Ocean State Research Institute Inc

ENDOTHELIAL INJURY AND REPAIR: CARDIOPULMONARY VASCULAR BIOLOGY COBRE

CARDIOPULMONARY VASCULAR BIOLOGY COBRE - CARDIOPULMONARY VASCULAR BIOLOGY COBRE TEAM SCIENCE SUPPLEMENT PROJECT SUMMARY: GOAL OF THE PARENT AWARD: THE VISION OF THE CARDIOPULMONARY VASCULAR BIOLOGY (CPVB) COBRE PROGRAM IS TO DEVELOP EFFECTIVE APPROACHES TO PREVENT AND TREAT VASCULAR DISEASES AFFECTING THE PULMONARY AND CARDIOVASCULAR SYSTEMS THROUGH BETTER UNDERSTANDING OF DISEASE MECHANISMS. THIS IS ACCOMPLISHED BY SERVING AS AN INTERDISCIPLINARY CENTER WHICH PROMOTES COLLABORATIVE RESEARCH AND PROVIDES EXCELLENT TECHNICAL SUPPORT AND RESOURCES TO INVESTIGATORS. THE OVERALL MISSION OF THE CPVB COBRE PROGRAM HAS BEEN TO BUILD THE HUMAN AND TECHNICAL INFRASTRUCTURE AND SERVICES THAT SERVE AS CATALYSTS TO INCREASE CPVB RESEARCH IN THE STATE. CARDIOVASCULAR AND PULMONARY DISEASES ARE AMONG THE LEADING CAUSES OF MORBIDITY AND MORTALITY IN THE US AND IN THE WORLD. THUS, THERE IS AN IMPORTANT NEED TO UNDERSTAND THE PATHOGENESIS OF CARDIOPULMONARY VASCULAR DISEASES IN ORDER TO DEVELOP MORE EFFECTIVE TREATMENTS AND PREVENTION. THE OVERALL GOAL OF THE CPVB COBRE PROGRAM IS TO FACILITATE HIGH IMPACT VASCULAR BIOLOGY RESEARCH. THE CPVB COBRE PROGRAM PROVIDES INFRASTRUCTURE WITH ADMINISTRATIVE, PILOT PROJECT, AND TWO TECHNICAL CORES, THUS PROVIDING OPPORTUNITIES TO EXPAND AREAS OF INVESTIGATION, EXPERIMENTAL AND TECHNICAL APPROACHES, AND SCIENTIFIC COLLABORATIONS. THE SPECIFIC AIMS OF PHASE III CPVB COBRE ARE TO: I) AWARD HIGH-IMPACT RESEARCH PROJECTS IN THE AREA OF CARDIOPULMONARY VASCULAR BIOLOGY; II) PROVIDE EFFECTIVE AND HIGH-QUALITY SERVICES IN CELL ISOLATION AND EX VIVO ORGAN FUNCTION (CIOF), MITOCHONDRIAL FUNCTION, AND IN VIVO IMAGING (MF-II); III) COLLABORATE WITH IDEA PROGRAMS IN RHODE ISLAND (RI) AND OTHER STATES TO FOSTER SCIENTIFIC NETWORKS BY PROVIDING PROGRAMMING, FUNDING, TECHNICAL SERVICES, AND RESOURCES TO ENHANCE RESEARCH PRODUCTIVITY; AND IV) MAINTAIN A ROBUST LINE OF INVESTIGATION IN VASCULAR BIOLOGY THAT MEETS THE NEEDS OF THE SCIENTIFIC COMMUNITY AND FURTHERS RESEARCH IN PREVENTION AND TREATMENT OF CARDIOPULMONARY VASCULAR DISEASES. WE WILL EXPAND AND ENRICH THE VASCULAR BIOLOGY RESEARCH COMMUNITY BY PROMOTING NEW COLLABORATIONS AND ENGAGING SCIENTISTS NEW TO THE FIELD FROM A VARIETY OF DISCIPLINES. AT THE END OF PHASE III, WE EXPECT TO TRANSITION TO A SUSTAINABLE CPVB CENTER SERVING AS A HOME TO THE CVPB RESEARCH COMMUNITY WITH HIGH QUALITY CORE SERVICES, SIGNIFICANT INSTITUTIONAL SUPPORT, AND COMMITMENT TO CONTINUE THE DEVELOPMENT OF EFFECTIVE APPROACHES TO COMBAT OR RESOLVE CARDIOPULMONARY VASCULAR DISEASES. RESEARCH QUESTION TO BE ADDRESSED BY THE SUPPLEMENT AWARD: RIGHT VENTRICULAR (RV) DYSFUNCTION IN SETTINGS OF PULMONARY HYPERTENSION (PH) IS ASSOCIATED WITH POOR OUTCOMES IRRESPECTIVE OF ASSOCIATED COMORBIDITIES AND UNDERLYING CONDITIONS. PH IS COMMON AND AFFLICTS ~ 1 % OF WORLD POPULATION, IS COMMONLY ASSOCIATED WITH CARDIOPULMONARY DISEASES, AND IN MANY CASES IS ASSOCIATED WITH PULMONARY VASCULAR REMODELING. DESPITE THE KNOWN POOR PROGNOSIS ASSOCIATED WITH RV DYSFUNCTION, TO DATE, NO RV TARGETED THERAPIES ARE AVAILABLE, AND THE UNDERLYING MECHANISMS OF RV DYSFUNCTION REMAIN UNCLEAR. THEREFORE, THERE IS AN UNMET NEED FOR A BETTER UNDERSTANDING OF CELLULAR AND MOLECULAR MECHANISMS ASSOCIATED WITH RV DYSFUNCTION AND TO CONVERT THIS KNOWLEDGE INTO THERAPIES. PATHOPHYSIOLOGICAL MECHANISMS ASSOCIATED WITH RV DYSFUNCTION INCLUDE CHANGES IN CELLULAR COMPOSITION OF THE MYOCARDIUM, MATRIX REMODELING (E.G., FIBROSIS), METABOLIC DYSFUNCTION RESULTING IN HEART FAILURE AND VENTRICULAR AND ATRIAL ARRHYTHMIAS. WHILE REDUCTIONIST APPROACHES HAVE RESULTED IN IMPORTANT INSIGHTS INTO ROLE OF SPECIFIC CELL TYPES AND SIGNALING PATHWAYS, A COMPREHENSIVE EVALUATION USING MULTI-SCALE AND MULTI- OMICS EVALUATION AND USE OF NOVEL DATA-SCIENCE ANALYTICAL TECHNIQUES TO IDENTIFY THE NETWORKS AND PATHWAYS THAT UNDERLIE MALADAPTIVE RV AND RV DYSFUNCTION HAS NOT BEEN PERFORMED AND IS THE OVERALL OBJECTIVE OF THIS PROPOSAL. WHY NEED FOR TEAM SCIENCE EFFORT? CONSIDERING THE MULTIPLE PATHOPHYSIOLOGICAL MECHANISMS, CELL TYPES AND PHENOTYPES (ARRHYTHMIA, ENERGETIC AND MECHANICAL FAILURE) ASSOCIATED WITH RV DYSFUNCTION, THERE IS NEED TO BRING TOGETHER EXPERTS IN MYOCARDIAL BIOLOGY, MITOCHONDRIAL BIOLOGY, AND ARRHYTHMIA BIOLOGY. FURTHERMORE, USE OF LARGE UNBIASED DATASETS TO UNRAVEL NOVEL NETWORKS AND PATHWAYS UNDERLYING RV DYSFUNCTION REQUIRES ANALYTICAL AND METHODOLOGICAL EXPERTISE IN REDUCING THE DIMENSIONALITY OF DATA AND IDENTIFICATION OF IMPORTANT MULTI-OMIC NETWORK FEATURES USING NOVEL ARTIFICIAL INTELLIGENCE BASED METHODOLOGY THAT RELATE WITH THE MALADAPTIVE PHENOTYPES IN SETTINGS OF RV DYSFUNCTION. THESE DATA, APPROACHES AND COLLABORATIONS ARE EXPECTED TO RESULT IN MULTI-PI AND PROGRAM PROJECT GRANT APPLICATIONS THAT WILL LEAD TO SUSTAINABLE TEAMS TO PERFORM IMPACTFUL SCIENTIFIC INVESTIGATION IN CARDIOPULMONARY VASCULAR DISEASES SUCH AS RV DYSFUNCTION AND FAILURE.

NEUROIMAGING BIOMARKER FOR SEIZURES

NEEDS, PREFERENCES, AND FUNCTIONAL ABILITIES OF VETERANS AND SERVICE MEMBERS WITH UPPER-LIMB AMPUTATION

LOW INTENSITY FOCUSED ULTRASOUND: A NEW PARADIGM FOR DEPRESSION AND ANXIETY - PROJECT SUMMARY/ABSTRACT CURRENT TREATMENTS FOR DEPRESSION AND ANXIETY ARE OFTEN LIMITED BY PARTIAL EFFICACY AND SIGNIFICANT SIDE EFFECTS. THESE DISORDERS CONSTITUTE SERIOUS PUBLIC HEALTH CHALLENGES DUE TO SIGNIFICANT BURDEN OF ILLNESS, AND THE LACK OF MORE EFFECTIVE TREATMENTS CONTRIBUTES TO SUBSTANTIAL SUICIDE RISKS. TO ADDRESS THESE UNMET NEEDS, NON-INVASIVE BRAIN STIMULATION IS A CIRCUIT-BASED TREATMENT WITH MINIMAL SIDE EFFECTS; IT IS CLINICALLY AVAILABLE FOR MAJOR DEPRESSION AND OBSESSIVE-COMPULSIVE DISORDER, WITH EVIDENCE FOR EFFICACY IN ANXIETY AND POSTTRAUMATIC STRESS DISORDER. ONE OF THE CORE BRAIN REGIONS INVOLVED IN THESE DISORDERS, AMONG OTHERS, IS THE AMYGDALA, WITH ITS CRITICAL ROLE IN SALIENCE DETECTION AND EMOTION PROCESSING. THIS REGION DEMONSTRATES PATHOLOGICAL ACTIVATION IN NEARLY ALL DEPRESSIVE AND ANXIETY DISORDERS, AND PATHOLOGICAL ACTIVITY CHANGES WITH SUCCESSFUL TREATMENT. YET, BECAUSE THE AMYGDALA IS DISTAL TO THE CORTICAL SURFACE IT IS NOT DIRECTLY ACCESSIBLE WITH CURRENT TECHNOLOGIES. OUR CHALLENGE IS TO FIND A WAY TO FOCALLY AND NON-INVASIVELY MODULATE THE AMYGDALA, WITH THE BROADER HYPOTHESIS THAT DIRECT ENGAGEMENT WILL YIELD TREATMENTS WITH SUPERIOR CLINICAL OUTCOMES. LOW INTENSITY PULSED FOCUSED ULTRASOUND (LIFU) APPLIES NON-INVASIVE ACOUSTIC ENERGY TO SAFELY MODULATE NEURAL ACTIVITY IN TRANSLATIONAL MODELS AND NON-HUMAN PRIMATES. UNLIKE TRANSCRANIAL MAGNETIC OR ELECTRICAL STIMULATION AND RELATED TECHNOLOGIES, LIFU IS ABLE TO DIRECTLY AND FOCALLY MODULATE ACTIVITY WITHIN DEEP BRAIN STRUCTURES. LIFU CAN SAFELY MODULATE HUMAN SOMATOSENSORY AND MOTOR CORTEX AND SAFELY SUPPRESS THALAMIC ACTIVITY; RECENT DATA INDICATES IT CAN SUPPRESS AMYGDALA ACTIVITY. FURTHERMORE, AN MRI-COMPATIBLE LIFU SYSTEM IS NOW AVAILABLE (BRAINSONIX, INC. LA, USA), THUS PERMITTING SIMULTANEOUS FMRI-LIFU EXPERIMENTS. THESE FACTORS CREATE A COMPELLING ARGUMENT TO DEVELOP LIFU AS A TREATMENT FOR DEPRESSION AND ANXIETY BY TESTING WHETHER IT CAN SAFELY MODULATE THE AMYGDALA. TO SET THE STAGE FOR FUTURE CLINICAL TRIALS, WE MUST FIRST TEST HOW LIFU ENGAGES THE AMYGDALA IN PATIENTS WITH DEPRESSION AND ANXIETY. IN ACCORDANCE WITH THE U01 RFA, WE PROPOSE SEVERAL PILOT EXPERIMENTS. WE WILL SYSTEMATICALLY ASSESS SAFETY (AIM 1) AS WE EVALUATE SPATIAL SPECIFICITY OF TARGET ENGAGEMENT, USING ONLINE AND OFFLINE APPROACHES (AIMS 2-3) USING A RANDOMIZED, ANATOMICALLY CONTROLLED, EXPERIMENTAL DESIGN, AND EXPLORE THE IMPACT OF LIFU ON CLINICAL SYMPTOMS. WE OBTAINED AN INVESTIGATIONAL DEVICE EXEMPTION (IDE) FROM THE FDA FOR THIS PROPOSAL AS IT IS WRITTEN. IF SUCCESSFUL, THIS FIRST-IN-HUMAN PROPOSAL WILL PROVIDE THE NECESSARY DATA TO SUPPORT A BROAD AND PROGRAMMATIC RESEARCH FOCUS ON CLINICALLY APPLIED LIFU FOR DEPRESSION AND ANXIETY. RESULTING DATA WILL INFORM FUTURE STUDIES, INCLUDING IMPROVEMENT OF INDIVIDUAL-LEVEL MODELING FOR LIFU, INFORMING OPTIMAL TARGETS TO ENGAGE, REFINEMENT OF LIFU SHAMS, AND EVALUATING EFFECTS OF VARIED LIFU PARAMETERS OR MULTIPLE SESSIONS.

COMBINING TARGETED DEMETHYLATION WITH NONCODING RNA-MEDIATED MRNA STABILIZATION AS A STRATEGY FOR THERAPEUTIC ARTERIOGENESIS IN THE AGED - ABSTRACT: AGING AND AGE-RELATED DISEASES LIKE PERIPHERAL ARTERY DISEASE (PAD) LEAD TO CONSIDERABLE MORBIDITY AND MORTALITY. AGING IS ASSOCIATED WITH IMPAIRED INFLAMMATORY ARTERIOGENESIS RESPONSES TO INJURY. WE DEFINED A MACROPHAGE SIGNALING AXIS THAT ACTIVATES THE MRNA STABILIZING PROTEIN, HUR, TO PROMOTE VEGF-A EXPRESSION REQUIRED FOR ARTERIOGENESIS. WE SEEK TO UNDERSTAND THE EFFECTS OF AGING ON THIS PATHWAY. MODERATELY AGED (52- WEEK-OLD) MICE DEMONSTRATED REDUCED BLOOD FLOW RECOVERY AND DECREASED ARTERIOGENESIS RELATIVE TO YOUNG (12- WEEK-OLD) MICE IN A FEMORAL ARTERY LIGATION MODEL OF ISCHEMIA. IN AGED MICE, ISCHEMIC MUSCLE TISSUE AND MACROPHAGES REVEALED REDUCED VEGF-A EXPRESSION. AGED MACROPHAGES DEMONSTRATED INCREASED GLOBAL DNA METHYLATION, AND THOUGH MACROPHAGE HUR EXPRESSION WAS NORMAL, THERE WAS REDUCED HUR BINDING TO VEGF-A MRNA WITH CONSEQUENT SHORTENED VEGF-A MRNA HALF-LIFE. SOMEWHAT SURPRISINGLY, DICER1, PREVIOUSLY ESTABLISHED AS DESTABILIZING FOR VEGF-A MRNA, WAS DOWNREGULATED IN AGED MACROPHAGES. THE DNMT INHIBITOR, RG108, LED TO INCREASED DICER1 AND VEGF-A EXPRESSION AND INCREASED HUR BINDING TO VEGF-A MRNA. MIR-29, AS A 3P MIRNA, APPEARS TO BE PARTICULARLY SENSITIVE TO CHANGES IN DICER1 EXPRESSION. AGED MACROPHAGES HAD DECREASED EXPRESSION OF MIR-29, WHOSE SEEDING SITE IN THE 3'-UTR OF VEGF-A IS ADJACENT TO THE HUR BINDING SITE. TRANSFECTION OF MACROPHAGES WITH MIR-29 MIMIC INCREASED VEGF-A EXPRESSION. MYELOID DICER1-DELETED MICE WERE PHENOTYPICALLY SIMILAR TO AGED MICE, HAVING DECREASED BLOOD FLOW RECOVERY, DECREASED VEGF-A EXPRESSION, AND DECREASED HUR BINDING TO VEGF-A MRNA WITH CONSEQUENT SHORTENED MRNA HALF-LIFE. OUR HYPOTHESIS IS THAT AGING ACQUIRED METHYLATION OF DICER1 WITH CONSEQUENT REDUCTIONS IN DICER1 DOSE-SENSITIVE MICRORNAS (I.E. MIR-29-3P) RESULTS IN REDUCED BINDING OF HUR TO VEGF-A MRNA AND REDUCTIONS IN BOTH VEGF-A EXPRESSION AND CONSEQUENT VEGF-A DEPENDENT ANGIO/ ARTERIOGENESIS. OUR AIMS SEEK TO 1) DEFINE DICER1 PROMOTER METHYLATION IN AGED MICE TO BE A MAJOR MECHANISM OF IMPAIRED VEGF-A- MEDIATED ARTERIOGENESIS WITH AGING; AND 2) DEFINE THE MOLECULAR MECHANISMS WHEREBY THE DICER1 DOSE- SENSITIVE MICRORNA, MIR-29-3P, PROMOTES HUR-BINDING TO VEGF-A MRNA WITH CONSEQUENT MESSAGE STABILIZATION. OUR STUDIES WILL LEAD TO A PARADIGM SHIFT FROM DICER1 AS A NEGATIVE REGULATOR OF VEGF-A TO THAT OF A POSITIVE REGULATOR. THE RESCUE OF MACROPHAGE VEGF-A EXPRESSION BY DEMETHYLATION OF DICER1 OR NONCODING RNA (I.E. MIR-29) MIMICS, MAY HAVE PROFOUND IMPLICATIONS IN THE DEVELOPMENT OF TREATMENT STRATEGIES THAT CAN PROMOTE ARTERIOGENESIS AND ASSOCIATED TISSUE PRESERVATION IN THE SETTING OF SEVERE AGE-RELATED VASCULOPATHIES.

METABOLIC MECHANISMS UNDERLYING BRONCHOPULMONARY DYSPLASIA-ASSOCIATED PULMONARY HYPERTENSION - SUMMARY BRONCHOPULMONARY DYSPLASIA (BPD) IS A CHRONIC LUNG DISEASE IN PREMATURE INFANTS, CAUSED BY MECHANICAL VENTILATION AND HYPEROXIA AMONGST OTHER FACTORS. THIRTY PERCENT OF INFANTS WITH BPD DEVELOP PULMONARY HYPERTENSION (PH), CHARACTERIZED BY PULMONARY VASCULAR (PV) REMODELING. THERE ARE NO CURATIVE THERAPIES FOR THIS DISEASE. MY LONG-TERM GOAL IS TO DEVELOP NOVEL TARGETED THERAPIES TO TREAT BPD ASSOCIATED PH (BPD-PH). PV REMODELING IS CHARACTERIZED BY INCREASED PULMONARY ARTERIAL MEDIA LAYER THICKENING. THIS RESULTS FROM PROLIFERATION OF VASCULAR SMOOTH MUSCLE CELLS (SMCS), OR TRANSDIFFERENTIATION FROM ENDOTHELIAL CELLS (ECS) TO SMCS (I.E., ENDOTHELIAL-MESENCHYMAL TRANSITION, ENDOMT). WE HAVE SHOWN THAT HYPEROXIA IN NEWBORN MICE AND MECHANICAL VENTILATION IN PRETERM LAMBS CAUSE PV REMODELING RESULTING IN PH, WHICH IS ASSOCIATED WITH INCREASED ENDOMT. WE PRELIMINARILY SHOW THAT ENDOMT IS ALSO OBSERVED IN THE LUNG OF PREMATURE HUMAN INFANTS REQUIRING MECHANICAL VENTILATION. BLOCKING ENDOMT PREVENTS THE PROGRESSION OF NEONATAL HYPEROXIA-INDUCED PV REMODELING AND PH IN MICE, SUGGESTING THAT ENDOMT PLAYS A CAUSATIVE ROLE IN INDUCING PH. WE OBSERVED NO INCREASE IN EDU INCORPORATION INTO SMCS IN HYPEROXIA-EXPOSED MICE, SUGGESTING PROLIFERATION IN THESE CELLS DOES NOT CONTRIBUTE TO PV REMODELING IN BPD-PH. WE RECENTLY REPORTED THAT NEONATAL HYPEROXIA CAUSES A PERSISTENT REDUCTION OF ENDOTHELIAL CARNITINE PALMITOYLTRANSFERASE 1A (CPT1A), THE RATE-LIMITING ENZYME OF THE CARNITINE SHUTTLE SYSTEM RESPONSIBLE FOR TRANSPORTING LONG-CHAIN FATTY ACIDS INTO MITOCHONDRIA FOR SS-OXIDATION DURING FATTY ACID OXIDATION. OUR PRELIMINARY DATA SHOW THAT LUNG CPT1A GENE EXPRESSION IS ALSO REDUCED IN MECHANICALLY VENTILATED PRETERM LAMBS AND PREMATURE HUMAN INFANTS. ADDITIONALLY, ENDOTHELIAL DELETION OF CPT1A INCREASES ENDOMT AND PV REMODELING IN NEONATAL MICE AFTER EXPOSURE TO HYPEROXIA. FURTHERMORE, PHARMACOLOGICAL UPREGULATION OF CPT1A ATTENUATES ENDOMT IN VITRO AND PREVENTS PV REMODELING IN NEONATAL MICE IN RESPONSE TO HYPEROXIA. WHETHER NEONATAL HYPEROXIA AND MECHANICAL VENTILATION REDUCE ENDOTHELIAL CPT1A, LEADING TO PH IS YET TO BE DETERMINED. THE CENTRAL HYPOTHESIS IS THAT NEONATAL HYPEROXIA AND MECHANICAL VENTILATION CAUSE ENDOMT BY DOWNREGULATING ENDOTHELIAL CPT1A LEVELS, THEREBY RESULTING IN PV REMODELING AND PH. WE WILL TEST THIS HYPOTHESIS IN THREE SPECIFIC AIMS. AIM 1 WILL DETERMINE THE MOLECULAR MECHANISMS BY WHICH CPT1A DOWNREGULATION CONTRIBUTES TO ENDOMT. IN AIM 2, WE WILL DEFINE THE CONTRIBUTION OF ENDOTHELIAL CPT1A REDUCTION TO BPD-PH AND ENDOMT. IN AIM 3, WE WILL EVALUATE ENDOTHELIAL CPT1A AS A THERAPEUTIC TARGET FOR BPD-PH USING BOTH LAMB AND MOUSE MODELS. THE COMBINATION OF CLINICALLY RELEVANT LAMB AND MOUSE MODELS WITH OUR NEWLY GENERATED EC-SPECIFIC CPT1A KO MICE AND THE NOVEL EC-TARGETED NANOPARTICLE DELIVERY SYSTEM PROVIDES AN INNOVATIVE APPROACH TO UNCOVER THE MECHANISMS BY WHICH CPT1A DOWNREGULATION MEDIATES ENDOMT AND ITS SIGNIFICANT ROLES IN BPD-PH. THIS CONTRIBUTION IS SIGNIFICANT BECAUSE IT IS LIKELY TO RESULT IN NEW THERAPIES SPECIFICALLY TARGETING ENDOTHELIAL CPT1A OR ENDOMT IN NEONATES TO TREAT BPD-PH.

DEVELOPMENT OF RAC-TARGETED THERAPEUTIC STRATEGY FOR TREATMENT OF CALCIFIC ATHEROSCLEROSIS

ROLE OF ENDOTHELIAL ANOCTAMIN-1 IN PULMONARY ARTERIAL HYPERTENSION

LONG-TERM OUTCOMES OF ANTIPSYCHOTIC MEDICATION USE IN VETERANS WITH PTSD

COMPARATIVE EFFECTIVENESS OF UPPER LIMB PROSTHESES AND COMPONENT EFFECTS. NEW AWARD.

NICOTINIC ACETYLCHOLINE RECEPTORS AND RV DYSFUNCTION IN PULMONARY HYPERTENSION

ROLE OF MITOCHONDRIAL C-SRC IN RIGHT VENTRICULAR DYSFUNCTION IN PULMONARY HYPERTENSION - PROJECT SUMMARY/ABSTRACT PULMONARY HYPERTENSION (PH) IS ASSOCIATED WITH POOR PROGNOSIS. RIGHT VENTRICULAR (RV) DYSFUNCTION/FAILURE CONSEQUENT TO HIGH RV AFTERLOAD IS THE PRIMARY CAUSE OF MORBIDITY AND MORTALITY IN PH, YET NO RV TARGETED THERAPIES ARE AVAILABLE. THIS CONTRASTS WITH SEVERAL DRUG CLASSES THAT ARE BENEFICIAL IN LV DYSFUNCTION. THEREFORE, THERE REMAINS AN UNMET NEED TO THERAPEUTICALLY TARGET THE MECHANISMS UNDERLYING RV DYSFUNCTION TO IMPROVE LONG-TERM OUTCOMES IN PH. CARDIOMYOCYTES DETERMINE RV FUNCTION IN PH. MITOCHONDRIA THROUGH OXIDATIVE PHOSPHORYLATION (OXPHOS) ARE THE MAJOR SOURCE OF ENERGY IN THE HEART. TARGETING RV MITOCHONDRIAL BIOENERGETICS AND FUNCTION IN SETTINGS OF PH MAY PROVIDE NOVEL THERAPEUTIC STRATEGIES TO IMPROVE RV FUNCTION IN PH. RESPIRATORY COMPLEXES IN THE MITOCHONDRIAL ELECTRON TRANSPORT CHAIN PLAY A CRITICAL ROLE IN OXIDATIVE PHOSPHORYLATION (OXPHOS) AND GENERATION OF REACTIVE OXYGEN SPECIES. OXPHOS MACHINERY SUBUNITS HAVE BEEN FOUND TO BE HIGHLY PHOSPHORYLATED, IMPLICATING PHOSPHORYLATION AS A MEANS WHEREBY OXPHOS IS REGULATED. TO DATE, TYROSINE PHOSPHORYLATION (P-TYR) IS RECOGNIZED AS A CRITICAL REGULATORY MECHANISM IN MITOCHONDRIA AND C-SRC IS THE MAJOR TYROSINE KINASE LOCALIZED IN MITOCHONDRIA. THE OVERALL GOAL OF THIS PROPOSAL IS TO DELINEATE THE MECHANISMS UNDERLYING IMPAIRED RV MITOCHONDRIAL ENERGETICS AND FUNCTION IN PH. OUR PRELIMINARY FINDINGS STRONGLY SUPPORT A NOVEL MECHANISM GOVERNING RV COMPLEX I ASSEMBLY AND FUNCTION IN PH THAT IS MEDIATED BY P-TYR OF COMPLEX PROTEINS. COMPLETION OF THIS STUDY IS EXPECTED TO IDENTIFY A NEW TARGETED STRATEGY TO PRESERVE/RESTORE ELECTRON TRANSFER CHAIN FUNCTION IN RV CARDIOMYOCYTES IN VIVO IN SETTINGS OF PH.

HDAC6 REGULATES CIGARETTE SMOKE-INDUCED ENDOTHELIAL BARRIER DYSFUNCTION AND LUNG INJURY

MYOARCHITECTURAL BASIS OF HEART FAILURE

RISK PREDICTION MODELS FOR RARE MELANOMAS

INCREASING EPILEPSY SELF-MANAGEMENT ACCESS FOR VETERANS BY EMBRACING A PARTNERED HUB AND SPOKE MODEL