM 2 WILL INVESTIGATE HOW LEC HIF-2A REDUCTION MAY CAUSE LEC PHENOTYPIC TRANSFORMATION, PROMOTE LYMPHATIC VASCULAR REMODELING, AND AGGRAVATE LYMPHATIC DRAINAGE INSUFFICIENCY. AIM 3 WILL STUDY HOW LEC HIF-2A REDUCTION AFFECTS LYMPHATIC STRUCTURE AND FUNCTION BY PROMOTING ABNORMAL CELLULAR METABOLISM. COLLECTIVELY, THE PROPOSED STUDIES ARE EXPECTED TO ADVANCE THE UNDERSTANDING OF THE ROLE THAT HIF-2A PLAYS IN LYMPHEDEMA WITH THE RATIONALE THAT THE KNOWLEDGE GAINED CAN FACILITATE MUCH- NEEDED THERAPEUTIC DEVELOPMENT.

CELLS PROCESSING HIGH DENSITY LIPOPROTEINS

DEPRESCRIBING CARDIOVASCULAR MEDICATIONS AMONG PERSONS WITH AND WITHOUT ALZHEIMER'S DISEASE AND RELATED DEMENTIAS IN LONG-TERM CARE - PROJECT SUMMARY/ABSTRACT THE USE OF PREVENTIVE CARDIOVASCULAR MEDICATIONS AMONG NURSING HOME RESIDENTS WITH ALZHEIMER'S DISEASE AND ALZHEIMER'S DISEASE RELATED DEMENTIAS (AD/ADRD) PRESENTS A CLINICAL CONUNDRUM. ON ONE HAND, THE MAJORITY OF NURSING HOME RESIDENTS WITH AD/ADRD HAVE A HISTORY OF CARDIOVASCULAR DISEASE, OR ARE AT HIGH RISK OF EVENTS. ON THE OTHER HAND, RESIDENTS WITH AD/ADRD ARE AT HIGHER RISK FOR MEDICATION-RELATED ADVERSE EVENTS AND HAVE LESS OPPORTUNITY TO BENEFIT FROM PREVENTIVE MEDICATIONS SUCH AS ASPIRIN AND STATINS. THIS HAS LED SOME PATIENTS AND THEIR PROVIDERS TO CONSIDER DEPRESCRIBING. DEPRESCRIBING IS THE PROCESS OF STOPPING A MEDICATION WHEN IT IS NO LONGER USEFUL, OR WHEN THE RISKS OUTWEIGH THE BENEFITS. DESPITE THE THOUSANDS OF RANDOMIZED CONTROLLED TRIALS THAT HAVE BEEN CONDUCTED FOR STARTING CARDIOVASCULAR MEDICATIONS, ONLY A HANDFUL HAVE BEEN CONDUCTED FOR DEPRESCRIBING. THE EFFECTS OF DEPRESCRIBING CARDIOVASCULAR MEDICATIONS, AND WHICH PATIENTS COULD BENEFIT, IS UNKNOWN. THE GOAL OF THIS RENEWAL APPLICATION IS TO PROVIDE NOVEL, UNPARALLELED EVIDENCE ON THE EFFECTS OF DEPRESCRIBING CARDIOPROTECTIVE MEDICATIONS IN PATIENTS WITH AND WITHOUT AD/ADRD. WE WILL BUILD UPON OUR PRIOR SUCCESSFUL COHORT OF NURSING HOME RESIDENTS (NEARLY HALF OF WHOM HAVE AD/ADRD) TO CONDUCT THIS RESEARCH IN APPROXIMATELY 150,000 RESIDENTS AGED 65 YEARS AND OLDER IN VETERAN'S HEALTH ADMINISTRATION (VA) NURSING HOMES. THE VA IS THE ONLY FEASIBLE SETTING TO EXECUTE THIS RESEARCH BECAUSE OF THE ABILITY TO LINK INPATIENT AND OUTPATIENT DATA WITH DATA FROM THE NURSING HOME. MOREOVER, UNLIKE DATA FROM THE CENTERS FROM MEDICAID/MEDICARE, THE VA INCLUDES DATA ON VITAL SIGNS, LABORATORY MEASUREMENTS, AND BAR-CODED MEDICATION ADMINISTRATIONS. WE WILL START WITH DESCRIPTIVE EPIDEMIOLOGY REGARDING THE FREQUENCY OF DEPRESCRIBING AS WELL AS THE COMMON PRECIPITATING EVENTS AND CHARACTERISTICS OF RESIDENTS WHOM ARE COMMONLY DEPRESCRIBED CARDIOVASCULAR MEDICATION. THIS WILL IDENTIFY WHICH DRUGS ARE THE MOST IMPORTANT TARGETS FOR FURTHER RESEARCH, AND THE POPULATIONS IN WHICH THERE IS CLINICAL UNCERTAINTY. TRADITIONAL CLINICAL TRIALS ARE CHALLENGING IN RESIDENTS WITH AD/ADRD DUE TO THEIR CARE COMPLEXITY AND OFTEN IMPAIRED DECISION-MAKING CAPACITY. THUS, WE WILL NEXT IMPLEMENT TARGET TRIAL EMULATION OF DEPRESCRIBING CARDIOVASCULAR MEDICATIONS; THIS IS A METHOD OF ESTIMATING TRIAL EFFECTS USING OBSERVATIONAL DATA. THIS APPROACH APPLIES A STRUCTURED ANALYTIC PROCESS TO ADDRESS COMMON BIASES IN OBSERVATIONAL RESEARCH AND LEVERAGES CAUSAL INFERENCE STATISTICS TO ADDRESS CONFOUNDING BY INDICATION. WE HAVE SUCCESSFULLY APPLIED THIS APPROACH TO STUDY THE EFFECT OF CHANGES IN ANTIHYPERTENSIVES IN OLDER RESIDENTS WITH AND WITHOUT AD/ADRD. IN THIS RENEWAL APPLICATION, WE WILL STUDY THE EFFECTS OF DEPRESCRIBING MULTIPLE CARDIOPROTECTIVE MEDICATIONS, SPECIFICALLY, ANTIPLATELETS INCLUDING ASPIRIN, STATINS, AND ANTICOAGULANTS IN NURSING HOME RESIDENTS WITH AND WITHOUT AD/ADRD.

THE NEUROBIOLOGY OF PSYCHOTHERAPY: EMOTIONAL REACTIVITY AND REGULATION IN PTSD

COMPLEMENT COMPONENTS AS MEDIATORS OF CELL AND TISSUE AGING

TUMOR AND IMMUNE PROGRAMMING OF TUMOR-ASSOCIATED ENDOTHELIUM

ULTRASHORT LIGHT PULSES AS A PERSONALIZED COUNTERMEASURE FOR CIRCADIAN DESYNCHRONY

NIH DIRECTOR'S PIONEER AWARD

NOVEL LYMPHOCYTE CHEMOATTRACTANT RECEPTOR AND LIGAND - PROJECT SUMMARY/ABSTRACT THE IMMUNE SYSTEM AT MUCOSAL SITES HAS EVOLVED TO MEDIATE RAPID IMMUNITY TO INVADING PATHOGENS, WHILE LIMITING OVER-REACTIVE RESPONSES THAT DRIVE CHRONIC INFLAMMATION. MECHANISMS OF LYMPHOCYTE TRAFFICKING ARE ESSENTIAL FOR THE FUNCTION AND SYSTEMIC INTEGRATION OF THE IMMUNE SYSTEM, AND IN PARTICULAR FOR TARGETING IMMUNE RESPONSES TO SPECIFIC MUCOSAL AND EPITHELIAL ORGANS AND TISSUES IN THE BODY. DESPITE IDENTIFICATION OF TRAFFICKING RECEPTORS FOR THE SMALL INTESTINES, COLON, AND SKIN, WE HAVE LIMITED KNOWLEDGE OF MECHANISMS OF LYMPHOCYTE RECRUITMENT TO THE LUNG AND TO MOST NON-INTESTINAL MUCOSAL SITES. DEFINING MECHANISMS CONTROLLING ORGANOTYPIC LYMPHOCYTE HOMING TO THESE TISSUES WHICH WILL BE CRITICAL FOR DEVELOPING THERAPIES TO CONTROL IMMUNE PATHOLOGIES. WE HAVE IDENTIFIED A NOVEL LYMPHOCYTE CHEMOATTRACTANT RECEPTOR AND ITS CHEMOATTRACTANT LIGAND, SELECTIVELY EXPRESSED IN LUNG, AIRWAYS, UPPER GI TRACT, GENITOURINARY MUCOSAE AND MUCOSA-ASSOCIATED GLANDS INCLUDING THE PANCREAS AND SALIVARY GLANDS. UNDER AIM 1 WE WILL MECHANISTICALLY PROBE THE RECEPTOR-LIGAND INTERACTIONS FOCUSING ON THE SPECIFICITY AND SIGNALING PATHWAYS ACTIVATED BY THE NOVEL RECEPTOR AND ITS ROLE AS A LYMPHOCYTE VS MYELOID CELL CHEMOTACTIC RECEPTOR. STRUCTURE-FUNCTION STUDIES WILL IDENTIFY LIGAND DOMAINS FOR RECEPTOR BINDING AND ACTIVATION. AIM 2 WILL DEFINE THE REGULATION OF THE RECEPTOR IN THE MOUSE, AND ITS ROLE IN LYMPHOCYTE POPULATION OF AND HOMING TO NON-LYMPHOID TISSUES DURING HOMEOSTASIS AND IN THE SETTING OF CHRONIC MULTI-ORGAN AUTOIMMUNE INFLAMMATION. THE ROLES OF THE PATHWAY IN IMMUNE CELL DEVELOPMENT WILL BE PROBED IN MIXED BONE MARROW CHIMERAS IN WHICH RECEPTOR-DEFICIENT VS WILD TYPE STEM CELLS COMPETE FOR RECONSTITUTION OF IMMUNE COMPARTMENTS IN LYMPHOID AND NON-LYMPHOID TISSUES. AIM 3 WILL ELUCIDATE THE TISSUE- AND CELL SUBSET- SPECIFIC EXPRESSION OF THE RECEPTOR AND LIGAND IN HUMANS. REGULATION OF THE RECEPTOR WILL BE STUDIED IN ORGANOTYPIC LYMPHOCYTE DEVELOPMENT AND ACTIVATION, IN HOMEOSTASIS, AND IN PULMONARY IMMUNE CHALLENGE AND INFECTION. WE WILL EMPLOY INNOVATIVE APPROACHES AND DEVELOP NEW TOOLS TO ADDRESS THE FUNDAMENTAL ROLE OF THE NOVEL PATHWAY IN THE IMMUNE SYSTEM, AND WHERE POSSIBLE, TRANSLATE OUR FINDINGS FROM MICE INTO HUMANS. RESULTS FROM THESE STUDIES WILL SIGNIFICANTLY ADVANCE OUR UNDERSTANDING OF THE SYSTEMIC ORGANIZATION AND INTEGRATION OF THE MUCOSAL IMMUNE SYSTEM. THE MECHANISMS IDENTIFIED WILL PROVIDE THE BASIS FOR NEW APPROACHES TO MANIPULATING IMMUNITY AND INFLAMMATION IN THE LUNGS AND EXTRAINTESTINAL MUCOSAE.

HOMECOMING LINE: TELEPHONE SUPPORT FOR VETERANS

RANDOMIZED, CONTROLLED TRIAL OF CBT TRAINING FOR PTSD PROVIDERS

MOLECULAR MECHANISMS OF MAMMALIAN SIRT6 FUNCTION

ALTERED ENS NEUROIMMUNE INTERACTIONS DISRUPT GASTROINTESTINAL MOTILITY IN ALZHEIMERS DISEASE - ABSTRACT GASTROINTESTINAL (GI) DISORDERS INCLUDING CONSTIPATION AND FECAL INCONTINENCE ARE COMMONLY FOUND IN PATIENTS WITH ALZHEIMER’S DISEASE (AD), THE MOST COMMON CAUSE OF DEMENTIA. THESE SAME DISORDERS ARE ALSO FREQUENTLY ENCOUNTERED IN THE ELDERLY, RAISING THE POSSIBILITY THAT A COMMON PROCESS MAY UNDERLIE GUT DISTURBANCES FOR BOTH AD AND AGING. IN HUMANS WITH AD AND AD ANIMAL MODELS, AMYLOID-SS (ASS) PLAQUES, ONE OF THE DISEASE HALLMARKS, HAVE BEEN DETECTED IN THE ENTERIC NERVOUS SYSTEM (ENS), AN AUTONOMOUS BRANCH OF THE PERIPHERAL NERVOUS SYSTEM THAT SPANS THE GI TRACT AND REGULATES GUT MOTILITY. ASS GUT ACCUMULATION APPEARS TO CAUSE ENS NEUROINFLAMMATION AND IMPAIRED GUT CONTRACTILITY BUT CURRENT LITERATURE PRECLUDES DEFINITIVE CONCLUSION. WHETHER AND HOW AD INVOLVES THE GUT IS OF INCREASING IMPORTANCE GIVEN EMERGING REPORTS THAT NEURODEGENERATIVE DISORDERS ARE TRANSMITTED FROM THE GUT TO THE BRAIN. THE PROPOSED MULTIDISCIPLINARY STUDY WILL INTEGRATE THE SCIENCE OF AD WITH THE BASIC BIOLOGY OF AGING. WE FOUND THAT AGE-RELATED CHANGES TO MUSCULARIS MACROPHAGES (MMS), A POPULATION OF TISSUE-RESIDENT MACROPHAGES IN THE ENS, DRIVE GERIATRIC ENS INFLAMMATION, WHICH IS ASSOCIATED WITH DISRUPTION OF GI MOTILITY AND IMPAIRED COGNITION. THIS MM ALTERATION IS DEPENDENT ON FACTORS IN THE MICROBIOTA AND MIRRORS AN AD DISEASED STATE FOUND IN MICROGLIA, THE PREDOMINANT MACROPHAGE POPULATION OF THE BRAIN. FOLLOWING ON THESE FINDINGS, WE POSIT THAT AD CAUSES MM CHANGES SIMILAR TO THOSE SEEN IN GERIATRIC SUBJECTS THAT RESULT IN ENS NEUROINFLAMMATION, ALTERED GI MOTILITY AND IMPAIRED COGNITION, AND DEPEND ON HOST-MICROBIOTA INTERACTIONS. THIS HYPOTHESIS WILL BE TESTED WITH THREE AIMS PERFORMED IN THE APP/PS1 AD MOUSE MODEL. FIRST, THE INVESTIGATORS WILL EVALUATE WHETHER AD CAUSES ENS NEUROIMMUNE CHANGES CHARACTERIZED BY A MM GERIATRIC DISEASE STATE (GDS). THEY WILL ASSESS WHETHER ALTERATIONS IN MMS LEAD TO GERIATRIC ENS NEUROINFLAMMATION WITH INFILTRATION OF IMMUNE CELLS AND ELEVATED PRO- INFLAMMATORY CYTOKINES, AND ENTERIC NEURONAL LOSS. SECOND, THE INVESTIGATORS WILL ASSESS WHETHER DISRUPTION IN GUT MOTILITY PRECEDES IMPAIRED COGNITION. FINALLY, USING EXPERIMENTAL MANIPULATION OF THE MICROBIOTA, THE INVESTIGATORS WILL EXPLORE THE ROLE OF HOST-MICROBIOTA INTERACTIONS IN AD-ASSOCIATED GI DISEASE AND THEIR RELATIONSHIP TO COGNITION. SPECIFICALLY, THE INVESTIGATORS WILL EXAMINE WHETHER AND HOW AD DISEASE PROGRESSION IS AFFECTED BY CHRONIC ANTIBIOTICS, FECAL MICROBIOTA TRANSPLANTATION OF STOOL FROM YOUNG OR OLD MICE, OR PROBIOTIC SUPPLEMENTATION WITH AKKERMANSIA MUCINOPHILA, A MICROBIOTA COMPONENT REDUCED IN OLD MICE. SUCCESSFUL COMPLETION OF THE PROPOSED STUDIES WILL IDENTIFY CRITICAL PATHOPHYSIOLOGICAL PATHWAYS THAT AFFECT THE GUT AND PRECEDE COGNITIVE DECLINE. THE RESULTS WILL INFORM NOVEL PREVENTION AND INTERVENTION STRATEGIES FOR AD AND AGING-ASSOCIATED DEMENTIA.

PROTEIN HOMEOSTASIS AND PROTEOTOXICITY MECHANISMS - PROTEIN MISFOLDING IS A PATHOGNOMONIC FEATURE OF NEURODEGENERATIVE DISEASES. THE MECHANISMS BY WHICH PROTEIN MISFOLDING CAUSES PROTEOTOXICITY AND NEURODEGENERATION ARE POORLY UNDERSTOOD. THE OVERALL GOAL OF OUR NEURODEGENERATION RESEARCH PROGRAM IS TO DECIPHER THE MECHANISMS THAT MAINTAIN PROTEIN QUALITY AND PREVENT PROTEOTOXICITY TO DEVELOP MECHANISM-BASED THERAPIES FOR THESE DISEASES. THE UNFOLDED PROTEIN RESPONSE (UPR) IS A CONSERVED INTRACELLULAR SIGNAL TRANSDUCTION MECHANISM ESSENTIAL FOR MAINTAINING PROTEIN FOLDING QUALITY. IN RESPONSE TO PROTEIN MISFOLDING, UPR INITIATES TRANSCRIPTIONAL AND TRANSLATIONAL PROGRAMS THAT ENHANCE THE PROTEIN FOLDING CAPACITY OF THE CELL; REMOVE AND DEGRADE MISFOLDED PROTEINS; AND SLOW THE PACE OF NEW PROTEIN TRANSLATION UNTIL PROTEOSTASIS IS RESTORED. IF PROTEIN MISFOLDING PERSISTS DESPITE THESE EFFORTS, UPR SIGNALING CAN TRIGGER APOPTOSIS. THESE FUNCTIONS IMPLICATE UPR AS A FUNDAMENTAL PATHOMECHANISM IN NEURODEGENERATION. IN PEOPLE, GENETIC VARIANTS IN THE UPR REGULATORY GENE, EIF2AK3, WHICH ENCODES THE PERK KINASE, INCREASE RISK FOR TAUOPATHIES. WE FOUND THAT EIF2AK3 TAUOPATHY RISK VARIANTS ENCODED FUNCTIONAL PERK HYPOMORPHS WITH BLUNTED SENSITIVITY TO ER STRESS/PROTEIN MISFOLDING THAT LEAD TO REDUCED KINASE ACTIVITY AND DOWNSTREAM UPR SIGNALING IN VITRO. FURTHERMORE, WE FOUND THAT INHIBITION OF PERK OR UPR SIGNALING INCREASED TAU AGGREGATION, VULNERABILITY TO ER STRESS, AND PROTEOTOXICITY IN CELLULAR MODELS. WE HYPOTHESIZE THAT PERK AND UPR SIGNALING PREVENTS TAU MISFOLDING AND NEURODEGENERATION. FURTHERMORE, OUR MODEL SUGGESTS THAT ENHANCING PERK AND UPR SIGNALING CAN PREVENT TAU NEUROPATHOLOGY AND THUS BENEFIT PATIENTS. TO TEST OUR HYPOTHESIS, WE WILL INVESTIGATE A NEW BRAIN ORGANOID MODEL OF TAUOPATHY WE DEVELOPED FROM PERK MUTANT STEM CELLS, WHERE WE FOUND SIGNIFICANT AT8+ TAU PROTEIN PATHOLOGY IN NEURONS AND OLIGODENDROGLIA. WE WILL ELUCIDATE THE CELLULAR AND MOLECULAR CAUSES FOR TAU MISFOLDING IN DIFFERENT BRAIN CELL TYPES IN THESE ORGANOIDS. THIS STEM CELL MODEL OF TAUOPATHY ALSO PROVIDES A PLATFORM TO IDENTIFY TREATMENTS TO PREVENT TAU PROTEIN AGGREGATION AND NEURODEGENERATION. WE RECENTLY IDENTIFIED NON-TOXIC CELL-PERMEABLE SMALL MOLECULES THAT ACTIVATE PERK SIGNAL TRANSDUCTION PATHWAY IN CELL CULTURE LINES. WE WILL TREAT PERK MUTANT BRAIN ORGANOIDS WITH THESE SMALL MOLECULE PERK/UPR ACTIVATING COMPOUNDS AND ASSESS IF TAU NEUROPATHOLOGY AND NEURODEGENERATION ARE MITIGATED. IN OUR FINAL AIM, WE WILL DETERMINE IF, WHEN, AND WHERE UPR DYSFUNCTION ARISES IN TAUOPATHY PATIENTS. WE WILL EVALUATE ALZHEIMER’S DISEASE AND RELATED TAUOPATHY BRAIN TISSUES AND TRANSCRIPTOMIC DATASETS FROM MULTIPLE ALZHEIMER’S DISEASE AND TAUOPATHY PATIENT BRAIN BANKS: WE WILL COMPARE UPR/PERK MOLECULAR SIGNATURES IN CONTROL VS ADVANCING TAUOPATHY PATIENTS TO QUANTIFY PERK AND UPR PROTEIN QUALITY CONTROL STRENGTH WITH PROGRESSIVE TAU PATHOLOGY. OUR STUDIES POSITIVELY IMPACT NEURODEGENERATION BY REVEALING HOW PROTEIN QUALITY CONTROL GENES AND PATHWAYS REGULATE TAUOPATHY PATHOGENESIS AND PROGRESSION. OUR STUDIES MAY IDENTIFY NEW DRUGS FOR TAUOPATHY PATIENTS THAT CAN BE RAPIDLY ADVANCED INTO CLINICAL TRIALS.

NOVEL MUCOSA-HOMING DENDRITIC CELL: DEVELOPMENT, TRAFFICKING AND FUNCTION

TREATMENTS FOR INSOMNIA, MEDIATORS, MODERATORS, AND QUALITY OF LIFE

FUNCTIONAL MAPPING AND PROTEIN ENGINEERING OF THROMBIN

ANDROGEN-ESTROGEN BALANCE IN CVD RISK

HYPO-LIPIDEMIC ACTIONS OF CREOSOTE BUSH-DERIVED NDGA

ROLE OF LONG-RANGE CHROMATIN INTERACTIONS IN GENETIC DISEASE

THE BENEFIT AND BURDEN OF ELECTRONIC REMINDERS FOR OPTIMIZING PATIENT CARE

THE ROLE OF THYMIC HOMING DENDRITIC CELLS IN ORAL TOLERANCE

TARGETING PCSK9 TRANSCRIPTION TO COMBAT HYPERCHOLESTEROLEMIA BY BERBERINE

IN-REACH FOR SUCCESSFUL AGING THROUGH EDUCATION(I-SAGE)

MULTIFACTOR RISK REDUCTION FOR OPTIMAL MANAGEMENT IN PAD

CHEMERIN IN TUMOR IMMUNITY AND SURVEILLANCE

MOLECULAR AND FUNCTIONAL CHARACTERIZATION OF CHEMERIN RECEPTORS

LARGE-SCALE CHARACTERIZATION OF AUTOANTIBODY RESPONSES IN RHEUMATOID ARTHRITIS

INFLAMMASOME ACTIVATION IN COMPLEX REGIONAL PAIN SYNDROME

EFFICACY OF TWICE WEEKLY HEMODIALYSIS IN PATIENTS WITH RESIDUAL KIDNEY FUNCTION

DNA VARIANTS AND AAA DISEASE

MOLECULAR REGULATION OF MYOGENIC DIFFERENTIATION

THE FUNCTION AND REGULATION OF PAX3 IN MUSCLE STEM CELLS

A NOVEL TOLERGENIC DENDRITIC CELL: BIOLOGY & THERAPEUTIC POTENTIAL

ASSISTANCE TO FIREFIGHTERS GRANT

INTENSIVE REFERRAL TO AL-ANON: BENEFITS TO CONCERNED OTHERS AND THEIR DRINKERS

TGF SIGNALING AS A NOVEL THERAPEUTIC TARGET FOR MILD TRAUMATIC BRAIN INJURY

CIRCULATORY REJUVENATING FACTORS FOR THE BRAIN

ACTIVATION OF BCL-2 IN HEMATOLOGIC MALIGNANCIES

LONG-TERM COGNITIVE EFFECTS OF MICROEMBOLIZATION ASSOCIATED WITH CAROTID STENTING

MICRORNA REGULATION OF NICOTINE ACCELERATED AAAS

TARGETING INFLAMMATORY ASTROCYTE REACTIVITY IN MILD TRAUMATIC BRAIN INJURY

ULTRASHORT (MSEC) LIGHT EXPOSURE AS A COUNTERMEASURE TO CIRCADIAN DESYNCHRONY

REGULATION OF T CELL CCR10 BY SUNLIGHT AND VITAMIN D

COMPLEMENT SYSTEM MODULATION OF NOCICEPTION AND INFLAMMATION AFTER INCISION

NIH DIRECTOR'S PIONEER AWARD (RMI)

INTERSECTING CLINICAL, GENOMIC, AND EXPERIMENTAL INVESTIGATION TO UNDERSTAND THE MECHANISMS AND IMPACT OF CORONARY ARTERY PATTERNING - PROJECT SUMMARY/ABSTRACT CORONARY ARTERY DISEASE (CAD) REMAINS A LEADING CAUSE OF DEATH DESPITE THE AVAILABILITY OF LIFESAVING PHARMA- COLOGICAL AND MECHANICAL INTERVENTIONS. COMPLEMENTARY TREATMENTS ARE DESPERATELY NEEDED, PARTICULARLY FOR INDIVIDUALS WITH ADVANCED DISEASE. HERE, WE PROPOSE FOUNDATIONAL WORK TOWARD REALIZING A HYPOTHETICAL `MEDI- CAL REVASCULARIZATION' THAT COULD ONE DAY HELP PATIENTS WITH CAD BY EXTENDING CORONARY ARTERIAL NETWORKS OR IN- DUCING NATURAL BYPASSES THROUGH COLLATERAL ARTERIES. AN OBSTACLE TO `MEDICAL REVASCULARIZATION' IS THE LACK OF KNOWN TARGETABLE PATHWAYS THAT CAN STIMULATE CORONARY ARTERY GROWTH AND COLLATERALIZATION. OUR PRINCIPAL RA- TIONALE FOR OVERCOMING THIS KNOWLEDGE GAP—BASED ON OUR PRIOR RESEARCH INDIVIDUALLY AND AS A TEAM—IS THAT STUDYING CORONARY ARTERY FORMATION DURING EMBRYONIC AND FETAL DEVELOPMENT SHOULD IDENTIFY PATHWAYS FOR RE- FORMING CORONARY ARTERIES DURING DISEASE. SINCE CORONARY DEVELOPMENT GENERATES VARIATIONS IN ANATOMY, WE PROPOSE TO IDENTIFY REGENERATIVE PATHWAYS BY STUDYING THE HUMAN POPULATION GENETICS OF CORONARY ARTERY ANA- TOMICAL VARIATION, OR PATTERNING, AND THEN INVESTIGATING THE UTILITY OF IDENTIFIED GENETIC REGULATORS USING PRE-CLINI- CAL EXPERIMENTATION. OUR LONG-TERM GOAL IS TO USE THIS INFORMATION TO DEVELOP NEW TRANSLATIONAL PATHWAYS. WE WILL FIRST ACCURATELY CLASSIFY THREE CORONARY PATTERNING PHENOTYPES ROUTINELY DOCUMENTED DURING CORONARY ANGI- OGRAPHY IN THE VETERAN AFFAIRS HEALTH CARE SYSTEM, INCLUDING ANOMALOUS CORONARY ARTERIES, CORONARY DOMI- NANCE, AND CORONARY COLLATERALIZATION, AND ASSESS THEIR IMPACT ON CLINICAL CARDIOVASCULAR OUTCOMES NATIONWIDE (AIM 1). NEXT, WE WILL CROSS REFERENCE THIS DATASET WITH THE MILLION VETERAN PROGRAM TO IDENTIFY THE GENETIC DE- TERMINANTS THROUGH GENOME WIDE ASSOCIATION STUDIES (GWAS) IN >90,000 PARTICIPANTS OF DIVERSE ANCESTRY, IN- CLUDING >16,000 AFRICAN AND >6,000 HISPANIC AMERICAN VETERANS. GENETIC DISCOVERY WILL BE EXTENDED INTO THE MULTI-ANCESTRY PENN MEDICINE BIOBANK THROUGH REPLICATION AND META-ANALYSIS. DOWNSTREAM ANALYSES ON GWAS SUMMARY STATISTICS WILL IDENTIFY THE MOST COMPELLING CANDIDATE CAUSAL GENES AT EACH SUSCEPTIBILITY LOCUS (AIM 2). THE FUNCTION OF PRIORITIZED CANDIDATE GENES WILL BE COMPREHENSIVELY TESTED USING MOUSE GENETIC MANIPULA- TIONS IN DEVELOPMENTAL AND INJURY MODELS AND A NOVEL HUMAN IPSC-TO-ARTERY DIFFERENTIATION METHOD (AIM 3). THE PROJECT IS INNOVATIVE BECAUSE IT LEVERAGES A COMBINATION OF THE NATION'S LARGEST INTEGRATED HEALTH CARE SYS- TEM, THE OLDEST ELECTRONIC HEALTH RECORD SYSTEM—INCLUDING ONE OF THE MOST COMPREHENSIVE REGISTRIES OF CORO- NARY CATHETERIZATION PROCEDURES—AND THE WORLD'S LARGEST ACTIVE BIOBANK TO CONDUCT TRANSLATIONAL RESEARCH. AD- DITIONALLY, CANDIDATE GENES WILL BE EXPERIMENTALLY VALIDATED IN DEVELOPMENTAL AND PRE-CLINICAL ASSAYS FOR CORO- NARY ARTERY AND COLLATERAL FORMATION. THIS RESEARCH IS SIGNIFICANT BECAUSE IT WILL SET THE STAGE FOR THE DEVELOP- MENT OF NOVEL THERAPIES ABLE TO PROMOTE THE GROWTH OF ARTERIES THAT COULD SUBSTANTIALLY IMPROVE BOTH THE QUALITY AND QUANTITY OF LIFE IN INDIVIDUALS SUFFERING FROM CAD.

THE PTSD PRACTITIONER REGISTRY: AN INNOVATIVE TRACKING, DISSEMINATION, AND SUPPORT TOOL FOR PROVIDERS IN MILITARY AND NONMILITARY SETTINGS.

MUCOSAL AND SYSTEMIC IMMUNE RESPONSES TO INFLUENZA VIRUS

NONINVASIVE CORTICAL STIMULATION TO IMPROVE MEMORY IN MILD COGNITIVE IMPAIRMENT

ONLINE YOGA VS ACCEPTANCE AND COMMITMENT THERAPY FOR TREATING CHRONIC MUSCULOSKELETAL PAIN - PROJECT SUMMARY/ABSTRACT MORE THAN 50% OF VETERANS IN PRIMARY CARE REPORT EXPERIENCING CHRONIC PAIN. CHRONIC PAIN IS TREATMENT- RESISTANT, AND MEDICATIONS OFTEN INCLUDE THE RISK OF ADDICTION OR OVERDOSE. IN RECOGNITION OF THE SCOPE OF THIS PROBLEM, THE VA HAS ENCOURAGED THE USE OF COMPLEMENTARY AND INTEGRATIVE HEALTH (CIH) IN CONJUNCTION WITH CONVENTIONAL PAIN TREATMENTS. YOGA IS A POPULAR CIH APPROACH AND IS EFFECTIVE IN TREATING MANY TYPES OF CHRONIC PAIN, INCLUDING MUSCULOSKELETAL PAIN WHICH IS THE MOST COMMON TYPE. WHILE ALL YOGA IS POTENTIALLY THERAPEUTIC, ONLINE DELIVERY OF YOGA (“TELEYOGA”) HAS MANY ADVANTAGES OVER IN-PERSON YOGA; IT CAN REACH INDIVIDUALS WHO LACK ACCESS TO HEALTHCARE DUE TO GEOGRAPHY, POOR HEALTH, OR OTHER BARRIERS. THE USE OF TELEHEALTH HAS BECOME WIDESPREAD, AND THE HIGH UTILIZATION OF YOGA FOR TREATING CHRONIC PAIN ILLUSTRATES A NEED FOR HIGH QUALITY EVIDENCE FOR THE EFFICACY OF TELEYOGA. HOWEVER, NO RANDOMIZED CLINICAL TRIAL (RCT) HAS ASKED WHETHER TELEYOGA IS AN EFFECTIVE TREATMENT FOR CHRONIC MUSCULOSKELETAL PAIN. TO ADDRESS THIS RESEARCH GAP, WE RECENTLY COMPLETED AN NCCIH-FUNDED R34 FEASIBILITY STUDY OF TELEYOGA FOR TREATING CHRONIC MUSCULOSKELETAL PAIN IN VETERANS. WE SHOWED THAT A SYNCHRONOUS TELEYOGA PROTOCOL DELIVERED IN REAL-TIME OVER ZOOM TO GROUPS OF VETERANS WAS A FEASIBLE TREATMENT AND THAT IT HAD PROMISE FOR ALLEVIATING PAIN. WE NOW PROPOSE A FULLY POWERED RCT TO EVALUATE THE EFFICACY OF TELEYOGA FOR CHRONIC MUSCULOSKELETAL PAIN. WE ARGUE THE MOST IMPACTFUL DESIGN IS TO COMPARE TELEYOGA TO A STANDARD PAIN TREATMENT. WE WILL USE ACCEPTANCE AND COMMITMENT THERAPY (ACT) AS A COMPARISON GROUP AS IT IS THE MOST ROBUST NONPHARMACOLOGICAL TREATMENT AVAILABLE FOR MUSCULOSKELETAL PAIN, IT IS RECOMMENDED BY THE VA AND AMERICAN PSYCHOLOGICAL ASSOCIATION AND HAS DEMONSTRATED EFFICACY IN VETERAN POPULATIONS. A NONINFERIORITY DESIGN WILL BE USED AS APPROPRIATE FOR TRIALS IN WHICH THE PRIMARY OBJECTIVE IS TO SHOW A NOVEL INTERVENTION (TELEYOGA) IS CLINICALLY NONINFERIOR TO A STANDARD WELL-ESTABLISHED TREATMENT (ACT). WE WILL RECRUIT AND RANDOMIZE 328 VETERANS WITH CHRONIC MUSCULOSKELETAL PAIN TO ONE OF TWO GROUPS (TELEYOGA, ACT; N=164 PER GROUP) AND TREATMENT WILL BE DELIVERED TO GROUPS OF APPROXIMATELY 5 INDIVIDUALS ONLINE OVER 8-WEEKS (ACT) OR 12-WEEKS (TELEYOGA). MEASURES WILL BE TAKEN AT BASELINE, END-OF-TREATMENT, AND 6 MONTHS AFTER TREATMENT, AND WILL INCLUDE PAIN INTERFERENCE WITH DAILY ACTIVITIES (PRIMARY OUTCOME), PAIN SEVERITY, DEPRESSION, SLEEP, AND DROPOUT. WE EXPECT PAIN INTERFERENCE WILL IMPROVE IN BOTH GROUPS FOLLOWING TREATMENT, AND THAT TELEYOGA WILL NOT BE CLINICALLY INFERIOR TO ACT. OVERALL, THIS TRIAL SEEKS TO PROVIDE HIGH-QUALITY EVIDENCE FOR THE EFFICACY OF TELEYOGA AS A TREATMENT FOR CHRONIC MUSCULOSKELETAL PAIN. THE RESULTS WILL HELP PROMOTE TELEYOGA AS A SCALABLE, ACCESSIBLE, AND EFFECTIVE TREATMENT.

DEFINING THE CONTRIBUTION OF ENAC TO ADH-MEDIATED WATER AND SODIUM EXCRETION

BECLIN 1 NEURODEGENERATION AND ALZHEIMER'S DISEASE

CAN A CANINE COMPANION MODIFY CARDIAC AUTONOMIC REACTIVITY AND TONE IN PTSD?

A HYBRID ELECTROCHEMICAL MICROSTIMULATOR IMPLANT FOR DENERVATED MUSCLES

TYROSINE KINASE PATHWAYS IN RHEUMATOID ARTHRITIS

TARGETING EPIGENETIC MECHANISMS IN PAIN DUE TO TRAUMA AND TRAUMATIC BRAIN INJURY (TBI)

STUDY OF ENDOTHELIAL-TO-MESENCHYMAL TRANSITION AND CARDIOVASCULAR DISEASE IN VETERANS WITH BURN PIT EXPOSURES USING ADVANCED IMAGING AND 3D HEART TISSUE MODELS

ANTIBIOTICS AND HUMAN MICROBIAL COMMUNITY DYNAMICS

MOLECULAR MECHANISMS OF MAMMALIAN SIRT6 FUNCTION

DEVELOPMENT OF A BIOENGINEERED THERAPEUTIC DEVICE FOR THE PREVENTION OF LYMPHEDEMA - ABSTRACT: LYMPHEDEMA AFFECTS APPROXIMATELY 200 MILLION PATIENTS GLOBALLY, AND IT IS CHARACTERIZED BY THE ACCUMULATION OF LYMPH FLUID IN SOFT TISSUES DUE TO OBSTRUCTIONS IN THE LYMPHATIC SYSTEM. IN WESTERN COUNTRIES, IT MOST COMMONLY OCCURS AS A DIRECT OUTCOME OF THE CANCER TREATMENT ITSELF, MOST FREQUENTLY IN SURVIVORS OF BREAST AND GYNECOLOGICAL CANCERS. LYMPHEDEMA IS A CHRONIC AND PROGRESSIVE DISEASE THAT HAS NO CURE. CURRENT TREATMENT APPROACHES MAINLY ADDRESS THE SYMPTOMS OF TISSUE SWELLING AND DISCOMFORT BY PHYSIOTHERAPY AND COMPRESSION. WE RECENTLY DEVELOPED AN ALIGNED-BRAIDED NANOFIBRILLAR COLLAGEN CONDUIT THAT IS IMPLANTED TO BRIDGE THE REGION OF LYMPHATIC OBSTRUCTION AS A NEW SURGICAL TREATMENT STRATEGY. OUR PRELIMINARY PRECLINICAL AND CLINICAL STUDIES DEMONSTRATE THAT IMPLANTATION OF THE CONDUIT REDUCES SYMPTOMS ASSOCIATED WITH LYMPHEDEMA. WE PROPOSE TO ADVANCE TRANSLATIONAL RESEARCH AND APPLICATION OF THIS NOVEL RESORBABLE CONDUIT TO DELIVER A MUCH- NEEDED SURGICAL PREVENTATIVE TREATMENT FOR LYMPHEDEMA. BASED ON TECHNOLOGY DEVELOPED BY FIBRALIGN CORP. AND A PREVIOUS VERSION OF THE CONDUIT THAT SHOWED PROMISING PRECLINICAL AND CLINICAL RESULTS IN LYMPHEDEMA TREATMENT, THE OBJECTIVE IS TO OPTIMIZE THE STRUCTURAL AND MECHANICAL PROPERTIES OF THE CONDUIT FOR TARGETING LYMPHEDEMA PREVENTION IN WELL-ESTABLISHED MOUSE AND RAT LYMPHEDEMA MODELS. ACCORDINGLY, IN SPECIFIC AIM 1, WE HYPOTHESIZE THAT ALIGNED NANOFIBRILLAR CONDUITS WITH OPTIMALLY ENGINEERED STRUCTURAL AND MECHANICAL PROPERTIES WILL PROMOTE CAPILLARY FLOW AND LYMPHATIC ENDOTHELIAL CELL (LEC) FUNCTION. WE WILL DETERMINE THE OPTIMAL PROPERTIES (STIFFNESS, NANOFIBRIL DIAMETER, DEGRADATION RATE, AND CAPILLARITY) OF THE CONDUIT THAT MAXIMIZE LEC PHENOTYPE AND LYMPHATIC SPROUTING. IN SPECIFIC AIM 2, WE WILL TEST THE HYPOTHESIS THAT OPTIMALLY ENGINEERED ALIGNED NANOFIBRILLAR CONDUITS WILL ACCELERATE LYMPHATIC REGENERATION AND NORMALIZE LYMPHATIC FLOW IN A MURINE TAIL MODEL OF SECONDARY LYMPHEDEMA. WE WILL FIRST TEST THE THERAPEUTIC EFFICACY IN A MOUSE MODEL OF LYMPHEDEMA, IN WHICH CONDUIT FORMULATIONS WILL BE IMPLANTED INTO THE MOUSE TAIL IMMEDIATELY AFTER INDUCTION OF LYMPHEDEMA. OUTPUT MEASURES WILL CONSIST OF TAIL VOLUME AND LYMPH DRAINAGE PATTERN, BASED ON INDOCYANINE GREEN (ICG) IMAGING. ICG IMAGING WILL ENABLE NON-INVASIVE TRACKING OF PERFUSION OVER TIME TO TRACK FOR THE ABILITY OF THE CONDUITS TO PROMOTE LYMPHANGIOGENESIS. THE CONDUIT WHOSE PROPERTIES MAXIMIZE LYMPHATIC REGENERATION AND LYMPH DRAINAGE WILL UNDERGO FURTHER ANALYSIS IN A MORE CLINICALLY RELEVANT RAT MODEL OF LYMPHEDEMA INDUCED BY LYMPH NODE RESECTION AND IRRADIATION IN AIM 3. HERE, CONDUITS WILL BE IMPLANTED IMMEDIATELY AFTER LYMPHEDEMA INDUCTION SURGERY AS A PREVENTATIVE INTERVENTION. TREATMENT GROUPS WILL CONSIST OF OPTIMALLY ENGINEERED CONDUIT COMPARED TO THE NO TREATMENT CONTROL GROUP OR TO REFERENCE CONDUIT FORMULATIONS. OVER 3 MONTHS, WE WILL QUANTIFY EDEMA ACCUMULATION BY MICRO COMPUTED TOMOGRAPHY, LYMPH DRAINAGE PATTERN BY ICG IMAGING, AND LYMPHATIC REGENERATION WILL BE CONFIRMED BY HISTOLOGICAL QUANTIFICATION OF LYMPHATIC DENSITY. THROUGH THIS INDUSTRY-ACADEMIA PARTNERSHIP, WE ANTICIPATE THESE STUDIES WILL ADVANCE THE SURGICAL PREVENTION OF LYMPHEDEMA.

ASSESSING THE IMPACT OF DTMS ON NEURAL TARGETS ASSOCIATED WITH ALCOHOL USE DISORDER - ABSTRACT BACKGROUND: CONVERGING LINES OF EVIDENCE SUGGEST THAT NEUROMODULATION OF THE NEURAL MECHANISMS UNDERLYING ALCOHOL USE DISORDER (AUD) ARE AN INNOVATIVE NEXT STEP IN IMPROVING TREATMENT OUTCOMES AND REDUCING RISK OF RELAPSE. EMERGING RESEARCH SUPPORTS THE SALIENCE NETWORK (SN) AS A PROMISING TARGET TO ACCOMPLISH THESE GOALS. DEEP TRANSCRANIAL MAGNETIC STIMULATION (DTMS) IS ONE TYPE OF NEUROMODULATION TECHNIQUE THAT ALLOWS FOR DEEPER STIMULATION OF CORTICAL NEURONS, THUS REACHING CORE NODES OF THE SN, SUCH AS THE DORSAL ANTERIOR CINGULATE CORTEX (DACC). OBJECTIVE: THE AIM OF THIS PROPOSAL IS TO 1) EVALUATE THE EFFICACY OF ACTIVE DTMS IN INCREASING DACC ACTIVATION AND REDUCING DRINKING RELATIVE TO A SHAM (PLACEBO) CONDITION, 2) TO ASSESS THE TRAJECTORY OF TARGET ENGAGEMENT CHANGES (I.E., INCREASED DACC ACTIVATION) THAT ARE EVIDENT AFTER 15 SESSIONS VERSUS 30 SESSIONS, AND 3) EVALUATE THE DURABILITY OF THE NEURAL CHANGES AND HOW THIS MIGHT IMPACT TREATMENT OUTCOMES (I.E., % DAYS ABSTINENT AND % HEAVY DRINKING DAYS). METHODS/DESIGN: WE WILL ENROLL 100 ADULTS WITH AUD INTO A 2-ARM RANDOMIZED, DOUBLE-BLIND, SHAM-CONTROLLED MECHANISTIC TRIAL TO CONFIRM TARGET ENGAGEMENT RELATIVE TO SHAM, ASSESS THE IMPACT OF THE PROTOCOL ON DRINKING BEHAVIORS, AND DETERMINE MODERATORS OF TREATMENT RESPONSE. PARTICIPANTS WILL BE RANDOMIZED IN A 1:1 RATIO TO RECEIVE EITHER 30 SESSIONS OF ACTIVE 20HZ DTMS TO THE MPFC AND DACC USING THE H7 COIL, OR AN EQUIVALENT SHAM CONDITION. PARTICIPANTS WILL RECEIVE 3 DTMS TREATMENTS PER DAY FOR 10 CONSECUTIVE BUSINESS DAYS (30 TOTAL TREATMENT SESSIONS) AND WILL COMPLETE NEUROIMAGING ASSESSMENTS AT BASELINE, AFTER ONE-HALF OF TREATMENT SESSIONS, POST-TREATMENT AND 1 MONTH AFTER TREATMENT. SPECIFIC AIMS: WE AIM 1) TO EVALUATE THE EFFICACY OF ACTIVE DTMS RELATIVE TO SHAM DTMS IN REDUCING 3-MONTH POST-TREATMENT DRINKING RATES AND TARGET ENGAGEMENT, 2) EVALUATE THE RELATIONSHIP BETWEEN DEGREE OF TARGET ENGAGEMENT TO DRINKING RATES AND IDENTIFY INDIVIDUAL VARIABILITY IN TARGET ENGAGEMENT TRAJECTORY, AND 3) TO EVALUATE THE ASSOCIATION OF TARGET ENGAGEMENT DURABILITY OF DTMS FOR RELAPSE PREVENTION. IMPACT: THE PROPOSED RESEARCH WILL ELUCIDATE MECHANISMS OF BRAIN AND BEHAVIOR CHANGE, ACCELERATE THE DEVELOPMENT OF NEW, DEVICE-BASED, TREATMENT OPTIONS AND WILL BE THE BASIS FOR DEVELOPING A LARGE-SCALE, DOSE- VARYING, CLINICAL TRIAL TO TEST NEW TREATMENT STRATEGIES FOR AUD.

PHOTOACTIVATED REGENERATIVE COLLAGEN SEALANT FOR RAPID VISION RESTORATION AFTER DEEP CORNEAL INJURIES

OXIDATIVE STRESS AND HEPATOCELLULAR CARCINOMA

BIPOLAR II DEPRESSION: LITHIUM, SSRI, OR THE COMBINATION

AN AUTOIMMUNE BASIS FOR PULMONARY HYPERTENSION.

RESTORATION OF BLADDER AND BOWEL FUNCTION USING ELECTRICAL STIMULATION AND BLOCK AFTER SPINAL CORD INJURY

OFFSPRING OF TWINS: G,E AND GXE RISKS FOR ALCOHOLISM

MECHANISMS OF NEUROINFLAMMATION AFTER FRACTURE

FEASIBILITY OF AT HOME TELEHEALTH YOGA FOR TREATING CHRONIC PAIN

GENETIC DETERMINANTS OF OPIOID-INDUCED HYPERALGESIA

ENDOTHELIAL CELL BIOLOGY IN INFLAMMATION

ENGAGEMENT OF VETERANS WITH LUNG CANCER

MECHANISMS HOW ADIPOCYTES AFFECT BONE IN AGING MICE

AGE-RELATED LONGITUDINAL CHANGES IN AVIATOR PERFORMANCE

TGFBETA SIGNALING IN NEURODEGENERATION AND ALZHIMER'S

ALCOHOL PROBLEMS: LONG-TERM COURSE IN LATE-LIFE

UNDERSTANDING THE MECHANISTIC INTERRELATIONSHIP BETWEEN SLEEP, CO-OCCURRING CANNABIS AND ALCOHOL USE DISORDER, AND NEUROCIRCUIT DYSFUNCTION DURING EARLY ABSTINENCE - ABSTRACT BACKGROUND: SLEEP MAY PLAY A KEY ROLE IN WITHDRAWAL. INDIVIDUALS WITHDRAWING FROM EITHER CANNABIS OR ALCOHOL HAVE SIGNIFICANT REDUCTIONS IN SLOW-WAVE SLEEP, AMONG OTHER OBJECTIVE SLEEP DISTURBANCES. INDEPENDENT FROM SUBSTANCE USE, OBJECTIVE SLEEP DISTURBANCES, INCLUDING IMPAIRMENTS IN SLOW-WAVE SLEEP DURATION, SLOW-WAVE ACTIVITY, AND HOMEOSTATIC SLEEP DRIVE, HAVE BEEN ASSOCIATED WITH ABERRANT FRONTO-LIMBIC NEGATIVE AFFECT NEUROCIRCUITRY AS WELL AS NEGATIVE AFFECT SYMPTOMS. CRITICALLY, THESE SAME FRONTO-LIMBIC CIRCUITS ARE ALSO IMPAIRED IN CANNABIS USE DISORDER (CUD) AND ALCOHOL USE DISORDER (AUD). THUS, SLEEP DISTURBANCE MAY BE A MECHANISTIC CONTRIBUTOR TO WITHDRAWAL SYMPTOMS, WITH FRONTO-LIMBIC DYSFUNCTION MEDIATING THIS RELATIONSHIP. OBJECTIVE: THIS PROPOSAL AIMS TO CHARACTERIZE THE TEMPORAL TRAJECTORY OF THESE OBJECTIVE SLEEP CHANGES IN INDIVIDUALS WITH CO-OCCURRING CUD+AUD DURING EARLY ABSTINENCE AND ESTABLISH HOW THESE CHANGES INTERRELATE WITH BOTH FRONTO-LIMBIC DYSFUNCTION AND WITHDRAWAL SYMPTOMS. METHODS/DESIGN: IN THE R61 PHASE WE AIM TO EXAMINE 40 ELIGIBLE ADULTS WITH CO-OCCURRING CANNABIS USE DISORDER IN A LONGITUDINAL OBSERVATIONAL STUDY TO RECORD OBJECTIVE MEASURES OF SLEEP, FRONTO-LIMBIC FUNCTION, AND NEGATIVE AFFECT WITHDRAWAL SYMPTOMS AT MULTIPLE TIMEPOINTS ACROSS A 28-DAY WITHDRAWAL PERIOD. PRIMARY SLEEP MEASURES INCLUDE SLOW-WAVE SLEEP DURATION (MINUTES IN STAGE N3), SLOW-WAVE ACTIVITY (RELATIVE SPECTRAL POWER BETWEEN 0.5 AND 4.0 HZ DURING NREM), AND HOMEOSTATIC SLEEP DRIVE (THE DECLINATION OF SLOW-WAVE EEG POWER IN SUBSEQUENT NREM CYCLES). FRONTO-LIMBIC FUNCTION WILL BE ASSESSED USING AN FMRI TASK OF NEGATIVE AFFECT REACTIVITY. NEGATIVE AFFECT WITHDRAWAL SYMPTOMS WILL FOCUS ON ANXIETY AND DEPRESSION. IF THE R61 MILESTONE CRITERIA ARE MET, IN THE R33 PHASE WE WILL ENROLL AN ADDITIONAL 80 ADULTS INTO A 2-ARM RANDOMIZED CONTROLLED MECHANISTIC TRIAL TO ADDRESS WHETHER INTERVENING IN THE SLEEP TRAJECTORY WILL INDUCE DOWNSTREAM CHANGES IN NEUROCIRCUIT TARGETS AS WELL AS HOW THESE TRAJECTORIES RELATE TO WITHDRAWAL SYMPTOMS. SPECIFIC AIMS: IN THE R61 PHASE WE AIM TO ESTABLISH THE EXTENT OF OBJECTIVE SLEEP DISTURBANCE ACROSS CUD+AUD WITHDRAWAL AND ITS ASSOCIATIONS WITH FRONTO-LIMBIC FUNCTION AND SYMPTOMS ACCORDING TO PRE-SPECIFIED MILESTONE CRITERIA. IN THE R33 WE AIM TO 1. EXAMINE THE MODIFIABILITY OF OBJECTIVE SLEEP DISTURBANCE DURING CUD+AUD WITHDRAWAL USING A WELL-VALIDATED SLEEP MANIPULATION. 2. ASSESS THE RELATIONSHIPS BETWEEN THE CHANGE IN OBJECTIVE SLEEP DISTURBANCE WITH BOTH FRONTO-LIMBIC DYSFUNCTION AND WITHDRAWAL SYMPTOMS. 3. DETERMINE SLEEP AND NEUROCIRCUIT MODERATORS OF TREATMENT OUTCOME. IMPACT: OUR NEUROBIOLOGICAL RESULTS WILL INFORM NOVEL SLEEP AND BRAIN TREATMENT TARGETS AND ESTABLISH THEIR MODIFIABILITY IN THOSE WHO HAVE CUD + AUD IN EARLY ABSTINENCE. THESE STUDIES ARE NEEDED TO UNDERSTAND THE CONTRIBUTION OF OBJECTIVE SLEEP DISTURBANCE TO WITHDRAWAL-RELATED NEUROCIRCUIT DYSFUNCTION AND SYMPTOMS, AND THEREFORE WILL INFORM WHETHER A TARGETED SLEEP INTERVENTION IN EARLY ABSTINENCE WOULD BE WARRANTED IN POLYSUBSTANCE USE.

META-ANALYSIS OF ALCOHOLISM TREATMENT OUTCOME RESEARCH

MATRIX-MEDIATED ENDOTHELIAL DIFFERENTIATION OF INDUCED PLURIPOTENT STEM CELLS

INTESTINAL MICROBIOTA OF MARINE MAMMALS IN HEALTH AND DISEASE

TOLEROGENIC DC AS THERAPEUTIC AGENTS IN GVHD

E-CIGARETTES EPIGENETICALLY AUGMENT TRANSGENERATIONAL ABDOMINAL AORTIC ANEURYSM - PROJECT SUMMARY ABDOMINAL AORTIC ANEURYSM (AAA) DISEASE IS A COMMON, MORBID AND HIGHLY LETHAL DISEASE. IMPORTANTLY, THERE ARE CURRENTLY NO THERAPEUTIC STRATEGIES THAT LIMIT THE GROWTH OF AAAS, DUE IN PART TO A LACK OF UNDERSTANDING OF THE MECHANISMS OF DISEASE AND PROGRESSION. IN ADDITION TO ADVANCED AGE, GENETIC PREDILECTION, AND MALE SEX, THE MOST CRUCIAL RISK FACTOR FOR AAA IS A HISTORY OF SMOKING, AND AT PRESENT, SMOKING CESSATION IS CONSIDERED THE MOST EFFECTIVE APPROACH TO DECREASING AAA INCIDENCE. THE RECENT EXPLOSION IN POPULARITY OF E-CIGARETTE “VAPING” HAS ALSO RAISED URGENT QUESTIONS AS TO THE SHORT AND LONG-TERM IMPACTS ON VASCULAR DISEASE RISK. PUBLISHED WORK FROM OUR LABORATORY HAS SHOWN THAT BOTH SUBCUTANEOUS INFUSION OF THE MAJOR TOBACCO COMPONENT, NICOTINE, AND INHALED E-CIGARETTE NICOTINE VAPOR, AUGMENT EXPERIMENTAL AAA. IT HAS BEEN RECENTLY APPRECIATED THAT EXPOSURE TO TOBACCO SMOKE, NICOTINE, AND VAPING CAN CAUSE CELLULAR EPIGENETIC ALTERATIONS, AND THAT IN SOME CASES THESE EFFECTS CAN BE TRANSMITTED IN A TRANSGENERATIONAL FASHION - NOT ONLY IN ANIMAL MODELS, BUT ALSO IN HUMANS. WE HAVE NEW DATA SHOWING THAT BOTH INFUSED NICOTINE AND E-CIG VAPING IN MICE AUGMENTS AAA IN THEIR PROGENY. ADDITIONALLY, WITH PARENTAL EXPOSURE WE OBSERVED THOUSANDS OF GENOME ALTERATIONS WITHIN THE BLOOD AND TISSUES OF BOTH PARENTS AND OFFSPRING, INCLUDING CHANGES TO BOTH DNA METHYLATION AND ACCESSIBILITY. IN PARTICULAR WE FIND CHANGES IN “IMPRINTED” GENES, CAPABLE OF TRANSMITTING CARDIOVASCULAR DISEASE RISK EPIGENETICALLY TO SUBSEQUENT GENERATIONS. THE OUTLINED STUDIES IN THIS PROPOSAL WILL EXAMINE THE EFFECTS OF NICOTINE AND E-CIGARETTE VAPOR ON THE CELLULAR EPIGENETIC MACHINERY IN VITRO AND IN VIVO, WITH A PARTICULAR EMPHASIS ON HERITABLE CHANGES CAPABLE OF AUGMENTING AAA. IN ORDER TO VERIFY THE SPECIFIC MECHANISMS INVOLVED, WE WILL ALSO SEEK TO INHIBIT THEIR IMPACT ON TRANSGENERATIONAL AAA RISK. IN SPECIFIC AIM 1, WE WILL DETERMINE THE IMPACT OF E-CIGARETTE VAPOR AND INFUSED NICOTINE ON EPIGENETIC PATTERNING AND IMPRINTED GENE EXPRESSION IN GERM CELLS AND EVALUATE THESE EFFECTS OVER TIME IN MICE USING MULTI-OMIC HIGH-THROUGHPUT METHODS. FOR SPECIFIC AIM 2 WE WILL EXAMINE THE EFFECTS OF THESE EPIGENETIC CHANGES ON CELLULAR SIGNALING PATHWAYS KNOWN TO BE CRUCIAL FOR AAA PATHOPHYSIOLOGY. FINALLY, IN SPECIFIC AIM 3 WE WILL SEEK TO INHIBIT E-CIGARETTE-INDUCED DNA ALTERATIONS, WITH A VIEW TO PREVENTING TRANSGENERATIONAL AAA AUGMENTATION DURING A MULTI-GENERATION IN VIVO TIME COURSE. THESE SPECIFIC AIMS WILL PROVIDE KEY INFORMATION REGARDING THE POTENTIAL TRANSGENERATIONAL RISK OF E-CIGARETTE USE ON VASCULAR DISEASE, AND FORM THE BASIS FOR ADVANCING FUTURE RESEARCH AND CLINICAL TRANSLATION, INCLUDING POTENTIAL SCREENING FOR HIGH-RISK EPIGENETIC CHANGES IN HUMANS.

VISUALIZATION OF PELVIC FLOOR REFLEXES

EMOTION REGULATION IN ANXIETY & DEPRESSION: A NOVEL NEUROBEHAVIORAL INTERVENTION

EMG-BASED ESTIMATION OF MUSCLE STRUCTURE AND FUNCTION

COMBINED ONLINE ASSISTANCE FOR CAREGIVER HEALTH (COACH): THE EFFICACY OF A COMBINED PHYSICAL ACTIVITY AND COPING SKILLS TRAINING INTERVENTION FOR CAR

EFFICACY OF REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION IMPROVEMENT OFMEMORY IN OLDER ADULTS WITH TBI

REGULATION OF LIVER LDL RECEPTOR EXPRESSION BY BERBERINE

DYSREGULATED METABOLIC-MATRIX AXIS IN MASH/HCC - PROJECT SUMMARY/ABSTRACT THE INCREASING PREVALENCE AND SEVERITY OF METABOLIC DYSFUNCTION ASSOCIATED STEATOHEPATITIS (MASH) AND ITS SEQUELAE RESULTED IN A RISE IN MORTALITY IN THE AGING POPULATION. MASH-RELATED HEPATOCELLULAR CARCINOMA (HCC) HAS A POOR PROGNOSIS IN OLDER PATIENTS, AND THE EFFECTS OF AGING-MEDIATED PATHWAYS ON MASH-DRIVEN HCC ARE NOT WELL UNDERSTOOD. THE SRC HOMOLOGY 2 DOMAIN CONTAINING COLLAGEN-RELATED (SHC) ADAPTOR PROTEINS INCREASE DURING AGING IN THE LIVER, AND INHIBITING SHC IN MASLD/MASH EITHER GENETICALLY OR PHARMACOLOGICALLY INCREASED BETA OXIDATION AND IMPROVED INFLAMMATION AND FIBROSIS. BASED ON THIS, WE NOW PROPOSE THAT AGE-RELATED MALADAPTIVE RESPONSES VIA SHC CREATE A NICHE THAT PREDISPOSE TO HCC BY MITOCHONDRIAL DYSFUNCTION, DECREASE IN FAO, LIPID PEROXIDATION, MODULATING MATRIX MECHANICS TO PROMOTE CELL INVASION. TO ADDRESS THIS HYPOTHESIS IN AIM 1 WE WILL STUDY DIETARY AS WELL AS SHC ISOFORM-SPECIFIC KNOCKDOWNS AND INDUCIBLE TRANSGENIC MODELS FOR MASH/HCC IN YOUNG VS. OLD MICE. WE WILL EVALUATE MITOCHONDRIAL OXPHOS, Β-OXIDATION, AS WELL AS THE EFFECTS OF BETA HYDROXYBUTYRATE PRODUCTION, INCLUDING HDAC1/2, AND P53 ACETYLATION. IN AIM 2, WE WILL STUDY MATRIX MECHANICS AND ARCHITECTURE THAT ARE MODULATED VIA SHC MEDIATED ADVANCED LIPOXYGENATION PRODUCTS. FORCE MAPS WILL BE MULTIPLEXED WITH CODEX TO EVALUATE CELL INTERACTOME AND MECHANICAL CHARACTERISTICS, IN SITU IN MASH/HCC. DETAILED ANALYSES OF THE MATRIX BY LC-MS, SHG MICROSCOPY, AND MODELING USING 3D HYDROGEL SYSTEMS WILL BE PERFORMED. IN AIM 3, WILL INVESTIGATE HOW P46SHC AND P52SHC INHIBITION WITH SMALL-MOLECULE SHC BLOCKERS IMPROVES MASH AND MASH-TO-HCC TRANSITION, EVALUATING BIOCHEMICAL, PHYSIOLOGICAL, METABOLIC AS WELL AS MATRIX ENDPOINTS IN AGED MICE, AND BY IN VITRO EXPERIMENTS. THESE STUDIES WILL ELUCIDATE AGE-SPECIFIC METABOLIC-MATRIX PATHWAYS THAT FAVOR HEPATOCARCINOGENESIS AND SET THE STAGE TO DEVELOP EFFECTIVE TREATMENT OPTIONS FOR THE ELDERLY.

2/2-A RANDOMIZED TRIAL OF INTERNET-BASED INTERVENTIONS FOR BIPOLAR DISORDER

BRITE PIVOT: ENGINEERED EXTRACELLULAR MATRIX CUES AFFECTING ENDOTHELIAL PHENOTYPIC CHANGE -BLOOD VESSEL CELLS KNOWN AS ENDOTHELIAL CELLS CAN CHANGE TO ANOTHER TYPE OF CELL AND CONTRIBUTE TO VASCULAR DISEASE. THIS CHANGE IS ASSOCIATED WITH PLAQUE FORMATION WITHIN ATHEROSCLEROTIC VESSELS. A KEY COMPONENT OF BLOOD VESSELS IS THE UNDERLYING SCAFFOLDING STRUCTURE THAT PROVIDES PHYSICAL SUPPORT AND INSTRUCTS ENDOTHELIAL CELLS. IT ISN'T KNOWN IF THE SMALL-SCALE MOLECULAR STRUCTURE OF THE BLOOD VESSEL AFFECTS THE CHANGES IN CELL TYPE. THIS BOOSTING RESEARCH IDEAS FOR TRANSFORMATIVE AND EQUITABLE ADVANCES IN ENGINEERING (BRITE) PIVOT AWARD SUPPORTS RESEARCH TO DISCOVER NEW KNOWLEDGE OF HOW THE MECHANICAL PROPERTIES OF THE SCAFFOLDING STRUCTURE INFLUENCE ENDOTHELIAL FATE. THE FINDINGS FROM THIS AWARD MAY INFLUENCE THE DESIGN OF NEW THERAPIES TO TREAT VASCULAR DISEASES. THEREFORE, THE FINDINGS FROM THIS AWARD WILL BENEFIT OUR SOCIETY BY ADVANCING NATIONAL HEALTH. THE EDUCATIONAL ACTIVITIES PROMOTE THE DEVELOPMENT OF MILITARY VETERAN COLLEGE STUDENTS FROM UNDERSERVED COMMUNITIES THROUGH LECTURES, LABORATORY TRAINING, AND SUMMER RESEARCH EXPERIENCES THAT BROADEN PARTICIPATION IN SCIENTIFIC RESEARCH. ENDOTHELIAL-MESENCHYMAL TRANSITION IS A BIOLOGICAL PROCESS IN WHICH VASCULAR ENDOTHELIAL CELLS ACQUIRE A MESENCHYMAL IDENTITY. THIS TRANSITION IS INVOLVED IN CARDIOVASCULAR DISEASES SUCH AS ATHEROSCLEROSIS, IN WHICH ENDOTHELIAL CELLS GIVE RISE TO SMOOTH MUSCLE-LIKE CELLS WITHIN THE PLAQUE LESION. HOW THE BIOCHEMICAL AND BIOMECHANICAL CUES FROM THE EXTRACELLULAR MATRIX MILIEU INFLUENCES THIS TRANSITION IS LARGELY UNKNOWN. THE PROJECT WILL ENGINEER MICROENVIRONMENTS COMPOSED OF COMBINATORIAL EXTRACELLULAR MATRIX PROTEINS TO MODEL THAT OF ATHEROSCLEROTIC PLAQUES IN WHICH THIS TRANSITION TAKES PLACE. THE RESEARCH OBJECTIVE IS TO APPLY MULTIVARIATE EXPERIMENTAL DESIGN AND ANALYSIS TO QUANTIFY THE ROLE AND INTERACTION EFFECTS AMONG EXTRACELLULAR MATRIX COMPONENTS AND SHEAR STRESS ON ENDOTHELIAL-MESENCHYMAL TRANSITION. THROUGH THIS AWARD, A DEEPER RESEARCH PROGRAM FOCUSED ON VASCULAR MECHANOBIOLOGY IN BOTH TECHNOLOGY DEVELOPMENT AS WELL IN THE APPLICATION OF SINGLE-CELL TRANSCRIPTOMICS AND MULTIFACTORIAL ANALYSIS, WILL BE ACHIEVED. THIS AWARD WILL FORM THE FOUNDATION OF A NEW RESEARCH TRAJECTORY FOCUSING ON THE MECHANOBIOLOGY OF EXTRACELLULAR MATRIX INTERACTIONS FOR IMPROVED UNDERSTANDING OF CARDIOVASCULAR DISEASE PROGRESSION. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.

TARGETING CHEMERIN RECEPTOR CMKLR1 IN MULTIPLE SCLEROSIS

DIETARY MANEUVERS TO REDUCE PRODUCTION OF COLON-DERIVED UREMIC SOLUTES

"A COMBINED TRAINING PROGRAM FOR VETERANS WITH AMNESIC MILD COGNITIVE IMPAIRMENT."

SUCCESSFUL STRATEGIES FOR ACTIVITY AND WELLNESS AFTER SPINAL CORD INJURY

THE ROLE OF OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTION IN COGNITIVE IMPAIRMENTS IN GULF WAR ILLNESS

CHROMATIN SIGNALING MECHANISMS IN METABOLIC AGING AND DISEASE - ABSTRACT OUR BROAD RESEARCH GOAL IS TO UNDERSTAND CHROMATIN REGULATORY MECHANISMS IN NUCLEAR AND EPIGENETIC PROGRAMS AND HOW THESE MECHANISMS ARE DEREGULATED IN AGING AND DISEASE. A FUNDAMENTAL MECHANISM FOR REGULATING CHROMATIN INVOLVES THE REVERSIBLE MODIFICATION OF HISTONES BY CHEMICAL MOIETIES SUCH AS ACETYL-, METHYL-, AND PHOSPHO- GROUPS. THESE DIFFERENT HISTONE MARKS ARE LINKED TO DISCRETE CHROMATIN STATES AND REGULATE THE ACCESSIBILITY OF DNA TO TRANSACTING FACTORS. IN BUDDING YEAST, HISTONE DEACETYLATION BY THE CHROMATIN SILENCING FACTOR SIR2 PREVENTS GENOMIC INSTABILITY AND AGING, AND IN MAMMALS, DE-REGULATION OF HISTONE ACETYLATION IS LINKED TO CELLULAR SENESCENCE AND AGING-RELATED PATHOLOGIES FROM NEURODEGENERATION TO CANCER. HERE, WE FOCUS ON THE MAMMALIAN SIR2 FAMILY MEMBER SIRT7, A CHROMATIN REGULATORY, HIGHLY SELECTIVE, LYSINE DEACETYLASE ENZYME. PREVIOUS STUDIES REPORTED THAT LOSS OF SIRT7 FUNCTION IN MICE LEADS TO GENOMIC INSTABILITY, SHORTENED LIFESPAN AND AGING-RELATED PHENOTYPES INCLUDING FATTY LIVER, CARDIAC DISEASE, AND HEMATOPOIETIC STEM CELL DYSFUNCTION. THIS PROJECT WILL STUDY NEW ROLES OF SIRT7-DEPENDENT HISTONE DEACETYLATION IN CHROMATIN REGULATORY MECHANISMS THAT ARE DEREGULATED IN AGING-ASSOCIATED METABOLIC PATHOLOGIES. IT EMPLOYS BIOCHEMICAL, CELLULAR, AND GENOMIC APPROACHES, AND LEVERAGES SIRT7 KNOCKOUT (SIRT7-KO) MICE AND NEW MOUSE MODELS IN WHICH SIRT7 IS OVEREXPRESSED (SIRT7-OE). A CENTRAL HYPOTHESIS IS THAT SIRT7 PROTECTS AGAINST AGING AND METABOLIC DISEASE PROCESSES AND ATTENUATES METABOLIC PATHOLOGIES WHEN OVEREXPRESSED IN MICE. THE PROJECT ALSO HYPOTHESIZES THAT A NOVEL HISTONE SUBSTRATE OF SIRT7, H3K36, CONTRIBUTES TO FUNCTIONS OF SIRT7 IN AGING AND METABOLIC PATHWAYS. LITTLE IS KNOWN ABOUT ACETYLATION OF H3K36, BUT DI-METHYLATION OF H3K36 (A HISTONE MODIFICATION LINKED TO GENE REGULATION) IS IMPLICATED IN MANY HUMAN CANCERS, DEVELOPMENTAL DISORDERS, AND RECENTLY, METABOLIC DISEASE. WE HYPOTHESIZE THAT DEACETYLATION OF H3K36 BY SIRT7 IS COUPLED TO METHYLATION BY LYSINE METHYLTRANSFERASE (KMT) ENZYMES. WE WILL TEST THE MODEL THAT A KEY MECHANISTIC FUNCTION OF SIRT7 IS TO CLEAR H3K36 ACETYLATION FROM LARGE SWATHS OF DNA ACROSS THE GENOME TO ENABLE METHYLATION BY KMTS, AND THAT SUCH A H3K36 ACETYL-METHYL SWITCH MECHANISM IS ESSENTIAL FOR PREVENTING AGING-ASSOCIATED GENE EXPRESSION REPROGRAMING IN METABOLIC TISSUES.

MODIFICATION DEOBLIGATION OF EXPRIRING FUNDS

THE BREAST CANCER DNA INTERACTOME

EARLY ALCOHOL USE ONSET: INFLUENCE OF RELIGION-SPIRITUALITY DIMENSIONS

VIRAL GASTROENTERITIS: BASIS OF VIRULENCE AND PROTECTION

ANTIMICROBIAL RESISTANCE AND HORIZONTAL GENE TRANSFER IN THE HUMAN GUT MICROBIOME IN RESPONSE TO AN ANTIBIOTIC

MUCOSAL IMMUNITY AND INFLUENZA VACCINES: PHENOTYPE AND ROLE OF ACTIVATED B CELLS

SCI WITH BRAIN INJURY: BEDSIDE-TO-BENCH MODELING FOR DEVELOPING TREATMENT AND REHABILITATION STRATEGIES

IMPROVING ACCESS TO PHARMACOTHERAPY FOR OPIOID USE DISORDER AMONG JUSTICE INVOLVED VETERANS

IMMUNOLOGICAL CONTRIBUTIONS TO THE CHRONIFICATION OF PAIN. NEW AWARD.

COLLABORATIVE RESEARCH: SCH: QUANTIFYING CARDIAC PERFORMANCE BY MEASURING MYOFIBER STRAIN WITH ROUTINE MRI -THE GOAL OF THIS RESEARCH IS TO DEVELOP A NEW METHOD TO QUANTIFY CARDIAC PERFORMANCE IN PATIENTS AFFECTED BY CARDIAC DISEASES. CURRENT STRATEGIES TO EVALUATE CARDIAC PERFORMANCE OFTEN RELY ON INADEQUATE GLOBAL MEASURES, SUCH AS EJECTION FRACTION, WHICH ARE NON-SPECIFIC AND OFTEN LATE OUTCOMES. CARDIAC MOTION IS DRIVEN BY BILLIONS OF HEART CELLS ACTING TOGETHER, WHOSE CONTRACTION AND RELAXATION CAN BE MEASURED USING MYOFIBER STRAIN. MYOFIBER STRAIN IS THEREFORE A DIRECT MEASURE OF CARDIAC FUNCTION AND IS AN IDEAL CANDIDATE TO EVALUATE CARDIAC PERFORMANCE, IMPROVING DIAGNOSIS AND THERAPY PLANNING. HOWEVER, THERE ARE THREE MAIN OBSTACLES THAT HINDER THE DEPLOYMENT OF MYOFIBER STRAIN IN A CLINICAL SETTING: (I) THERE IS NO METHOD TO RELIABLY COMPUTE MYOFIBER STRAIN FROM IMAGES THAT ARE ROUTINELY ACQUIRED; (II) THERE ARE NO RELIABLE ERROR ESTIMATES FOR THE EVALUATED STRAINS, PREVENTING THEIR USE TO DISTINGUISH BETWEEN HEALTH AND DISEASE; AND (III) THERE IS NO FRAMEWORK TO COMPUTE MYOFIBER STRAIN ON DEMAND WITHOUT HARDWARE AND TECHNICAL BARRIERS. THIS PROJECT AIMS AT OVERCOMING THESE OBSTACLES BY COMBINING COMPUTATIONAL MODELING AND ARTIFICIAL INTELLIGENCE WITH READILY AVAILABLE MAGNETIC RESONANCE IMAGING. THE TRANSITION TO THE CLINIC WILL BE HIGHLY FACILITATED BY DEPLOYING THE PROPOSED FRAMEWORK IN A COMPLETELY ONLINE PLATFORM LEVERAGING ON-DEMAND CLOUD COMPUTING. INVESTIGATORS AROUND THE GLOBE WILL BE ABLE TO TEST REMOTELY THE NEWLY PROPOSED TECHNOLOGY WITHOUT THE NEED FOR SPECIFIC HARDWARE OR ADDITIONAL SOFTWARE. THE MULTIDISCIPLINARY RESEARCH CARRIED OUT IN THIS PROJECT WILL TRAIN THE NEXT GENERATION OF SCIENTISTS, WHO WILL BE CAPABLE OF CARRYING OUT PROJECTS IN SMART HEALTH AND BIOMEDICAL RESEARCH AT THE FOREFRONT OF MEDICAL IMAGING, ARTIFICIAL INTELLIGENCE, AND COMPUTATIONAL MODELING. THE PROPOSED APPROACH WILL ESTIMATE MYOFIBER STRAIN BY MINIMIZING THE DIFFERENCE BETWEEN COMPUTED AND MEASURED SURFACE CARDIAC MOTION. MEASURED SURFACE MOTION IS EXTRACTED FROM CINE MAGNETIC RESONANCE IMAGING (MRI), WHICH IS ROUTINELY ACQUIRED IN A CLINICAL MRI SETTING. COMPUTED LEFT VENTRICULAR SURFACE MOTION IS OBTAINED BY SOLVING A COMPUTATIONAL KINEMATICS MODEL BASED ON THE BIOMECHANICS OF MYOFIBER SHORTENING AND RELAXATION. UNCERTAINTY IN MYOFIBER STRAIN PREDICTIONS WILL BE EVALUATED BASED ON IMAGING DATA NOISE AND MODEL ASSUMPTIONS. FAST AND ACCURATE HIGH-FIDELITY MODELS AND BAYESIAN ERROR ESTIMATORS WILL PROPAGATE EXPERIMENTAL AND MODEL UNCERTAINTIES TO ESTABLISH CONFIDENCE IN MYOFIBER STRAIN ESTIMATES. AS A RESULTS, THE GENERATED MODELS WILL ALLOW TO CHARACTERIZE STRAINS? UNCERTAINTY AND VARIATION IN HEALTHY AND DISEASED INDIVIDUALS. THE PROPOSED APPROACH WILL BE DEMONSTRATED AND VALIDATED IN A PILOT STUDY TO AID THERAPY PLANNING IN PATIENTS AFFECTED BY AORTIC STENOSIS. THIS NEW APPROACH PAVES THE WAY TO IMPROVE DIAGNOSIS, PROGNOSIS, AND THERAPY PLANNING FOR PATIENTS AFFECTED BY A WIDE RANGE OF CARDIOMYOPATHIES RESULTING IN COMPROMISED LEFT VENTRICULAR FUNCTION AND THEREFORE MYOFIBER MECHANICS. THIS AWARD REFLECTS NSF'S STATUTORY MISSION AND HAS BEEN DEEMED WORTHY OF SUPPORT THROUGH EVALUATION USING THE FOUNDATION'S INTELLECTUAL MERIT AND BROADER IMPACTS REVIEW CRITERIA.

DECIPHERING THE MOLECULAR MECHANISMS OF RESPONSE TO COVID VACCINE IN KIDNEY TRANSPLANT RECIPIENTS - PROJECT SUMMARY / ABSTRACT SOLID ORGAN TRANSPLANT RECIPIENTS HAVE INCREASED MORBIDITY AND MORTALITY IN RESPONSE TO INFECTION WITH SARS- COV-2, THE VIRUS RESPONSIBLE FOR COVID19. WHILE THE GENERAL POPULATION HAS GREATLY BENEFITED FROM THE RAPID DEVELOPMENT OF SEVERAL VACCINES THAT ARE PROTECTIVE AGAINST THE DEVELOPMENT OF SEVERE INFECTION, THE TRANSPLANT RECIPIENT POPULATION HAS SUB-OPTIMAL RESPONSES TO SIMILAR VACCINATION REGIMENS. HEREIN, WE BUILD ON OUR PUBLISHED AND PRELIMINARY DATA ON THE CELLULAR AND SEROLOGICAL RESPONSES TO SARS-COV-2 MRNA VACCINATION IN BOTH LIVER AND KIDNEY TRANSPLANT RECIPIENTS. LIVER TRANSPLANT RECIPIENTS ARE SIGNIFICANTLY MORE LIKELY TO RESPOND TO A TWO-DOSE REGIMEN WITH BOTH VIRAL SPECIFIC T CELLS AND SEROCONVERSION WHEN COMPARED WITH KIDNEY TRANSPLANT RECIPIENTS. INTERESTINGLY, ALTHOUGH BOTH SEROCONVERSION EFFICIENCY AND T CELL ACTIVATION ARE AFFECTED BY THE LEVELS OF IMMUNOSUPPRESSION, THE ORGAN TRANSPLANTED (LIVER VERSUS KIDNEY) HAS AN INDEPENDENT EFFECT ON THE HUMORAL AND CELLULAR RESPONSES. HOWEVER, AN IN DEPTH, MECHANISTIC EVALUATION OF THESE ADAPTIVE IMMUNE RESPONSES IS LACKING. WE HYPOTHESIZE THAT THERE ARE INTRINSIC DIFFERENCES IN IMMUNE FUNCTION, IRRESPECTIVE OF THE DEGREE OF IMMUNOSUPPRESSION, BETWEEN LIVER AND KIDNEY TRANSPLANT RECIPIENTS. THIS PROPOSAL BUILDS ON AN ALREADY PRODUCTIVE COLLABORATION BETWEEN THE LABORATORIES OF JONATHAN MALTZMAN AND PAOLO CRAVEDI. THE OVERALL GOAL OF THIS WORK IS TO USE CRYOPRESERVED SAMPLES TO MECHANISTICALLY UNDERSTAND THE FEATURES THAT CHARACTERIZE EFFECTIVE IMMUNE RESPONSE TO SARS-COV-2 VACCINATION IN KIDNEY TRANSPLANT RECIPIENTS. TO ADDRESS THIS GOAL, WE PROPOSE THE FOLLOWING SPECIFIC AIMS: AIM 1: ASSESS THE DIFFERENCES IN T CELL PHENOTYPE AND FUNCTION BETWEEN SOLID ORGAN TRANSPLANT (SOT) RECIPIENTS THAT ARE SARS-COV-2 VACCINE RESPONDERS VERSUS NON-RESPONDERS; AIM 2: DETERMINE DIFFERENCES IN INNATE AND ADAPTIVE IMMUNE CELL POPULATIONS BETWEEN VACCINE RESPONDERS VERSUS NON-RESPONDERS BY MEASURING CHROMATIN ACCESSIBILITY AND GENE EXPRESSION. THIS PROJECT BUILDS UPON THE PRODUCTIVE COLLABORATION BETWEEN THE MALTZMAN AND CRAVEDI LABORATORIES AND LEVERAGES THEIR EXPERTISE. SUCCESS OF THIS HIGH-RISK PROPOSAL HAS THE POTENTIAL TO COMPREHENSIVELY DELINEATE THE IMMUNE RESPONSES IN BOTH KIDNEY AND LIVER TRANSPLANT RECIPIENTS UPON SARS- COV-2 VACCINATION, A POINT OF CRITICAL IMPORTANCE TO DEFINE BIOMARKERS OF RESPONSE AND ENVISION STRATEGIES TO IMPROVE RESPONSE (HIGH REWARD).

NOTCH SIGNALING AND SATELLITE CELL ACTIVATION

EMOTION REGULATION IN ANXIETY & DEPRESSION: A NOVEL NEUROBEHAVIORAL INTERVENTION

IN-HOME SLEEP MONITORING TO DETECT SUICIDE RISK IN VETERANS

ESTABLISHING A TASK-EVOKED MAGNETIC RESONANCE SPECTROSCOPY APPROACH FOR TESTING THE GABA DEFICIT HYPOTHESIS IN SCHIZOPHRENIA

THE PRODUCTION OF UREMIC SOLUTES BY COLON MICROBES

THE COMBINATION OF ANTI-AMYLOID THERAPY AND RTMS FOR AD - PROJECT SUMMARY / ABSTRACT MANY INDIVIDUALS SUFFER FROM DEMENTIA-RELATED COGNITIVE IMPAIRMENT DUE TO MILD COGNITIVE IMPAIRMENT (MCI) AND ALZHEIMER’S DISEASE (AD). THIS NUMBER IS EXPECTED TO GROW AS THE POPULATION AGES AND LIFESPAN INCREASES. DEVELOPING EFFECTIVE TREATMENT STRATEGIES IS OF THE UPMOST IMPORTANCE, AS THIS IMPAIRMENT PLACES A HUGE BURDEN ON THE PATIENTS THEMSELVES, THEIR CAREGIVERS, AND HEALTHCARE RESOURCES. THE NEWEST MONOCLONAL ANTIBODY TREATMENTS CAN REDUCE AMYLOID ACCUMULATION BUT WITH ONLY A MODEST IMPACT ON COGNITIVE DECLINE. HOWEVER, REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION (RTMS) IS A PROMISING TREATMENT STRATEGY THAT UTILIZES ELECTROMAGNETICS TO NONINVASIVELY ACTIVATE CORTICAL CELLS AND RESTORE COGNITIVE FUNCTION. WE BELIEVE THAT AMYLOID MUST BE REDUCED IN ORDER TO MAXIMIZE THE MEMORY-BOOSTING EFFECT OF RTMS. THEREFORE, COMBINING A PHARMACOLOGICAL INTERVENTION TO REDUCE PLAQUE ACCUMULATION WITH BRAIN STIMULATION TO RESTORE COGNITION COULD PROVE TO BE AN EFFECTIVE TREATMENT STRATEGY FOR THE MULTI-DIMENSIONAL COMPONENTS TO MCI AND AD. THIS PROPOSAL AIMS TO SYSTEMATICALLY TEST THE COMBINED EFFECTS OF ANTI-AMYLOID TREATMENT AND BRAIN STIMULATION IN THE 3XTG-AD MOUSE LINE BY UTILIZING BIOCHEMISTRY, ELECTROCORTICOGRAPHY (ECOG), AND MOUSE BEHAVIORAL ANALYSIS. MICE WILL BE EXPOSED TO ONE OF TWO ANTIBODY DOSES AND AN RTMS PROTOCOL PREVIOUSLY SHOWN TO IMPROVE COGNITION IN 3XTG-AD MICE IN OUR LABORATORY. TREATMENT CONDITIONS FOR THE 3XTG-AD MICE INCLUDE 1) BOTH TREATMENTS, 2) ONE TREATMENT WITH SHAM OR VEHICLE, OR 3) BOTH SHAM AND VEHICLE. WILD TYPE MICE (B6) WILL BE INCLUDED TO QUALITATIVELY MEASURE STIMULATION AND VEHICLE SHAM INJECTION EFFECTS. WE WILL ASSESS ALL MICE FOR A BIOCHEMICAL RESPONSE (AIM 1), AS WELL AS MEMORY AND ECOG IMPROVEMENTS (AIM 2). TO BRIDGE THE GAP BETWEEN HUMAN AND RODENT RESEARCH, WE WILL QUANTIFY ECOG AND STIMULUS-EVOKED RESPONSES WITH THE EXPECTATION TO NORMALIZE HYPERACTIVITY. ECOG MEASUREMENTS WILL ALSO DOUBLE AS AN ASSESEMENT FOR SEIZURE-RELATED ACTIVITY TO TEST FOR TRANSLATABLE SAFETY CONCERNS. RESULTS FROM THIS PROPOSAL WILL PROVIDE VALUABLE INSIGHT INTO COMBINING TWO THERAPIES, CAPABLE OF TACKLING DIFFERENT ASPECTS OF MCI AND AD. SUCCESSFUL IMPLEMENTATION OF THIS RESEARCH COULD OPEN THE DOOR TO A NEW AVENUE OF TREATMENT FOR NEURODEGENERATION AND RESULT IN IMPROVEMENT IN THE QUALITY OF LIFE FOR MANY SUFFERING FROM THIS DISEASE.

GOALS AND SHORT-TERM OUTCOMES OF AL-ANON

METABOLIC SYNDROME AS WOMEN UNDERGO MENOPAUSAL TRANSITION: A MULTI-ETHNIC STUDY

PARTICIPATORY SYSTEM DYNAMICS FOR EVIDENCE-BASED ADDICTION AND MENTAL HEALTHCARE

AN AUTOIMMUNE BASIS FOR PULMONARY HYPERTENSION

LEVERAGING CONSANGUINITY IN PAKISTAN TO UNCOVER THE GENOMIC ARCHITECTURE OF ALZHEIMER'S DISEASE: FEASIBILITY STUDY WITH ENIGMA-PAK - PROJECT SUMMARY/ABSTRACT CURRENTLY, THERE ARE ALMOST 55 MILLION PEOPLE LIVING WITH DEMENTIA WORLDWIDE, AND THIS NUMBER IS ESTIMATED TO DOUBLE EVERY 20 YEARS, REACHING ABOUT 131.5 MILLION IN 2050. MOST OF THE PATIENTS SUFFERING FROM DEMENTIA (58%) LIVE IN LOW- AND MIDDLE-INCOME COUNTRIES (LMIC), WITH THE FASTEST GROWTH IN THE ELDERLY POPULATION TAKING PLACE IN CHINA, PAKISTAN, AND THEIR SOUTH ASIAN AND WESTERN PACIFIC NEIGHBORS. PAKISTAN IS THE FIFTH MOST POPULOUS COUNTRY IN THE WORLD AND CURRENTLY HAS AN ESTIMATED 150,000–200,000 PATIENTS WITH DEMENTIA. IMPORTANTLY, MORE THAN 63% OF ALL MARITAL UNIONS IN PAKISTAN ARE CONSANGUINEOUS POSING A GREATER IMPACT ON GENETICALLY TRANSMITTED DISEASES LIKE AD. CONSANGUINITY, ALTHOUGH PREVALENT IN DENSELY POPULATED LMICS (E.G., MIDDLE EASTERN AND NORTH AFRICAN COUNTRIES), IS GRAVELY UNDERREPRESENTED IN CURRENT INTERNATIONAL AD RESEARCH INITIATIVES. THUS, INCLUDING THE PAKISTANI POPULATION, PROVIDES A UNIQUE OPPORTUNITY TO FURTHER DIVERSIFY GENOMIC STUDIES OF AD AND RELATED DEMENTIA. THEREFORE, THE ENIGMA-PAK TEAM ALONG WITH AGA KHAN UNIVERSITY (AKU) IN KARACHI, PAKISTAN, AND NIA-FUNDED ADSP INVESTIGATORS HAVE JOINED HANDS TO CONDUCT A PILOT STUDY TO ESTABLISH FEASIBILITY AND COLLECT PRELIMINARY GENETIC DATA FROM A CONSANGUINEOUS COHORT (N=200) FROM AN URBAN AND A PERI-URBAN SITE IN PAKISTAN. ADDITIONALLY, MRI DATA FROM 10 INDIVIDUALS WILL ALSO BE COLLECTED ON ADNI-3 PROTOCOL TO SHOW FEASIBILITY. THE STUDY WILL LEVERAGE EXISTING NIA-FUNDED RESOURCES, INCLUDING (1) URDU-TRANSLATED CONSENT FORMS AND INSTRUMENTS AS WELL AS DATA PROTOCOL FROM THE LONGITUDINAL AGING STUDY IN INDIA - DIAGNOSTIC ASSESSMENT OF DEMENTIA (LASI-DAD) STUDY, WHICH IS BASED IN INDIA; (2) NIA-FUNDED NATIONAL CELL REPOSITORY FOR AD (NCRAD) AND NIA GENETICS OF ALZHEIMER'S DISEASE DATA STORAGE (NIAGADS) WHICH WILL PROCESS AND STORE GENETIC DATA; AND (3) THE PHENOTYPE HARMONIZATION CENTER (PHC) TO HARMONIZE THE PHENOTYPIC DATA. THE MAIN AIMS OF THIS FEASIBILITY STUDY ARE TO HARMONIZE DATA ACQUISITION WITH THE PROTOCOL USED IN THE LASI-DAD STUDY (AIM 1), COLLECT BLOOD AND MRI DATA FROM SMALL COHORTS AND TO HARMONIZE BOTH GENETIC AND PHENOTYPIC DATA WITH NIA-FUNDED ADSP CORES (AIM 2). EVENTUALLY, THE GOAL IS TO ACQUIRE FEASIBILITY DATA FROM PAKISTAN THAT IS VERIFIED AND HARMONIZED BY THE ADSP CORES TO ALLOW US TO PURSUE SUBSEQUENT NIA FUNDING UNDER THE “ADSP FOLLOW-UP STUDY (FUS) 2.0: THE DIVERSE POPULATION INITIATIVE''.

STATIN-BERBERINE COMBINATION THERAPY IN HYPERLIPIDEMIA

TARGETING THE DEFAULT MODE NETWORK: A TMS-FMRI STUDY - PROJECT SUMMARY / ABSTRACT POST-TRAUMATIC STRESS DISORDER (PTSD) IS A DEVASTATING ILLNESS IN WHICH TRAUMATIC AUTOBIOGRAPHICAL MEMORIES ARE INTRUSIVE AND LEAD TO ANXIETY SYMPTOMS. THESE SYMPTOMS ALIGN WITH THE FUNCTIONS OF THE DEFAULT MODE NETWORK (DMN) AND, IN FACT, PTSD PATIENTS HAVE ABNORMALITIES WITHIN THE DMN AND IN ITS INTERACTIONS WITH OTHER NETWORKS, NOTABLY THE SALIENCE NETWORK AND THE FRONTOPARIETAL OR CENTRAL EXECUTIVE NETWORK. FOCAL REPETITIVE PULSE TRANSCRANIAL MAGNETIC STIMULATION (RTMS) ENABLES NEUROMODULATION OF SELECTED BRAIN REGIONS AND CONNECTED NETWORKS TO TREAT SPECIFIC SYMPTOMS, BUT THE BRAIN TARGETS TO SUPPORT THIS THERAPY IN PTSD ARE UNDER DISCOVERY. A RECENT ANALYSIS UNCOVERED A BRAIN CIRCUIT ASSOCIATED WITH IMPROVEMENT IN ANXIETY AND SOMATIC SYMPTOMS FOLLOWING THE RTMS TREATMENT OF DEPRESSION. THE LEFT HEMISPHERE REGION WITH THE STRONGEST FMRI FUNCTIONAL CONNECTIVITY WITH THIS CIRCUIT LIES WITHIN ANATOMICAL AREA 8AV AND THE DMN. THIS ASSOCIATION SUGGESTS THAT MODULATING THE DMN THROUGH STIMULATION AT LEFT 8AV COULD BE A NOVEL RTMS APPROACH FOR THE TREATMENT OF ANXIETY AND MAY HELP AMELIORATE ANXIETY SYMPTOMS IN PTSD. THIS TARGET WOULD BE NOVEL SINCE THE VAST MAJORITY OF CLINICAL TRIALS OF RTMS IN PTSD HAVE TARGETED THE RIGHT FRONTAL REGIONS OF THE SALIENCE AND FRONTOPARIETAL NETWORKS INSTEAD OF THE DMN. ONE POTENTIAL REASON IS THAT THE MOST ESTABLISHED NODES OF THE DMN DO NOT LIE DIRECTLY BELOW THE SCALP/SKULL AND ARE THUS UNREACHABLE BY RTMS. IN THIS PROPOSAL WE TEST THE OVERALL HYPOTHESIS THAT LEFT AREA 8AV CAN SERVE AS A ROBUST, DIRECT BRAIN TARGET FOR THE DMN THUS FACILITATING THERAPY FOR PTSD AND THE MANY OTHER DISORDERS INVOLVING THE DMN. WE PROPOSE TO USE TMS-FMRI IN 30 VETERANS WITH PTSD TO TEST THE CAUSAL CONNECTIONS BETWEEN LEFT 8AV AND OTHER REGIONS THAT COULD MEDIATE A RESPONSE. WE WILL TEST THE CONNECTIVITY BETWEEN 8AV AND THE INFERIOR PARIETAL LOBE (IPL), A REGION IN THE DMN INVOLVED IN CONTEXT PROCESSING, AND OTHER NODES OF THE DMN (E.G., POSTERIOR CINGULATE, VENTROMEDIAL PREFRONTAL CORTEX). WE HAVE PILOT DATA IN WHICH WE FOUND THE FUNCTIONAL CONNECTION BETWEEN 8AV AND THE IPL TO BE ABNORMAL RELATIVE TO CONTROLS, AND ALSO THAT DELIVERING RTMS TO THESE REGIONS AMELIORATES ANXIETY. WE WILL ALSO EXPLORE WHETHER STIMULATION AT 8AV MODULATES THE ANTERIOR INSULA, A NODE OF THE SALIENCE NETWORK WHOSE FUNCTIONAL CONNECTIVITY PREDICTS BENEFIT FROM PROLONGED EXPOSURE THERAPY IN PTSD. WE WILL MEASURE THE TMS INDUCED BOLD RESPONSE IN THESE AREAS TO STIMULATION OF 8AV AND COMPARE THIS RESPONSE TO CONVENTIONAL SEED-BASED RESTING-STATE FMRI FUNCTIONAL CONNECTIVITY ANALYSES THAT COULD SERVE AS AN ALTERNATIVE MARKER FOR CAPACITY FOR MODULATION. IN ADDITION WE WILL DELIVER THETABURST RTMS STIMULATION AND STUDY HOW CONNECTIVITY CHANGES WITH RESPECT TO BASELINE. OUR OVERALL GOAL IS TO CHARACTERIZE LEFT 8AV FUNCTIONAL CONNECTIVITY IN PTSD, AND EXPLORE THE EFFECTS OF RTMS STIMULATION PARAMETERS. THIS PROJECT WILL THUS PROVIDE A MECHANISTIC UNDERSTANDING OF RTMS THERAPY AT 8AV, AND WILL REVEAL THE EFFECTS OF A NOVEL CONNECTIVITY-BASED ATLAS TARGET.

THE IN SILICO GENETIC ANALYSIS OF OPIOID ADAPTATIONS

THROMBOMODULIN RECEPTORS ON IMMUNE CELLS

GINSENOSIDE RB1 DECREASES INJURY-INDUCED VASCULAR RESTENOSIS

NEUROIMAGING CORRELATES OF MEMORY DECLINE FOLLOWING CAROTID INTERVENTIONS

ISS: TISSUE ENGINEERED MUSCLE IN MICROGRAVITY AS A NOVEL PLATFORM TO STUDY SARCOPENIA

CITRULLINATION OF APOA1 AS A NOVEL CONTRIBUTOR TO INFLAMMATORY ATHEROGENESIS

NOVEL DENDRITIC CELL CHEMOATTRACTANT AND RECEPTOR

CELLS PROCESSING HIGH DENSITY LIPOPROTEINS

IMPACT OF SOCIAL NETWORKING ON DOSE AND EFFECTS OF CANCER SURVIVORSHIP TRIALS

PAIN, DEPRESSION AND ALCOHOL USE IN LATER LIFE

ROLE OF PERIPHERAL DENDRITIC CELLS IN CENTRAL AND ORAL TOLERANCE

DIVALPROEX AND PLACEBO, LITHIUM, OR QUETIAPINE FOR MANIA

EFFECTS OF INHALED NICOTINE ON VASCULAR MIR-24 ACTIVITY AND AAA FORMATION

NOVEL FC RECEPTOR BLOCKERS AS DISEASE-MODIFYING ANALGESICS

APPLICATION OF ELECTRICAL CURRENT FOR PROMOTING LYMPHATIC REGENERATION

TOWARDS AN UNBIASED ESTIMATE OF THE EFFECTIVENESS OF ALCOHOLICS ANONYMOUS

MOLECULAR MECHANISMS OF MAMMALIAN SIRT6 FUNCTION

A NEW FMRI METHOD TO MEASURE SUBSTANTIA NIGRA SIGNALING DURING REWARD PROCESSING

NEW AWARD - TARGETING MITOCHONDRIAL ENERGY METABOLISM FOR SYMPTOMATIC IMPROVEMENTS IN GULF WAR ILLNESSES, SIGNED 4/15/2020, EFFECTIVE 7/1/2020, DISTRIBUTED 4/20/20, FAADC 4/20/2020

SKELETAL MUSCLE GROWTH HORMONE RESISTANCE IN UREMIA

ENHANCING EMOTION REGULATION DURING DRIVING IN OEF/OIF VETERANS

TESTOSTERONE REPLACEMENT THERAPY IN ADVANCED CHRONIC KIDNEY DISEASE

TARGETING THE NOCICEPTIN/ORPHANIN FQ RECEPTOR FOR SCLERODERMA THERAPY

LEUKOTRIENE B4-MEDIATED PULMONARY ARTERIAL HYPERTENSION

FEASIBILITY OF CCR5 INHIBITORS IN PREVENTING MATERNAL TO INFANT SIV TRANSMISSION

AN EVALUATION OF COGNITIVE PROCESSING THERAPY TO TREAT VETERANS IN A PTSD RESIDENTIAL REHABILITATION PROGRAM

ENAC REGULATION BY CELL SURFACE ASSOCIATED SGK1

MOLECULAR MECHANISMS OF MAMMALIAN SIRT6 FUNCTION

ALCOHOLISM COURSE THROUGHOUT MIDLIFE

DEVELOPING METHODS FOR BRAIN STIMULATION ENHANCED FEAR REVERSAL IN PTSD

ALCOHOL SCREENING SCORES AND MEDICAL OUTCOMES: AGE AND GENDER INFLUENCES

REGULATION OF ROTAVIRUS REPLICATION AND VIRULENCE BY THE INNATE AND ADAPTIVE IMMUNE SYSTEMS

RESPIRATORY TRACT MICROBIOTA OF THE BOTTLENOSE DOLPHIN

7TH ANNUAL CONFERENCE ON ARTERIOSCLEROSIS, THROMBOSIS AND VASCULAR BIOLOGY

COLLABORATIVE RESEARCH: A MINIATURIZED UROPATHOGEN DETECTION SYSTEM

ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY/PERIPHERAL VASCULAR DISEASE 2017 SCIENTIFIC SESSIONS

2018 WESTERN EPITHELIAL BIOLOGY SOCIETY (WEBS) MEETING

GRADUATE PSYCHOLOGY EDUCATION PROGRAMS