Cedars Inc

HOST FACTORS IN REGULATION OF INFLAMMATORY AND FIBROPROLIFERATIVE LUNG DISEASE

IBD: GENETICS AND IMMUNOPATHOLOGIC MECHANISMS

PROSTATE CANCER BONE METASTASIS: BIOLOGY AND TARGETING

MOLECULAR TRANSDUCERS OF PHYSICAL ACTIVITY CLINICAL CENTERS (U01) - PITTSBURGH ADULT CLINICAL CENTER

ASSESSMENT OF BIOMARKER GUIDED CNI SUBSTITUTION IN KIDNEY TRANSPLANTATION - CURRENT STANDARD OF CARE FOR KIDNEY TRANSPLANT (KTX) RECIPIENTS HAS ONLY MODESTLY IMPROVED LONG-TERM AGGREGATE GRAFT AND/OR PATIENT SURVIVAL, IDENTIFYING A CRUCIAL UNMET MEDICAL NEED. AS THE AT-RISK KTX POPULATION IS HETEROGENEOUS, THE CURRENTLY EMPLOYED AND RELATIVELY HOMOGENEOUS THERAPEUTIC APPROACH TO IMMUNOSUPPRESSION IN KTX IN THE US AND CANADA IS SUBOPTIMAL, AND RESULTS IN A SIGNIFICANT PROPORTION OF OVER- IMMUNOSUPPRESSED RECIPIENTS, MANY WITH TACROLIMUS-RELATED TOXICITIES. IN THIS U01 APPLICATION, CO-PIS HEEGER AND NICKERSON WILL BUILD UPON THEIR PAST, PRODUCTIVE COLLABORATIVE EFFORTS, THEIR ESTABLISHED MULTICENTER TRIAL CONSORTIUM AND INFRASTRUCTURE, AS WELL AS THEIR EXPERTISE IN BIOMARKERS AND MECHANISTIC STUDIES TO ADDRESS THIS UNMET NEED. THE OVERARCHING GOAL OF THE PROPOSED WORK IS TO DETERMINE THE UTILITY OF THE HLA-DR/DQ MOLECULAR MISMATCH (MMM) SCORE, AS A RISK STRATIFYING BIOMARKER IN KTX. WHILE RETROSPECTIVE STUDIES SHOWED STRONG CORRELATIONS BETWEEN THE HLA-DR/DQ MMM SCORE AND THE RISK OF DEVELOPING BIOPSY PROVEN ACUTE REJECTION (BPAR) AND/OR DONOR SPECIFIC ANTIBODIES (DSA), NO PROSPECTIVE STUDIES HAVE TESTED THE HLA MMM SCORE AS A RISK STRATIFYING BIOMARKER FOR IMMUNOLOGICAL KTX INJURY. NOR HAVE ANY STUDIES ATTEMPTED TO TEST WHETHER AND HOW THE HLA-DR/DQ MMM SCORE PERFORMS AS A PREDICTOR OF OUTCOME FOLLOWING A CHANGE IN TRANSPLANT IMMUNOSUPPRESSION. HEREIN, WE PROPOSE A MULTICENTER OBSERVATIONAL STUDY WITH A NESTED RANDOMIZED CONTROLLED (RCT) TRIAL TO ADDRESS THESE DEFICIENCIES. WE WILL PROSPECTIVELY TEST THE UTILITY OF THE HLA-DR/DQ MMM SCORE AS A PROGNOSTIC BIOMARKER OF PRIMARY ALLOIMMUNITY [T CELL MEDIATED REJECTION (TCMR), DSA, AND ANTIBODY MEDIATED REJECTION (ABMR)] IN KTX (AIM 1, OBSERVATIONAL STUDY OF 800 KTX). WE WILL ALSO TEST THE HYPOTHESIS THAT THE HLA-DR/DQ MMM SCORE IS A PREDICTIVE BIOMARKER THAT IDENTIFIES KTX RECIPIENTS WHO WILL TOLERATE SUBSTITUTING THE CALCINEURIN INHIBITOR WITH SELF-ADMINISTERED, SUBCUTANEOUS ABATACEPT (COSTIMULATORY BLOCKADE), WITHOUT AN UNACCEPTABLE INCREASED RISK OF BPAR, WHILE REDUCING THE MORBIDITY OF CNI OFF-TARGET EFFECTS (300 KTX, NESTED RCT WITH A NON-INFERIORITY ENDPOINT, AIM 2). ACCOMPANYING MECHANISTIC STUDIES (AIM 3) WILL PROVIDE NOVEL IMMUNOLOGICAL AND MOLECULAR INSIGHTS THAT WILL ALSO AID IN INTERPRETING GRAFT AND RECIPIENT OUTCOMES OF THE TRIAL. IF SUCCESSFUL, THE WORK WILL PROVIDE CRUCIAL INFORMATION CAPABLE OF POSITIVELY, AND DIRECTLY AFFECTING CLINICAL CARE. THE RESULTS FROM THE PROPOSED WORK ALSO HAVE THE POTENTIAL TO INFLUENCE POSITIVELY THE DESIGN OF FUTURE RCTS BY PROVIDING AN HLA-DR/DQ MMM SCORE-BASED STRATIFICATION OR ENRICHMENT STRATEGY FOR ENROLLING SUBJECTS INTO TRIALS MOST LIKELY TO BE INFORMATIVE FOR THE PROPOSED STUDY AGENT-- THEREBY INCREASING LIKELIHOOD OF TRIAL SUCCESS IN THE SHORTEST POSSIBLE TIME.

MITOCHONDRIAL QUALITY IN CARDIOPROTECTION: OVERCOMING CO-MORBIDITIES

COLON CANCER FAMILY REGISTRY COHORT

MECHANISMS AND TREATMENT DEVELOPMENT FOR PANCREATITIS RESULTING FROM ALCOHOL ABUSE AND SMOKING

HEART FAILURE WITH PRESERVED EJECTION FRACTION: MECHANISMS AND NOVEL THERAPEUTICS

MAPPING THE GENES FOR IBD BY ADMIXTURE LINKAGE DISEQUILIBRIUM IN PUERTO RICANS

CEDARS-SINAI BIOBANK AND TRANSLATIONAL RESEARCH CORE FACILITY (CS-BRCF)

DETERMINANTS OF LIVER METASTASIS

DIVERSITY AND DETERMINANTS OF THE IMMUNE-INFLAMMATORY RESPONSE TO SARS-COV-2

THE MICROVASCULAR AGING AND EICOSANOIDS - WOMEN'S EVALUATION OF SYSTEMIC AGING TENACITY (MAE-WEST) ("YOU ARE NEVER TOO OLD TO BECOME YOUNGER!") SPECIALIZED CENTER FOR RESEARCH EXCELLENCE (SCORE)

SEX, CHROMOSOMES, AND IMMUNITY IN BLADDER CANCER - OVERALL – SUMMARY BLADDER CANCER (BC) IS 3-5 TIMES MORE COMMON IN MEN EVEN WHEN ADJUSTED FOR ENVIRONMENTAL FACTORS SUCH AS SMOKING, THE PRIMARY RISK FACTOR FOR THIS DISEASE. THE GOAL OF THIS PROGRAM PROJECT GRANT (PPG) IS TO ADVANCE OUR KNOWLEDGE OF “SEX AS A BIOLOGICAL VARIABLE (SABV)” IN BC, WITH THE ULTIMATE OBJECTIVE OF IMPROVING PATIENT OUTCOMES BY DISCOVERING SEX-SPECIFIC DRIVERS THAT CAN BE TARGETED THERAPEUTICALLY. BENCHMARKS OF SUCCESS AND IMPACT FOR THE PROGRAM INCLUDE IDENTIFICATION OF KEY IMMUNOLOGICAL, HORMONAL, CHROMOSOMAL, GENETIC, AND EPIGENETIC PATHWAYS RESPONSIBLE FOR SEX-DRIVEN BIOLOGICAL PHENOTYPES IN BC TO INSPIRE THE DESIGN OF A NOVEL LINE OF BC THERAPEUTICS BASED ON EACH PATIENT’S BIOLOGICAL SEX. TO THIS END, THE PPG WILL UNITE THREE LEADING LABORATORIES IN THEIR RESPECTIVE FIELDS, EACH TACKLING THE PROBLEM OF SABV FROM A UNIQUE AND COMPLEMENTARY STANDPOINT OF EXPERTISE: IMMUNOLOGY, CANCER BIOLOGY/FUNCTIONAL GENOMICS, AND EPIGENETICS. THESE THREE RESEARCH GROUPS, SUPPORTED BY CEDARS-SINAI MEDICAL CENTER CANCER CENTER AND THE OHIO STATE UNIVERSITY COMPREHENSIVE CANCER CENTER, HAVE A PROVEN HISTORY OF COLLABORATION, WITH NINE JOINT PUBLICATIONS SINCE 2017 AND MULTIPLE CO- AUTHORED PAPERS IN THE PIPELINE. PROJECT 1 AIMS TO UNCOVER THE IMMUNOLOGICAL BASIS OF SEX DIFFERENCES IN BC, TAKING ADVANTAGE OF A RECENT DISCOVERY IN T CELL INTRINSIC ANDROGEN RECEPTOR SIGNALING IN CD8+ T CELL EXHAUSTION. PROJECT 2 WILL FOCUS ON THE ROLE OF THE Y CHROMOSOME AND THE Y-LINED EPIGENETIC REGULATORS IN DRIVING BC PROGRESSION AND RESISTANCE TO IMMUNE CHECKPOINT BLOCKADE (ICB); AND PROJECT 3 WILL INVESTIGATE TUMOR SUPPRESSING ACTIVITY OF THE X CHROMOSOME-LINKED EPIGENETIC REGULATOR AND THE ROLES OF ANDROGEN AND ESTROGEN- DEPENDENT SEX HORMONE PATHWAYS, AIMING TO ELUCIDATE THE EPIGENETIC BASIS OF SEX DIFFERENCES IN BC. ALL THREE PROJECTS WILL BE SUPPORTED BY AN ADMINISTRATIVE CORE (ADMIN CORE) AND TWO SHARED RESOURCE CORES – THE SYSTEMS PATHOLOGY CORE (CORE 1) AND THE DATA SCIENCE CORE (CORE 2). ADMIN CORE WILL MANAGE AND SUPPORT THE ENTIRE PROGRAM BY OFFERING ADMINISTRATIVE AND FISCAL MANAGEMENT SUPPORT AND FACILITATING COMMUNICATION AND SCIENTIFIC INTERACTIONS. CORE 1 WILL PROVIDE STATE-OF-THE-ART DIGITAL PATHOLOGY SERVICES, AUTOMATED AND PERSONALIZED IMAGE ANALYSES, AND MULTIPARAMETER IMMUNE MONITORING. CORE 2 WILL PROVIDE UNIFIED DATA PROCESSING, ANALYTICAL PIPELINES, DATA INTEGRATION, DATA REPOSITORY, AND STATISTICAL CONSULTATION. BECAUSE MALE PREVALENCE IN CANCER INCIDENCE AND MORTALITY IS OBSERVED ACROSS MANY OTHER CANCER TYPES, OUR SCIENTIFIC FINDINGS WILL LIKELY HAVE BROAD IMPLICATIONS IN CANCER MEDICINE FAR BEYOND BC.

BARBER-PHARMACIST COORDINATION TO IMPROVE BLOOD PRESSURE MANAGEMENT IN BLACK MEN

MECHANISMS OF EPITHELIAL ALTERATIONS IN DIABETIC CORNEA

CSMC SPECIAL PATHOGENS REGIONAL EMERGING SPECIAL PATHOGEN TREATMENT CENTER COOPERATIVE AGREEMENT YEAR 1 - THE RECIPIENT, CEDARS-SINAI MEDICAL CENTER (CSMC), SUPPORTS THIS FIVE-YEAR REGIONAL EMERGING SPECIAL PATHOGEN TREATMENT CENTER COOPERATIVE AGREEMENT IN COLLABORATION WITH FEDERAL, STATE, AND LOCAL STAKEHOLDERS RELATED TO SPECIAL PATHOGENS (SP) PREPAREDNESS, RESPONSE, AND TREATMENT. THE GOAL OF THE CSMC SP PROGRAM IS TO CONTINUE TO SUSTAIN AND ADVANCE COMPREHENSIVE, COORDINATED RESPONSE AND TREATMENT FOR SP PATIENTS WITHIN HEALTH AND HUMAN SERVICES (HHS) REGION 9 (R9) AND FURTHER ABROAD, AS NEEDED. THE APPROACH IS TO EXPAND PREPAREDNESS EFFORTS AND ADVANCE TREATMENT AND RESEARCH CAPABILITIES WITHIN HHS R9 AS PART OF THE NATIONAL SPECIAL PATHOGENS PREPAREDNESS SYSTEM (NSPS). THE OBJECTIVES ARE: 1) TO MAINTAIN THE ABILITY TO BE READY TO ACCEPT AND TREAT SP PATIENTS USING STANDARDIZED PROTOCOLS; 2) ENHANCE CAPABILITY AND CAPACITY TO PARTICIPATE IN SP RESEARCH; 3) TRAIN AND MAINTAIN A WORKFORCE CAPABLE OF PROVIDING SP PATIENT CARE; 4) SUPPORT CONTINUED PLANNING FOR DEVELOPMENT OF A REGIONAL NETWORK FOR SP PATIENT CARE DELIVERY; 5) MAINTAIN COORDINATION PLANS TO ENABLE REGIONAL PARTNERS TO HAVE THE CAPABILITIES TO CARE FOR SP PATIENTS; 6) ENGAGE IN EVALUATION ACTIVITIES AND ASSESSMENTS TO ENSURE READINESS TO ACCEPT AND TREAT A SP PATIENT AND; 7) PROVIDE EVALUATION AND PERFORMANCE MEASUREMENT OF ACTIVITIES. THE OUTCOMES ARE TO PROMOTE QUALITY, COORDINATED SP CARE THAT IS EQUALLY ACCESSIBLE TO ALL PATIENTS THROUGH THE DEVELOPMENT OF A SPECIALIZED WORKFORCE, ENHANCEMENT OF RESEARCH CAPABILITIES, AND IMPROVED COORDINATION OF CARE ACROSS HHS R9. THE PRODUCTS FROM THIS AGREEMENT WILL BE: 1) A FINAL COMPREHENSIVE SP PROGRAM REPORT INCLUDING PEER-EVALUATED ASSESSMENTS OF PREVIOUSLY DESCRIBED OBJECTIVES; 2) PUBLISHED ARTICLES; 3) A WEBSITE; AND 4) WORKFORCE ENHANCING TRAINING OPPORTUNITIES.

GENETIC FACTORS IN KERATOCONUS

NEURONAL MECHANISMS OF HUMAN EPISODIC MEMORY

QUANTITATION OF FACTORS REGULATING GLUCOSE TOLERANCE

ZZ-3K3A-201: SAFETY EVALUATION OF 3K3A-APC IN ISCHEMIC STROKE

THE SKELETAL DYSPLASIAS

1/24 HEALTHY BRAIN AND CHILD DEVELOPMENT NATIONAL CONSORTIUM - PROJECT SUMMARY/ABSTRACT NEURODEVELOPMENTAL PROCESSES ARE SHAPED BY DYNAMIC INTERACTIONS BETWEEN GENES AND ENVIRONMENTS. MALADAPTIVE EXPERIENCES EARLY IN LIFE CAN ALTER DEVELOPMENTAL TRAJECTORIES, LEADING TO HARMFUL AND ENDURING DEVELOPMENTAL SEQUELAE. PRE- AND POSTNATAL HAZARDS INCLUDE MATERNAL SUBSTANCE EXPOSURE, TOXICANT EXPOSURES IN PREGNANCY AND EARLY LIFE, MATERNAL HEALTH CONDITIONS, PARENTAL PSYCHOPATHOLOGY, MALTREATMENT, STRUCTURAL RACISM, AND EXCESSIVE STRESS. TO ELUCIDATE HOW VARIOUS ENVIRONMENTAL HAZARDS IMPACT CHILD DEVELOPMENT, IT IS IMPERATIVE THAT A NORMATIVE TEMPLATE OF DEVELOPMENTAL TRAJECTORIES OVER THE FIRST 10 YEARS OF LIFE BE ESTABLISHED BASED ON A SUFFICIENTLY LARGE AND DEMOGRAPHICALLY DIVERSE SAMPLE OF THE US POPULATION. TO ACCOMPLISH THIS, THE HEALTHY BRAIN AND CHILD DEVELOPMENT NATIONAL CONSORTIUM (HBCD-NC) HAS BEEN FORMED TO DEPLOY A HARMONIZED, OPTIMIZED, AND INNOVATIVE SET OF NEUROIMAGING (MRI, EEG) MEASURES COMPLEMENTED BY AN EXTENSIVE BATTERY OF BEHAVIORAL, PHYSIOLOGICAL, AND PSYCHOLOGICAL TOOLS, AND BIOSPECIMENS TO UNDERSTAND NEURODEVELOPMENTAL TRAJECTORIES IN A SAMPLE OF 7,500 MOTHERS AND INFANTS ENROLLED AT 24 SITES ACROSS THE UNITED STATES (US). THE HBCD-NC WILL CARRY OUT A COMMON RESEARCH PROTOCOL UNDER DIRECTION OF THE HBCD- NC ADMINISTRATIVE CORE (HCAC) AND WILL ASSEMBLE AND DISTRIBUTE A COMPREHENSIVE AND WELL-CURATED RESEARCH DATASET TO THE SCIENTIFIC COMMUNITY AT LARGE UNDER THE DIRECTION OF THE HBCD-NC DATA COORDINATING CENTER (HDCC). THE OVERARCHING GOAL OF THE HBCD-NC IS TO CREATE A COMPREHENSIVE, HARMONIZED, AND HIGH- DIMENSIONAL DATASET THAT WILL CHARACTERIZE TYPICAL NEURODEVELOPMENTAL TRAJECTORIES IN US CHILDREN AND THAT WILL ASSESS HOW BIOLOGICAL AND ENVIRONMENTAL EXPOSURES AFFECT THOSE TRAJECTORIES. A SPECIAL EMPHASIS WILL BE PLACED ON UNDERSTANDING THE IMPACT OF PRE- AND POSTNATAL EXPOSURE TO OPIOIDS, MARIJUANA, ALCOHOL, TOBACCO AND/OR OTHER SUBSTANCES. TO ADDRESS THESE BROAD OBJECTIVES, THE SAMPLE OF WOMEN ENROLLED WILL INCLUDE: 1) A RACIALLY, ETHNICALLY, AND SOCIOECONOMICALLY DIVERSE COHORT THAT IS REPRESENTATIVE OF THE US POPULATION; 2) PREGNANT WOMAN WITH USE OF TARGETED SUBSTANCES (OPIOIDS, MARIJUANA, ALCOHOL, TOBACCO); AND 3) DEMOGRAPHICALLY AND BEHAVIORALLY SIMILAR WOMEN WITHOUT SUBSTANCE USE IN PREGNANCY TO ENABLE VALID CAUSAL INFERENCES. IN ADDITION, THE HBCD-NC WILL IDENTIFY KEY DEVELOPMENTAL WINDOWS DURING WHICH BOTH HARMFUL AND PROTECTIVE ENVIRONMENTS HAVE THE MOST INFLUENCE ON LATER NEURODEVELOPMENTAL OUTCOMES. THE LARGE, MULTI- MODAL, LONGITUDINAL, AND GENERALIZABLE DATASET THAT WILL BE PRODUCED FOR THE FIRST TIME BY THIS STUDY WILL PROVIDE NOVEL INSIGHTS INTO CHILD DEVELOPMENT USING STATE-OF-THE-ART METHODS. THE HBCD-NC STUDY WILL INFORM PUBLIC POLICY TO IMPROVE THE HEALTH AND DEVELOPMENT OF CHILDREN ACROSS THE NATION.

MULTIPLEXED PROTEIN BIOMARKER-BASED ASSAY FOR THE DETECTION OF BLADDER CANCER

INHIBITION OF AN APICAL CAMP TRANSPORTER (MRP4) IN THE GUT INDUCES DIARRHEA

ARTIFICIAL INTELLIGENCE STRATEGIES FOR ALZHEIMER'S DISEASE RESEARCH - ALZHEIMER'S DISEASE (AD) IS A COMMON DISEASE THAT IS PARTLY DUE TO PROTEIN MISFOLDING AND AGGREGATION. RESEARCH ON AD IS A NATIONAL PRIORITY WITH 5.5 MILLION AMERICANS AFFECTED AT AN ANNUAL COST OF MORE THAN $250 BILLION AND NO AVAILABLE CURE. THIS IS DESPITE HEAVY INVESTMENTS IN THE COLLECTION OF DIVERSE CLINICAL AND BIOLOGICAL DATA IN EXPERIMENTAL AND POPULATION-BASED STUDIES. ARTIFICIAL INTELLIGENCE (AI) AND MACHINE LEARNING HAVE THE POTENTIAL TO REVEAL PATTERNS IN CLINICAL AND MULTI-SOURCE LARGE-SCALE ALZHEIMER’S DATA THAT HAVE NOT BEEN FOUND USING STANDARD APPROACHES. WE PROPOSE HERE A COMPREHENSIVE BIOMEDICAL COMPUTING AND HEALTH INFORMATICS RESEARCH PROJECT TO DEVELOP AND APPLY CUTTING-EDGE AI ALGORITHMS AND BIOMEDICAL SOFTWARE FOR THE ANALYSIS OF LARGE- SCALE AD DATA. AT THE HEART OF THIS PROPOSED INFORMATICS PROGRAM IS THE PENNAI METHOD AND SOFTWARE FOR AUTOMATING MACHINE LEARNING THROUGH AN AI ALGORITHM THAT CAN LEARN FROM PRIOR ANALYSES. THIS APPROACH TAKES THE GUESSWORK OUT OF PICKING THE RIGHT MACHINE LEARNING ALGORITHMS AND PARAMETER SETTINGS THUS MAKING THIS COMPUTING TECHNOLOGY ACCESSIBLE TO EVERYONE. SPECIFICALLY, WE WILL DEVELOP THREE NOVEL INFORMATICS METHODS TO TAILOR PENNAI TO THE ANALYSIS OF AD DATA. FIRST, WE WILL DEVELOP A MULTI-MODAL INTERACTION (M2I) FEATURE SELECTION ALGORITHM FOR IDENTIFYING GENETIC INTERACTIONS THAT ARE PREDICTIVE OF AD (AIM 1). SECOND, WE WILL DEVELOP A KNOWLEDGE-DRIVEN MULTI-OMICS INTEGRATION (KMI) ALGORITHM FOR COMBINING OMICS FEATURES FOR AI ANALYSIS OF AD (AIM 2). THIRD, WE WILL DEVELOP A MULTIDIMENSIONAL BRAIN IMAGING OMICS (MBIO) INTEGRATION FRAMEWORK FOR THE JOINT ANALYSIS OF MULTI-SOURCE LARGE-SCALE DATA FOR PREDICTING AD. FINALLY, WE WILL INTEGRATE ALL THREE BIOMEDICAL INFORMATICS METHODS INTO OUR OPEN-SOURCE PENNAI SOFTWARE PACKAGE AND APPLY IT TO TWO LARGE POPULATION-BASED STUDIES OF AD. WE EXPECT PENNAI WILL REVEAL NEW BIOMARKERS FOR AD THAT WILL OPEN THE DOOR FOR BETTER TREATMENTS AND CLINICAL DECISION SUPPORT.

CARDIAC MICROSTRUCTURE AND HEART FAILURE RISK IN THE COMMUNITY

NON-TOLL-LIKE RECEPTOR INNATE IMMUNE SIGNALING

MATHEMATICAL ONCOLOGY SYSTEMS ANALYSIS IMAGING CENTER (MOSAIC) - SUMMARY: OVERALL: MATHEMATICAL ONCOLOGY SYSTEMS ANALYSIS IMAGING CENTER GLIOBLASTOMA (GBM), THE MOST AGGRESSIVE PRIMARY BRAIN CANCER, IS AMONGST THE MOST HETEROGENEOUS OF CANCERS, BOTH INTRA- AND INTER-TUMORALLY. GBMS ARE AN ADMIXTURE OF NEOPLASTIC GLIOMA CELLS AND NON-NEOPLASTIC / REACTIVE BRAIN PARENCHYMA THAT CONTRIBUTE TO THE OVERALL IMAGEABLE TUMOR MASS. AS SUCH, CELLULAR CONTENT, INCLUDING BOTH CELLULAR DENSITY AND CELLULAR COMPOSITION, IS CRITICALLY IMPORTANT FOR UNDERSTANDING THE STATUS AND EVOLUTION OF A GIVEN TUMOR. ALTHOUGH MRI PROVIDES EXCELLENT SOFT TISSUE CONTRAST AND CAN NONINVASIVELY CHARACTERIZE ANATOMY, NO METHODS EXIST TO INTEGRATE A SPATIAL AND TEMPORAL UNDERSTANDING OF THE CELLULAR COMPONENTS OF THE TUMOR INFERRED FROM IMAGING IN VIVO. IT HAS BECOME INCREASINGLY CLEAR THAT PRECISION ONCOLOGY STRATEGIES RELY ON A QUANTITATIVE AND PREDICTIVE UNDERSTANDING OF THE STATE OF THE CANCER COMPLEX SYSTEM EVOLVING WITHIN EACH PATIENT. RECENT FINDINGS FROM OUR GROUP HAVE REVEALED TWO KEY OPPORTUNITIES WE SEEK TO LEVERAGE IN OUR PROPOSED MATHEMATICAL ONCOLOGY SYSTEMS ANALYSIS IMAGING CENTER (MOSAIC). FIRST, MOLECULAR ANALYSIS OF A COHORT OF OUR IMAGE-LOCALIZED BIOPSIES OF GBM HAVE INSPIRED THE CONCEPT OF GLIOMA TISSUE STATES AS A COMPOSITE CLASSIFICATION OF TISSUE SAMPLES. OUR FINDINGS FROM SINGLE NUCLEUS RNASEQ REVEAL THAT SPECIFIC SUBPOPULATIONS AND CELLULAR PHENOTYPES OF NEOPLASTIC AND NON- NEOPLASTIC CELLS SHOW DISTINCT PATTERNS OF CO-HABITATION CONSTRAINING POTENTIAL CROSS-TALK SIGNALING. SECOND, WE HAVE FOUND MATHEMATICAL MODELING AND MACHINE LEARNING ANALYSES OF CLINICAL MRI FEATURES OF GBM BIOPSIES ARE ABLE TO PREDICT LOCO-REGIONAL FEATURES OF GBM BIOLOGY IN VIVO. THESE IMAGE-BASED MODELS PROVIDE THE PROMISE TO TRACK ASPECTS OF INTRA- AND INTER-TUMORAL HETEROGENEITY PREVIOUSLY UNATTAINABLE DURING PATIENT CARE. OUR OVERALL CENTER VISION IS TO BUILD A CONCEPTUAL FRAMEWORK TO UNDERSTAND TISSUE STATE-ASSOCIATED CELLULAR COMPOSITION TRANSITIONS THAT HAPPEN IN GLIOMA AND THE WAYS TO INTERPRET MRI RELATIVE TO THOSE CHANGES FOR THESE KEY CELLULAR PHENOTYPES. SPECIFICALLY, IN PROJECT 1 WE WILL EXPLORE STRATEGIES TO TARGET UNFAVORABLE (UNRESPONSIVE) TISSUE STATES TO NAVIGATE TRANSITIONS OF THE CANCER COMPLEX SYSTEM TOWARDS MORE FAVORABLE (RESPONSIVE) TISSUE STATES. IN PROJECT 2 WE WILL LEVERAGE MATHEMATICAL MODELING AND MACHINE LEARNING APPROACHES TO FUSE MRI AND IMAGE-LOCALIZED BIOPSY QUANTIFIED TISSUE STATES TO ENABLE TRACKING TISSUE STATE CHANGES IN PATIENT RECEIVING STANDARD OF CARE AND IMMUNOTHERAPY STRATEGIES. THUS, OUR MOSAIC PERFECTLY ALIGNS WITH THE CSBC INITIATIVE, INTEGRATING EXPERIMENTAL BIOLOGY WITH COMPUTATIONAL MODELING, USING METHODS FROM IMAGING PHYSICS, MATHEMATICAL TUMOR GROWTH MODELING, IMAGE-GUIDED BIOPSIES, MOLECULAR BIOLOGY, MACHINE LEARNING, AND INTEGRATIVE BIOINFORMATICS TO DEVELOP VALIDATED ADVANCES IN CANCER SYSTEMS BIOLOGY.

EFFECT OF AGING ON PREADIPOCYTE DIFFERENTIATION

SIMVASTATIN TREATMENT TO IMPROVE PATIENT-REPORTED OUTCOMES IN PATIENTS WITH CHRONIC PANCREATITIS

THERAPEUTIC DEVELOPMENT OF NONCODING RNA DRUG TY1 FOR SCLERODERMA

THE ROLE OF GK IN HSV-1 INDUCED CORNEAL SCARRING

PRE-DETERMINE: ADVANCING SUDDEN ARRHYTHMIC DEATH PREDICTION IN CORONARY ARTERY DISEASE IN THE ABSENCE OF SEVERE SYSTOLIC DYSFUNCTION - SUDDEN AND/OR ARRHYTHMIC DEATH (SAD), WHICH TYPICALLY RESULTS FROM LETHAL VENTRICULAR ARRHYTHMIAS (VENTRICULAR TACHYCARDIA AND VENTRICULAR FIBRILLATION, VT/VF) IN THE SETTING OF CORONARY HEART DISEASE (CHD), AFFLICTS AN ESTIMATED 310,000 PERSONS ANNUALLY IN THE UNITED STATES. REDUCTIONS IN SAD HAVE CONTINUED TO LAG THOSE OBSERVED FOR OTHER CORONARY HEART DISEASE (CHD) OUTCOMES DESPITE ADVANCES IN RESUSCITATION THERAPIES AND THE USE OF IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS (ICDS). CURRENT APPROACHES TO SAD PREVENTION REMAIN CENTERED ON PLACING ICDS IN PATIENTS WITH LEFT VENTRICULAR EJECTION FRACTION (LVEF) <30-35% – EVEN THOUGH THE MAJORITY OF SAD OCCURS IN THE SETTING OF LVEF >30-35%. IN EFFECT, THE PROPORTIONATELY LARGER SEGMENT OF THE AT-RISK POPULATION HAS BEEN UNDERSTUDIED AND THUS UNDERTREATED. DESPITE THIS UNMET NEED, THERE REMAIN VERY FEW, IF ANY, PROSPECTIVE STUDIES EXAMINING SAD RISK PREDICTION IN INDIVIDUALS WITH CHD AND LVEF >30-35% OVER A LONG ENOUGH TIME HORIZON WHERE ICD THERAPY MIGHT BE COST-EFFECTIVE. FOR THIS VERY REASON, THE PRE- DETERMINE COHORT STUDY WAS INTENTIONALLY DESIGNED TO ADDRESS THIS SCIENTIFIC GAP AND PROSPECTIVELY STUDY CLINICALLY RELEVANT APPROACHES TO SAD RISK PREDICTION IN CHD PATIENTS WITH LVEF >30-35%. IN THIS APPLICATION, WE PROPOSE TO LEVERAGE THE ORIGINALLY NHLBI-FUNDED BASE COHORT RESOURCE TO CONTINUE ADJUDICATION OF ACCRUING SAD AND VT/VF EVENTS, IN ADDITION TO COMPETING CAUSES OF DEATH, TO ATTAIN 10+ YEARS OF ENDPOINT ADJUDICATION TO ENABLE THE DEVELOPMENT AND VALIDATION OF MULTI-MARKER SAD RISK PREDICTION MODELS BASED ON COMBINATIONS OF MULTI-DIMENSIONAL CLINICAL, ECG, IMAGING, BIOMARKER, AND GENETIC DATA GENERATED IN THIS UNIQUE MULTICENTER COHORT OF 5761 CHD PATIENTS. WE WILL ALSO LEVERAGE THE BASE COHORT TO INTERROGATE NOVEL FATTY ACID DERIVED EICOSANOIDS AND PUTATIVE ARRHYTHMIA MODULATING PROTEOMIC ANALYTES IN RELATION TO RISK FOR SAD AND COMPETING CAUSES OF MORTALITY IN PATIENTS WITH CHD. NOVEL METHODS OF COMPETING RISK ANALYSES WILL BE USED TO INTEGRATE ABSOLUTE AND PROPORTIONAL SAD RISK INTO SAD RISK PREDICTION MODELS AND TO ELUCIDATE SEPARATE ASSOCIATIONS BETWEEN SAD VS. NON-SAD CAUSES OF DEATH. MACHINE LEARNING APPROACHES WILL BE APPLIED TO UNCOVER INTER-RELATIONS AND LATENT FEATURES FROM MULTI-MODALITY DATA NOT EASILY DETECTED BY CONVENTIONAL MODELS. AN OVERARCHING GOAL OF OUR WORK IS TO ACCURATELY IDENTIFY THOSE INDIVIDUAL SUBSETS OF THE BROADER POPULATION WHO HAVE SUFFICIENTLY HIGH ABSOLUTE AND PROPORTIONAL RISK FOR SAD THAT THEY WARRANT INCLUSION IN RANDOMIZED TRIALS OF PRIMARY PREVENTION ICD THERAPY. THE AIMS OF THE CURRENT PROPOSAL ALSO OFFER NEW OPPORTUNITIES TO IDENTIFY POTENTIAL MECHANISTIC PATHWAYS UNDERLYING THE GENESIS OF LETHAL VENTRICULAR ARRHYTHMIAS THAT COULD SERVE AS NOVEL TARGETS FOR SAD PREVENTION – EXTENDING BEYOND ICD PLACEMENT – IN PATIENTS WITH CHD AND POSSIBLY EVEN IN THE GENERAL POPULATION WHEREIN CHD UNDERLIES MOST SAD EVENTS. THE CONTINUATION AND EXPANSION OF THE PRE-DETERMINE STUDY WILL PROVIDE THE SCIENTIFIC FIELD WITH A ONE-OF-A KIND RESOURCE FOR INVESTIGATORS AND TRAINEES COLLABORATING TOWARD THE COMMON GOAL OF REDUCING THE BURDEN OF SAD.

HIGH-PERFORMANCE AUTOMATED SYSTEM FOR ANALYSIS OF CARDIAC SPECT

QUANTITATIVE STUDIES OF METABOLIC ORGAN DYNAMICS

PATHOPHYSIOLOGY, EPIDEMIOLOGY, AND PREVENTION OF PANCREATOGENIC DIABETES

MILITARY OPERATING ROOM OF THE FUTURE

DIAGNOSIS OF DISCOGENIC LOW BACK PAIN USING PH LEVEL-DEPENDENT MRI

RAL IN HUMAN BLADDER CANCER PROGRESSION

DEVELOPMENT OF A MICROPHYSIOLOGICAL ORGAN-ON-CHIP SYSTEM TO MODEL AMYOTROPHIC

MOLECULAR REGULATION OF PROGRESSIVE PULMONARY FIBROSIS

BIOINFORMATICS STRATEGIES FOR GENOME-WIDE ASSOCIATION STUDIES

TRAINING IN ADVANCED HEART DISEASE RESEARCH

PATIENT-SPECIFIC OUTCOME PREDICTION FROM CARDIOVASCULAR MULTIMODALITY IMAGING BY ARTIFICIAL INTELLIGENCE - PROJECT SUMMARY CORONARY ARTERY DISEASE (CAD) REMAINS A MAJOR PUBLIC HEALTH CONCERN WITH A HIGH PREVALENCE IN THE US POPULATION. FUNCTIONAL, MOLECULAR, AND STRUCTURAL IMAGING OFFER A UNIQUE OPPORTUNITY TO UNDERSTAND THE PATHOPHYSIOLOGY OF CAD, ESPECIALLY IN HIGH-RISK GROUPS SUCH AS PATIENTS WITH OBESITY, DIABETES, AND CHRONIC KIDNEY DISEASE (CARDIOMETABOLIC DISEASE). CAD EVALUATION BY IMAGING IS BASED ON MODALITIES THAT ASSESS (1) MYOCARDIAL ISCHEMIA AND MYOCARDIAL BLOOD FLOW (2) ANATOMIC BURDEN OF ATHEROSCLEROSIS, AND (3) DISEASE ACTIVITY USING NOVEL TECHNIQUES. HOWEVER, PHYSICIANS ARE NOT YET ABLE TO USE THESE DATA OPTIMALLY TO IDENTIFY PATIENTS AT HIGHEST RISK OF ADVERSE EVENTS—DUE TO TECHNICAL COMPLEXITY OF ADVANCED MULTIVARIABLE DATA, AND LACK OF AUTOMATION AND INTEGRATIVE TOOLS. WHILE POSITRON EMISSION TOMOGRAPHY (PET) CAN MEASURE MYOCARDIAL BLOOD FLOW, AND DEPICT HIGH-RISK PLAQUE IN THE ARTERIES AND CT CAN RELIABLY DETECT CORONARY ARTERY CALCIUM —AN UNEQUIVOCAL MARKER FOR ATHEROSCLEROTIC DISEASE– PHYSICIANS ARE NOT ABLE TO COMBINE THESE DATA EFFECTIVELY TO IDENTIFY PATIENTS AT HIGHEST RISK OF ADVERSE EVENTS, DUE TO COMPLEXITY AND LACK OF AUTOMATION. CRITICALLY, THERE IS AN UNMET NEED FOR EFFICIENT INTEGRATION OF DIVERSE IMAGING AND CLINICAL DATA BY A ROBUST, AUTOMATED CLINICAL TOOL AFTER NON-INVASIVE IMAGING. HIGHLY EFFICIENT ARTIFICIAL INTELLIGENCE (AI) METHODS ARE REVOLUTIONIZING IMAGE ANALYSIS AND COULD IMPROVE CAD DETECTION AND MANAGEMENT. THE OVERALL VISION FOR THE RESEARCH PROGRAM IS TO FURTHER THE CLINICAL UTILITY OF PET/CT IN DETECTING HIGH-RISK CAD AND GUIDING SUBSEQUENT MANAGEMENT BY AUTOMATION AND INTEGRATING ALL IMAGE AND CLINICAL DATA WITH STATE-OF-THE-ART AI. WE WILL ESTABLISH A LARGE MULTICENTER PET AND CT IMAGING REGISTRY AND WITH IMAGE-BASED AI, AUTOMATE ANALYSIS AND QUALITY CONTROL FOR ROBUST ANALYSIS EVEN AT LESS EXPERIENCED CENTERS, AND DEVELOP DECISION SUPPORT TOOLS UTILIZING COLLECTIVELY ALL AVAILABLE PET/CT IMAGES AND CLINICAL INFORMATION (BEYOND WHAT IS POSSIBLE BY SUBJECTIVE VISUAL ANALYSIS AND MENTAL INTEGRATION). WE WILL DEVELOP DIRECT INTERPRETATION OF IMAGES BY AI, AND PATIENT-SPECIFIC EXPLANATION OF THE AI FINDINGS TO THE PHYSICIAN. PRECISE QUANTITATIVE RESULTS WILL BE PRESENTED TO CLINICIANS (AND PATIENTS) IN EASY TO UNDERSTAND TERMS (E.G., % RISK PER YEAR OR AS THE RELATIVE RISK OF ONE THERAPY COMPARED TO THE ALTERNATIVE) FOR A SPECIFIC PATIENT. THIS WORK WILL ALLOW ACCURATE IDENTIFICATION OF PATIENTS WITH HIGH-RISK DISEASE WHO CAN BENEFIT TREATMENT FROM ADVANCED THERAPIES AND ENABLE PRECISE PATIENT-SPECIFIC RISK ESTIMATES AND TREATMENT RECOMMENDATIONS IN CHALLENGING CLINICAL SCENARIOS—IN CAD WITH CARDIOMETABOLIC DISEASE AND ADVANCED HIGH- RISK DISEASE.

CELLULAR CARDIOMYOPLASTY FOR ACUTE AND CHRONIC ISCHEMIC

ULTRASOUND-MEDIATED NANOBIOMATERIAL DELIVERY FOR SEGMENTAL BONE FRACTURE REPAIR

COLLABORATIVE CARE TEAMS FOR HOSPITALIZED PATIENTS WITH OPIOID USE DISORDERS: TRANSLATING EVIDENCE INTO PRACTICE

ALZHEIMER'S DISEASE HALLMARK PATHOLOGY AND ASSOCIATED INFLAMMATION IN THE RETINA

PREDICTING PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) THROUGH ARTIFICIAL INTELLIGENCE ANALYSIS OF PRE-DIAGNOSTIC CT IMAGES - THE OBJECTIVE OF THE PROPOSED PROJECT IS TO DEVELOP A PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) PREDICTION MODEL TO IDENTIFY INDIVIDUALS WHO HAVE HIGH RISK FOR PDAC IN THE NEXT 3 YEARS THROUGH ARTIFICIAL INTELLIGENCE (AI) ANALYSIS OF PRE-DIAGNOSTIC CT IMAGES AND NON-IMAGING FACTORS. PDAC IS THE FOURTH LEADING CAUSE OF CANCER- RELATED DEATHS IN BOTH MEN AND WOMEN IN THE UNITED STATES DESPITE ITS LOW INCIDENCE RATE. THE 5-YEAR SURVIVAL RATE FOR ALL STAGES OF PDAC IS 10% BUT CAN BE AS HIGH AS 50% WITH EARLY-STAGE DIAGNOSIS. THEREFORE, IDENTIFICATION OF INDIVIDUALS AT HIGH RISK FOR PDAC HAS HIGH CLINICAL SIGNIFICANCE AS FOLLOW-UP IMAGING EXAMINATIONS OR BIOPSY MAY ASSIST IN EARLY DETECTION AND ALLOW SURGICAL INTERVENTION WHILE THE TUMORS ARE STILL RESECTABLE. HOWEVER, PDAC PREDICTION IS DIFFICULT DUE TO THE LACK OF RELIABLE SCREENING TOOLS, THE ABSENCE OF SENSITIVE AND SPECIFIC SYMPTOMS AND BIOMARKERS, AND LOW PREVALENCE. ABDOMINAL PAIN IS THE SINGLE MOST COMMON REASON THAT AMERICANS VISIT THE EMERGENCY ROOM (ER), WHERE AN ABDOMINAL COMPUTED TOMOGRAPHY (CT) SCAN IS USUALLY PERFORMED. EVEN THOUGH MOST SCANS DON’T SHOW ANY SIGNS OF CANCER VISIBLE TO THE NAKED EYES OF RADIOLOGISTS, SOME SUBJECTS EVENTUALLY DEVELOP PDAC IN THE NEXT FEW YEARS. THESE PRE-DIAGNOSTIC CT IMAGES PROVIDE CRITICAL MORPHOLOGICAL INFORMATION ASSOCIATED WITH BIOLOGICAL CHANGES AT THE PRE-CANCER OR EARLY CANCER STAGE, WHICH CAN BE EXTRACTED USING AI TO PREDICT PDAC RISK. THEREFORE, THE OBJECTIVE OF THE PROPOSED PROJECT IS TO UNCOVER UNIQUE FEATURES IN PRE-DIAGNOSTIC IMAGES USING AI AND DEVELOP PDAC PREDICTION MODEL BASED ON THESE FEATURES. NON-IMAGING FACTORS SUCH AS DEMOGRAPHIC, EPIDEMIOLOGIC, AND ANTHROPOMETRIC FACTORS, CLINICAL COMORBIDITIES, AND LABORATORY TESTS WILL BE INCLUDED IN THE MODEL TO IMPROVE THE PREDICTION ACCURACY. THE PRIMARY HYPOTHESES ARE A) AI ALLOWS EXTRACTION OF UNIQUE IMAGE FEATURES IN PRE-DIAGNOSTIC CT IMAGES ASSOCIATED WITH PRE-CANCER OR EARLY CANCER BIOLOGICAL CHANGES THAT ARE INVISIBLE TO NAKED EYES AND B) THE COMBINATION OF PRE-DIAGNOSTIC IMAGE FEATURES AND NON- IMAGING FACTORS IMPROVES THE ACCURACY OF PDAC RISK STRATIFICATION AND PREDICTION OVER THAT USING CONVENTIONAL NON-IMAGING FACTORS ALONE. TO VERIFY THESE HYPOTHESES, WE WILL RETROSPECTIVELY EVALUATE CT PANCREATIC IMAGES OBTAINED UP TO 3 YEARS PRIOR TO PDAC DIAGNOSIS THAT WERE DEEMED NON-CANCEROUS BY RADIOLOGISTS. A GROUP OF SUBJECTS WHO UNDERWENT SIMILAR IMAGING STUDIES FOR NON-GASTROINTESTINAL DISORDERS AND WERE AGE/GENDER MATCHED WITH PRE-DIAGNOSTIC IMAGING WILL SERVE AS HEALTHY CONTROLS. ACCURATELY STRATIFYING HIGH RISK INDIVIDUALS MAY ALLOW FOR EARLY DETECTION OF PDAC IN THE FUTURE. A MAJOR CHALLENGE OF THE PROJECT IS THE SCARCITY OF THE APPROPRIATE IMAGING DATA BECAUSE OF THE LOW PREVALENCE OF PDAC AND STRINGENT ENROLLMENT CRITERIA. EIGHT MAJOR MEDICAL CENTERS WILL PARTICIPATE IN COLLECTION OF 1,064 CASES. THE END POINT OF THIS PROJECT IS THE DEVELOPMENT, TRAINING, AND VALIDATION OF AN AI-BASED PDAC PREDICTION MODEL, WHICH WILL IDENTIFY INDIVIDUALS WHO ARE AT HIGH RISK FOR DEVELOPING PDAC WITHIN THE NEXT 3 YEARS.

LPS BINDING TO TLR4 REGULATES HEPATIC STELLATE CELL ACTIVATION AND FIBROSIS

REGULATION OF CYTOSOLIC PATTERN RECOGNITION RECEPTOR SIGNALING IN MACROPHAGES

ROLE OF TLR4 IN COLITIS ASSOCIATED NEOPLASIA

ENDOTHELIAL PROGENITOR CELL TRANSPLANT TO ACCELERATE HEMATOPOIETIC RECOVERY

TOX, A NOVEL REGULATOR OF THYMOCYTE SELECTION

ROLE OF BLIMP-1 IN PREVENTING CHRONIC INTESTINAL MUCOSAL INFLAMMATION.

INNATE IMMUNE MECHANISMS IN NON-INFECTIOUS LUNG INFLAMMATION

INNATE IMMUNE MECHANISMS AND TLRS IN BACTERIAL LIGAND-INDUCED ARTERITIS

INTRA-GRAFT C1 ESTERASE INHIBITOR THERAPY FOR DECEASED KIDNEY TRANSPLANTATION - KIDNEY TRANSPLANTATION IS THE OPTIMAL THERAPY FOR END STAGE KIDNEY DISEASE (ESKD) BUT CURRENT TRANSPLANT OUTCOMES ARE SUBOPTIMAL, PARTICULARLY FOR RECIPIENTS OF ORGANS OBTAINED FROM DECEASED DONORS (DD). ISCHEMIA REPERFUSION INJURY (IRI), WHICH OCCURS IN ESSENTIALLY ALL RECIPIENTS FOLLOWING DD KIDNEY TRANSPLANTATION, CONTRIBUTES TO POORER OUTCOMES IN DD TRANSPLANT RECIPIENTS. PRECLINICAL STUDIES IMPLICATE ACTIVATION OF THE COMPLEMENT SYSTEM THROUGH THE MANNAN BINDING LECTIN (MBL) PATHWAY AS ONE CRUCIAL DRIVER OF POST-TRANSPLANT IRI AND ITS DOWNSTREAM EFFECTS ON ALLOGRAFT FUNCTION. ADDITIONAL PRECLINICAL WORK SHOWED THAT BLOCKADE OF MBL COMPLEMENT ACTIVATION USING PERI-TRANSPLANT ADMINISTRATION OF C1 ESTERASE INHIBITOR (C1INH) CAN PROMOTE RECOVERY OF ALLOGRAFT FUNCTION FOLLOWING ISCHEMIA-REPERFUSION-(IR)-INDUCED ACUTE KIDNEY INJURY. OUR RESEARCH GROUP PERFORMED TWO SINGLE CENTER RANDOMIZED CONTROLLED PILOT TRIALS OF C1INH THERAPY TO LIMIT THE DOWNSTREAM CONSEQUENCES OF IRI IN HUMAN KIDNEY TRANSPLANT RECIPIENTS. THE RESULTS OF THESE PILOT TRIALS SUPPORT THE NOVEL HYPOTHESIS THAT COMPLEMENT SYSTEM INHIBITION WITH PRE-IMPLANTATION INJECTION OF C1 ESTERASE INHIBITOR (C1INH) INTO THE DONOR ORGAN RENAL ARTERY ALTERS THE REPARATIVE PROCESS INDUCED BY IR FOLLOWING DD KIDNEY TRANSPLANTATION AND IMPROVES ALLOGRAFT FUNCTION AT 1 YEAR. WE PROPOSE TO DETERMINE THE EFFECTS OF PRE- IMPLANTATION, INTRARENAL ARTERY INJECTION OF C1INH ON KIDNEY TRANSPLANT OUTCOMES THROUGH A RANDOMIZED CONTROLLED, DOUBLE BLIND, MULTICENTER TRIAL (AIM 1). WE WILL FOLLOW SUBJECTS FOR 12-MONTHS POST-TRANSPLANT TO ASSESS THE PRIMARY ENDPOINT OF EGFR. SECONDARY ENDPOINTS WILL BE BIOPSY PROVEN ACUTE REJECTION (BPAR) EFFICACY FAILURE (COMPOSITE OF BPAR, GRAFT LOSS, DEATH, AND LOSS TO FOLLOW UP), AND THE 12-MONTH ABBREVIATED IBOX SCORE. MULTIPLE EXPLORATORY ENDPOINTS INCLUDE DGF INCIDENCE/SEVERITY. ALL SUBJECTS WILL BE FOLLOWED FOR 3 YEARS TO ASSESS THE IMPACT OF THE INTERVENTION ON LONG TERM OUTCOMES. ASSOCIATED MECHANISTIC STUDIES (AIM 2) USING BIOPSY TISSUE AND PERIPHERAL BLOOD SAMPLES WILL PROVIDE INSIGHT INTO DETECTED ENDPOINT DIFFERENCES BETWEEN STUDY ARMS, IF OBSERVED, AND IF NO DIFFERENCES ARE DETECTED, WILL DETERMINE WHY THE INTERVENTION WAS INEFFECTIVE. APPROACHES WILL INCLUDE SPATIAL TRANSCRIPTOMICS, FUNCTIONAL IMMUNE ASSAYS, AND STUDIES OF GRAFT- DERIVED EXOSOMES, ALL PERFORMED USING STATE-OF-THE-ART TECHNIQUES. THE WORK WILL BE COMPLETED OVER 7 YEARS, WITH THE ABILITY TO DELIVER THE PRIMARY ENDPOINT CLINICAL RESULTS WITHIN 4-5 YEARS. THE ADDITIONAL TIME PERMITS EXTENDED FOLLOW-UP AND MECHANISTIC ANALYSES. THIS PROPOSED WORK ADDRESSES A KEY UNMET NEED IN KIDNEY TRANSPLANTATION, EMPLOYS A UNIQUE THERAPEUTIC STRATEGY, AND WILL BE PERFORMED BY AN EXPERIENCED TEAM. WE CONTEND THAT IF THE STUDY IS SUCCESSFUL IN IMPROVING POSTTRANSPLANT OUTCOMES, IT COULD TRANSFORM THE FIELD.

UNDERSTANDING THE RHOGDI2 METASTASIS SUPPRESSOR GENE

MECHANISMS OF MACROPHAGE ACTIVATION IN LUNG INFLAMMATION

STEM CELL THERAPY AND GROWTH FACTOR THERAPY FOR ALS

THE ROLE OF MICRORNAS IN NORMAL AND DISEASED CORNEAL EPITHELIAL HOMEOSTASIS

IBD:TNF-ALPHA AND CROHN'S DISEASE MUCOSAL INFLAMMATION

ASSESSMENT OF BIOMARKER GUIDED CNI SUBSTITUTION IN KIDNEY TRANSPLANTATION - CURRENT STANDARD OF CARE FOR KIDNEY TRANSPLANT (KTX) RECIPIENTS HAS ONLY MODESTLY IMPROVED LONG-TERM AGGREGATE GRAFT AND/OR PATIENT SURVIVAL, IDENTIFYING A CRUCIAL UNMET MEDICAL NEED. AS THE AT-RISK KTX POPULATION IS HETEROGENEOUS, THE CURRENTLY EMPLOYED AND RELATIVELY HOMOGENEOUS THERAPEUTIC APPROACH TO IMMUNOSUPPRESSION IN KTX IN THE US AND CANADA IS SUBOPTIMAL, AND RESULTS IN A SIGNIFICANT PROPORTION OF OVER- IMMUNOSUPPRESSED RECIPIENTS, MANY WITH TACROLIMUS-RELATED TOXICITIES. IN THIS U01 APPLICATION, CO-PIS HEEGER AND NICKERSON WILL BUILD UPON THEIR PAST, PRODUCTIVE COLLABORATIVE EFFORTS, THEIR ESTABLISHED MULTICENTER TRIAL CONSORTIUM AND INFRASTRUCTURE, AS WELL AS THEIR EXPERTISE IN BIOMARKERS AND MECHANISTIC STUDIES TO ADDRESS THIS UNMET NEED. THE OVERARCHING GOAL OF THE PROPOSED WORK IS TO DETERMINE THE UTILITY OF THE HLA-DR/DQ MOLECULAR MISMATCH (MMM) SCORE, AS A RISK STRATIFYING BIOMARKER IN KTX. WHILE RETROSPECTIVE STUDIES SHOWED STRONG CORRELATIONS BETWEEN THE HLA-DR/DQ MMM SCORE AND THE RISK OF DEVELOPING BIOPSY PROVEN ACUTE REJECTION (BPAR) AND/OR DONOR SPECIFIC ANTIBODIES (DSA), NO PROSPECTIVE STUDIES HAVE TESTED THE HLA MMM SCORE AS A RISK STRATIFYING BIOMARKER FOR IMMUNOLOGICAL KTX INJURY. NOR HAVE ANY STUDIES ATTEMPTED TO TEST WHETHER AND HOW THE HLA-DR/DQ MMM SCORE PERFORMS AS A PREDICTOR OF OUTCOME FOLLOWING A CHANGE IN TRANSPLANT IMMUNOSUPPRESSION. HEREIN, WE PROPOSE A MULTICENTER OBSERVATIONAL STUDY WITH A NESTED RANDOMIZED CONTROLLED (RCT) TRIAL TO ADDRESS THESE DEFICIENCIES. WE WILL PROSPECTIVELY TEST THE UTILITY OF THE HLA-DR/DQ MMM SCORE AS A PROGNOSTIC BIOMARKER OF PRIMARY ALLOIMMUNITY [T CELL MEDIATED REJECTION (TCMR), DSA, AND ANTIBODY MEDIATED REJECTION (ABMR)] IN KTX (AIM 1, OBSERVATIONAL STUDY OF 800 KTX). WE WILL ALSO TEST THE HYPOTHESIS THAT THE HLA-DR/DQ MMM SCORE IS A PREDICTIVE BIOMARKER THAT IDENTIFIES KTX RECIPIENTS WHO WILL TOLERATE SUBSTITUTING THE CALCINEURIN INHIBITOR WITH SELF-ADMINISTERED, SUBCUTANEOUS ABATACEPT (COSTIMULATORY BLOCKADE), WITHOUT AN UNACCEPTABLE INCREASED RISK OF BPAR, WHILE REDUCING THE MORBIDITY OF CNI OFF-TARGET EFFECTS (300 KTX, NESTED RCT WITH A NON-INFERIORITY ENDPOINT, AIM 2). ACCOMPANYING MECHANISTIC STUDIES (AIM 3) WILL PROVIDE NOVEL IMMUNOLOGICAL AND MOLECULAR INSIGHTS THAT WILL ALSO AID IN INTERPRETING GRAFT AND RECIPIENT OUTCOMES OF THE TRIAL. IF SUCCESSFUL, THE WORK WILL PROVIDE CRUCIAL INFORMATION CAPABLE OF POSITIVELY, AND DIRECTLY AFFECTING CLINICAL CARE. THE RESULTS FROM THE PROPOSED WORK ALSO HAVE THE POTENTIAL TO INFLUENCE POSITIVELY THE DESIGN OF FUTURE RCTS BY PROVIDING AN HLA-DR/DQ MMM SCORE-BASED STRATIFICATION OR ENRICHMENT STRATEGY FOR ENROLLING SUBJECTS INTO TRIALS MOST LIKELY TO BE INFORMATIVE FOR THE PROPOSED STUDY AGENT-- THEREBY INCREASING LIKELIHOOD OF TRIAL SUCCESS IN THE SHORTEST POSSIBLE TIME.

TIME-RESTRICTED EATING AND CANCER: CLINICAL OUTCOMES, MECHANISMS, AND MODERATORS - ABSTRACT COMBINING FASTING WITH CHEMOTHERAPY CAN CAUSE COMPLETE TUMOR REGRESSION IN ANIMAL MODELS. ACUTE FASTING IS THOUGHT TO SENSITIZE TUMOR CELLS TO THE CYTOTOXIC EFFECTS OF CHEMOTHERAPY AND RADIATION, WHILE PROTECTING HEALTHY CELLS BY INCREASING STRESS RESISTANCE—A PHENOMENON KNOWN AS THE DIFFERENTIAL STRESS SENSITIZATION THEORY. HOWEVER, THE POTENTIAL RISKS OF EXTENDED CALORIC RESTRICTION HAMPER CLINICAL IMPLEMENTATION. TIME-RESTRICTED EATING (TRE) IS A PROMISING ALTERNATIVE, WHICH INVOLVES EATING WITHIN A PERIOD OF 10 HOURS OR LESS, FOLLOWED BY FASTING FOR AT LEAST 14 HOURS DAILY. BECAUSE OF ITS SIMPLICITY, TRE MAY BE MORE SUSTAINABLE. MOREOVER, OUR PILOT DATA SUGGEST THAT TRE HAS SEVERAL ANTI-CANCER EFFECTS: IT DECREASES IGF-1 LEVELS, REDUCES OXIDATIVE STRESS, UPREGULATES ANTIOXIDANT DEFENSES, AND ENHANCES AUTOPHAGY. WE PROPOSE TO CONDUCT THE FIRST CLINICAL TRIAL OF TRE IN CANCER PATIENTS UNDERGOING ACTIVE TREATMENT, AS WELL AS THE LARGEST RANDOMIZED CONTROLLED TRIAL OF ANY FORM OF INTERMITTENT FASTING IN CANCER PATIENTS. WE WILL FOCUS ON RECTAL CANCER BECAUSE IT IS ONE OF ONLY A COUPLE CANCERS WHERE TUMOR SIZE AND CHARACTERISTICS CAN BE MEASURED BEFORE AND AFTER TREATMENT. WE WILL ENROLL 300 NEWLY DIAGNOSED LOCALIZED RECTAL CANCER PATIENTS (STAGE II-III) AGED =18 (BMI = 18.5 KG/M2). ALL PARTICIPANTS WILL RECEIVE THE STANDARD OF CARE DURING ONCOLOGICAL TREATMENT AT CEDARS-SINAI MEDICAL CANCER (LOS ANGELES, CA) OR THE UNIVERSITY OF ALABAMA O’NEAL COMPREHENSIVE CANCER CENTER (BIRMINGHAM, AL) AND BE RANDOMIZED TO ONE OF TWO EATING SCHEDULES: (1) CONTROL SCHEDULE: 12-HOUR OR LONGER DAILY EATING PERIOD; (2) TRE: 8-HOUR DAILY EATING PERIOD (16 HOURS OF DAILY FASTING). PARTICIPANTS WILL BE COUNSELED TO MAINTAIN THEIR WEIGHT. ALL ENDPOINTS WILL BE MEASURED AT LEAST THREE TIMES: AT DIAGNOSIS PRIOR TO THE ONSET OF CHEMORADIATION (BASELINE), AFTER CHEMORADIATION TREATMENT, AND AT TUMOR RESECTION (POST-INTERVENTION). OUR PRIMARY AIM IS TO DETERMINE HOW TRE AFFECTS CLINICAL OUTCOMES, INCLUDING TREATMENT-RELATED ADVERSE EFFECTS (TOXICITY INDEX BASED ON CTCAE V.5), PATIENT-REPORTED OUTCOMES (PRO-CTCAE) AND QUALITY OF LIFE (EORTC QLQ-C30), AND CLINICAL (CCR) AND PATHOLOGICAL (PCR) COMPLETE RESPONSE RATES. AIM 2 TESTS THE DIFFERENTIAL STRESS SENSITIZATION THEORY—THE FIRST COMPLETE TEST OF THIS THEORY IN HUMANS. WE TEST WHETHER TRE ACTS THROUGH THE IGF-1 PATHWAY TO INCREASE STRESS RESISTANCE IN HEALTHY CELLS (DNA DAMAGE AND ANTIOXIDANT DEFENSES AS MEASURED BY GAMMA-H2AX AND TOTAL ANTIOXIDANT CAPACITY, RESPECTIVELY) AND ENHANCE TUMOR CELL DEATH (APOPTOSIS AND AUTOPHAGY AS MEASURED BY ACTIVATED CASPASE-3 AND LC3-I/LC3-II, RESPECTIVELY). AIM 3 COMPARES LONGITUDINAL CHANGES IN MOOD, SOCIAL FUNCTIONING, SLEEP, DIET, AND DAILY PHYSICAL ACTIVITY ACROSS INTERVENTION ARMS (CONTROL VS. TRE) AND EXPLORE HOW THESE CHANGES INTERACT WITH INTERVENTION ARMS TO PREDICT CLINICAL OUTCOMES. WE EXPECT THIS INNOVATIVE TRIAL WILL HELP IMPROVE CANCER TREATMENT OUTCOMES AND RESHAPE THE STANDARD OF CARE FOR CANCER PATIENTS.

SPATIAL REPROGRAMMING OF TUMOR IMMUNE MICROENVIRONMENTS BY PREOPERATIVE RADIOTHERAPY AND IMMUNE CHECKPOINT INHIBITION IN HER2 NEGATIVE BREAST CANCER

PHAGOSOMAL TARGETING OF CARD PROTEINS

ROLE OF MACROPHAGES IN CONTROL OF OCULAR HSV

RANDOMIZED-CONTROLLED TRIAL OF VIRTUAL REALITY FOR CHRONIC LOW BACK PAIN TO IMPROVE PATIENT-REPORTED OUTCOMES AND PHYSICAL ACTIVITY

ROLE OF PTPRS IN RHEUMATOID ARTHRITIS

CONSORTIUM ON INTESTINAL REGENERATION AND FETAL REVERSION: FROM ATLAS TO THERAPY - ABSTRACT FETAL REVERSION IS A NOVEL REGENERATIVE PHENOMENON IN WHICH CELLS OF THE INTESTINAL EPITHELIUM RESPOND TO DAMAGE BY DOWNREGULATING THE NORMAL GENE EXPRESSION PROGRAM OBSERVED DURING HOMEOSTASIS AND BY ACQUIRING A FETAL- LIKE TRANSCRIPTIONAL STATE THAT PROMOTES CELL PROLIFERATION AND INTESTINAL REPAIR. FETAL REVERSION HAS BEEN OBSERVED IN DIFFERENT INTESTINAL INJURY MODELS IN THE MOUSE, INCLUDING DAMAGE FROM PARASITIC OR VIRAL INFECTION, RADIATION, AND CHEMICAL INSULTS. IT IS UNKNOWN IF FETAL REVERSION IS A UNIVERSAL PROPERTY OF INTESTINAL HEALING OR IF IT OCCURS ONLY DURING CERTAIN TYPES OF REPAIR. RECENT EVIDENCE INDICATES THAT THIS PHENOMENON MAY ALSO OCCUR IN THE HUMAN INTESTINE; HOWEVER, THIS HAS ALSO NOT BEEN INTERROGATED IN A SYSTEMATIC WAY. THIS PROJECT WILL CREATE A UNIQUE LARGE-SCALE RESEARCH RESOURCE – AN ATLAS OF INTESTINAL INJURY ACROSS MULTIPLE SPECIES (MOUSE, HUMAN) AND DAMAGE MODELS THAT CONTAINS COMPREHENSIVE SINGLE CELL MULTIOMIC DATASETS OF REGULATORY AND TRANSCRIPTIONAL DYNAMICS DURING INTESTINAL REPAIR AFTER INJURY. THE ATLAS WILL BE A TOOL FOR FUTURE HYPOTHESIS GENERATION FOR FUNCTIONAL STUDIES AND WILL BE AN IMPORTANT COMMUNITY-WIDE RESOURCE AVAILABLE TO THE ENTIRE SCIENTIFIC COMMUNITY. GENES AND PATHWAYS ESSENTIAL FOR FETAL REVERSION, AND FOR ANY OTHER COMMON INTESTINAL REGENERATION PROGRAMS, WILL BE IDENTIFIED USING ATLAS DATA. FUNCTIONAL STUDIES TO EXPLORE PATHWAYS AND GENES WILL BE CONDUCTED IN MOUSE MODELS THROUGH GAIN- AND LOSS-OF-FUNCTION EXPERIMENTS AND WILL BE INTERROGATED IN THE HUMAN CONTEXT USING INTESTINAL ORGANOIDS AS A MODEL SYSTEM. A HIGH-THROUGHPUT DRUG SCREENING ASSAY WILL BE USED TO IDENTIFY COMPOUNDS THAT INDUCE FETAL REVERSION, AND TOP COMPOUNDS IDENTIFIED WILL BE ASSESSED FOR THEIR ABILITY TO INDUCE THE FETAL REVERSION STATE THROUGH TRANSCRIPTOMIC AND EPIGENOMIC ASSAYS, AND TO ENHANCE ORGANOID-ENGRAFTMENT AND INJURY REPAIR IN VIVO THROUGH TRANSPLANTATION ASSAYS. THIS PROJECT WILL CREATE A MULTI-SPECIES INJURY-REPAIR ATLAS AND COMPREHENSIVELY CHARACTERIZE DIFFERENT MODES OF INTESTINAL REGENERATION, INCLUDING FETAL REVERSION, PROVIDING AN UNPRECEDENTED UNDERSTANDING OF INTESTINAL INJURY- REPAIR. ALL DATA, ANALYSES, METHODS, MODELS AND SCREENING PROTOCOLS WILL BE SHARED WITH THE RESEARCH COMMUNITY FOR EXPLORATION AND FURTHER ANALYSIS FOLLOWING ESTABLISHED SHARING MODELS. THE STUDIES PROPOSED HERE WILL IDENTIFY COMMON AND UNIQUE REGENERATIVE PROGRAMS THAT ARE ACTIVE IN DIFFERENT INJURY CONTEXTS, CREATING A PARADIGM SHIFT IN OUR UNDERSTANDING OF GUT REPAIR, AND LAYING THE FOUNDATION FOR NEW FIELDS OF RESEARCH AND THERAPEUTICS.

IS OBESITY AN INFECTIOUS DISEASE?: GUT BACTERIAL AND FUNGAL TRANSLOCATION AS AN UNDERAPPRECIATED DRIVER OF VISCERAL ADIPOSE EXPANSION. - PROJECT SUMMARY/ABSTRACT CURRENTLY, OVER 70% OF THE U.S. ADULT POPULATION IS OVERWEIGHT OR OBESE, AND THIS NUMBER IS ONLY INCREASING. EVEN MORE ALARMING IS THAT 1 IN 6 CHILDREN IS NOW OVERWEIGHT OR OBESE, A NUMBER THAT HAS BEEN RISING EVEN MORE RAPIDLY THAN THE ADULT POPULATION. WHILE LIFESTYLE MODIFICATIONS AND GASTRIC BYPASS SURGERIES ARE PROVEN APPROACHES TO REDUCING ADIPOSITY AND METABOLIC DYSFUNCTION, THERE IS STILL NO SIGN THAT OBESITY AND ITS CO- MORBIDITIES ARE ABATING. SAFE, NEW STRATEGIES TO MITIGATE WEIGHT GAIN, IN COMBINATION WITH LIFESTYLE CHOICES, MAY PROVE MORE EFFECTIVE THAN ANY ONE STRATEGY ALONE. OUR LONG-TERM GOAL FOR THIS CATALYST PROJECT IS TO DEVELOP AN OBESITY-MITIGATING STRATEGY THAT LEVERAGES THE ACTIVITIES OF THE GUT MICROBIOME TO SELECTIVELY TARGET VISCERAL ADIPOSE DEPOTS. OUR RATIONALE FOR THIS IS BASED ON RECENT FINDINGS FROM MY LAB WHILE STUDYING CROHN’S DISEASE. WE REPORTED THAT CERTAIN LIPID-LOVING BACTERIA AND FUNGI IN THE GUT, CAN TRANSLOCATE FROM THE GUT TO MESENTERIC VISCERAL ADIPOSE TISSUE IN CROHN’S DISEASE PATIENTS. THE INTERACTION OF THESE MICROORGANISMS IN THE ADIPOSE TISSUE, PROMOTED TISSUE EXPANSION AND THE PHENOMENON KNOWN AS ‘CREEPING FAT’ (HA ET AL., CELL 2020). MANY FEATURES OF CROHN’S CREEPING FAT APPEAR SIMILAR TO OBESE VISCERAL ADIPOSE. THEREFORE, IF MICROBES MAY BE A POTENT DRIVER OF CREEPING FAT, PERHAPS THEY ARE A POTENT DRIVER OF VISCERAL ADIPOSITY IN OBESITY. OUR APPROACH TO THIS QUESTION WILL INVOLVE THE USE OF HUMAN GASTRIC BYPASS TISSUES TO FIRST CHARACTERIZE THE MICROBIAL PRESENCE IN THESE TISSUES, AND THEN TEST THESE ORGANISMS PROSPECTIVELY IN GNOTOBIOTIC MICE. WE WILL IN PARALLEL CREATE IPSC-DERIVED ORGANOIDS FROM OBESE PATIENTS TO TEST SPECIFIC HOST-MICROBE CELLULAR INTERACTIONS. THIS CONTRIBUTION IS INNOVATIVE BECAUSE IT POSES A RADICALLY NEW, FRINGE CONCEPT THAT GUT BACTERIA ARE DIRECTLY INTERACTING WITH ADIPOSE TISSUE TO INFLUENCE ITS BEHAVIOR. IF SO, WE MAY BE ABLE TO TARGET THESE SPECIFIC ORGANISMS IN THE GUT BEFORE THEY TRANSLOCATE, WHICH WE PROPOSE COULD BE ACHIEVED THROUGH PHAGE-MEDIATED KILLING RATHER THAN ANTIBIOTICS. IT IS HIGH-RISK BECAUSE THERE IS NO ESTABLISHED BODY OF LITERATURE TO SUPPORT THE NOTION THAT BACTERIA ARE DIRECTLY DRIVING THE BEHAVIOR OF ADIPOSE THROUGH CELL-CELL INTERACTIONS, BUT IF IT PROVES TO BE TRUE, WILL NECESSITATE A PARADIGM SHIFT IN HOW WE THINK ABOUT OBESITY. FINALLY, THE CONTRIBUTION IS SIGNIFICANT, BECAUSE IT MAY OPEN ENTIRELY NEW AVENUES FOR MAINTAINING METABOLIC HEALTH IN THE POPULATION, AND PARTICULARLY IN OUR MOST VULNERABLE, PEDIATRIC POPULATION.

EXOSOME-MEDIATED CARDIOPROTECTION AND REGENERATION

SK CURRENT AND VENTRICULAR ARRHYTHMIAS.

A MULTICENTER RCT OF PHARMACIST-DIRECTED TRANSITIONAL CARE TO REDUCE POST-HOSPITALIZATION UTILIZATION

A NOVEL MECHANISM FOR NLRP3 INFLAMMASOME ACTIVATION IN HUMAN MACROPHAGES - INFECTIONS AND CELLULAR STRESS CAN TRIGGER CYTOPLASMIC PATTERN RECOGNITION RECEPTORS TO ASSEMBLE AN INFLAMMASOME COMPLEX, WHICH PROMOTES THE RELEASE OF THE INFLAMMATORY CYTOKINES IL-1SS, IL-18 AND THE INDUCTION OF PYROPTOTIC CELL DEATH. INFLAMMASOME RESPONSES ARE ALSO PERPETUATED AND PROPAGATED TO BYSTANDER CELLS. ULTIMATELY, THIS RESPONSE CONTRIBUTES TO PATHOGEN CLEARANCE AND WOUND HEALING. HOWEVER, EXCESSIVE INFLAMMASOME ACTIVATION CAN CONTRIBUTE TO- OR CAUSE DEBILITATING SYMPTOMS ASSOCIATED WITH INFLAMMATORY DISEASES. PARTICULARLY, THE NLRP3 INFLAMMASOME HAS BEEN DIRECTLY LINKED TO NUMEROUS DISEASES. IT HAS A UNIQUE POSITION BY NOT ONLY SENSING INFECTIONS, BUT ALSO CELLULAR STRESS AND TISSUE DAMAGE. EVEN THOUGH THE NLRP3 INFLAMMASOME IS OF UTMOST IMPORTANCE FOR BALANCING BETWEEN HOMEOSTASIS AND DISEASE, AND IS THEREFORE A PRIME TARGET FOR NOVEL TREATMENT STRATEGIES, THE UNDERLYING MOLECULAR MECHANISMS, PARTICULARLY IN HUMAN MACROPHAGES, ARE STILL POORLY UNDERSTOOD. THERE ARE NUMEROUS HUMAN INFLAMMASOME COMPONENTS THAT ARE ABSENT IN MICE AND THEIR FUNCTIONAL CONTRIBUTION TO HUMAN HEALTH AND DISEASE ARE EVEN LESS WELL UNDERSTOOD THAN THE MORE CONSERVED FACTORS. ELUCIDATING UNIQUE HUMAN RESPONSES IS THE MAIN FOCUS OF OUR LAB. INNATE IMMUNE RECEPTOR OLIGOMERIZATION INITIATES INFLAMMATORY HOST RESPONSES, INCLUDING INFLAMMASOME ACTIVATION. THE RESEARCH OUTLINED IN THIS PROPOSAL IS DESIGNED TO MECHANISTICALLY UNRAVEL A NOVEL NLRP3 INFLAMMASOME ACTIVATION CONCEPT IN HUMAN MACROPHAGES. WE DISCOVERED A NOVEL NLRP3 INFLAMMASOME COMPONENT IN HUMAN MACROPHAGES, WHICH INTERACTS WITH NLRP3, BUT IS ABSENT FROM MICE AND OUR PRELIMINARY STUDIES REVEALED THAT NLRP3 REQUIRES THIS CO-SENSOR FOR OLIGOMERIZATION AS WELL AS FOR RECRUITING THE INFLAMMASOME ADAPTOR, ASC. FURTHERMORE, NLRP3 AND ITS CO-SENSOR ARE NECESSARY FOR EFFICIENTLY NUCLEATING ASC POLYMERIZATION AND CASPASE-1 ACTIVATION. KNOCK OUT OF THE CO-SENSOR PHENOCOPIES NLRP3 KNOCK OUT IN HUMAN MACROPHAGES. SIGNIFICANTLY, IT IS ABSOLUTELY NECESSARY FOR CYTOKINE RELEASE DRIVEN BY NLRP3 MUTATIONS THAT CAUSE CRYOPYRIN-ASSOCIATED PERIODIC SYNDROME (CAPS). WE PROPOSE TWO SPECIFIC AIMS THAT INVESTIGATE THE MECHANISM AND FUNCTION OF THE CO-SENSOR IN NLRP3 INFLAMMASOME ASSEMBLY AND ACTIVATION IN MACROPHAGES, AS WELL AS THE MOLECULAR EVENTS THAT ENABLE THIS CO-SENSOR TO PROMOTE NLRP3 INFLAMMASOME ACTIVATION. WE WILL UTILIZE CRISPR/CAS9 KNOCK OUT AND RESTORED EXPRESSION OF WILD TYPE AND MUTANT CO-SENSOR PROTEINS AND A HUMANIZED MOUSE EXPRESSING THE HUMAN CO-SENSOR FOR STUDYING ITS FUNCTION IN VIVO. WE EXPECT THAT OUR RESEARCH WILL UNCOVER NOVEL MOLECULAR MECHANISMS THAT NOT ONLY CHANGE OUR CURRENT UNDERSTANDING OF CONTROL MECHANISMS THAT PREVENT INAPPROPRIATE NLRP3 INFLAMMASOME ACTIVATION FOR MAINTAINING HOMEOSTASIS AND HUMAN HEALTH, BUT ALSO NLRP3-DRIVEN PATHOLOGIES IN INFLAMMATORY DISEASES. THE OUTCOMES OF OUR STUDY WILL MOVE THE FIELD FORWARD AND WILL BE HIGHLY SIGNIFICANT FOR UNDERSTANDING DISEASE PATHOLOGIES AND FOR THE DEVELOPMENT OF NOVEL THERAPIES THAT BENEFIT PATIENTS AND POSITIVELY AFFECT HUMAN HEALTH.

THE ROLE OF FOXC1 IN BASAL-LIKE BREAST CANCER

THE EPIDEMIOLOGY OF INTERSTITIAL CYSTITIS IN A NATIONWIDE MULTIETHNIC VA COHORT

OVERCOMING IMMUNOTHERAPY RESISTANCE IN BREAST CANCER USING RT-MEDIATED IMMUNOMODULATION

SMALL MOLECULE INHIBITORS OF LMPTP: AN OBESITY DRUG TARGET

ROLE OF TRIF-DEPENDENT TLR SIGNALING IN INTESTINAL IMMUNITY

CHARACTERIZING OLDER MEXICAN (AMERICAN) PARTICIPATION IN ACTIVITY DIGITALLY, RELIABLY, AND ECOLOGICALLY WITH THE CART PLATFORM (COMPADRE CART): IMPLICATIONS FOR COGNITION AND ADRD - PROJECT SUMMARY/ABSTRACT THE PREVALENCE OF ALZHEIMER’S DISEASE AND RELATED DEMENTIAS (ADRD) IS PROJECTED TO DOUBLE OVER THE NEXT 20 YEARS. ETHNIC AND RACIAL MINORITIES WILL BEAR A DISPROPORTIONATE BURDEN OF DISEASE WITH THE MOST STAGGERING INCREASE OF NEARLY SIX-FOLD ANTICIPATED AMONG MEXICAN AMERICANS AND OTHER HISPANIC GROUPS. NONETHELESS, THERE IS MARKED VARIABILITY IN COGNITIVE TRAJECTORIES, AND APPROXIMATELY TWO-THIRDS OF MEXICAN AMERICANS SURVIVING INTO THEIR 80’S WILL REMAIN DEMENTIA-FREE. THE VARIABILITY IN OUTCOMES HIGHLIGHTS THE INFLUENCE OF RISK AND RESILIENCE FACTORS, WHICH MAY ALTER NEURODEGENERATIVE DISEASE COURSE. RECENT STUDIES HAVE SUGGESTED THAT UPWARDS OF 40% OF ALL DEMENTIA CASES MAY BE ATTRIBUTABLE TO POTENTIALLY MODIFIABLE RISK FACTORS. AMONG THESE, THE DATA SUPPORTING THE PROTECTIVE BENEFITS OF LIFESTYLE FACTORS, SUCH AS PHYSICAL, COGNITIVE, AND SOCIAL ACTIVITY ENGAGEMENT, ARE SO COMPELLING THAT THE NATION’S LEADING HEALTH ORGANIZATIONS HAVE ADOPTED THESE FINDINGS AS RECOMMENDATIONS FOR ATTENUATING ADRD RISK. HOWEVER, THE PROTECTIVE EFFECTS OF LIFESTYLE FACTORS IN MEXICAN AMERICANS, WHICH MAY INTERACT WITH SOCIOECONOMIC FACTORS, COMORBID DISEASE BURDEN, GENETIC LOADING, AND CULTURAL FACTORS, WARRANTS FURTHER INVESTIGATION. ASSESSMENT OF ACTIVITY ENGAGEMENT HAS TYPICALLY RELIED ON SELF- REPORT, WHICH IS PRONE TO INACCURACIES DUE TO THE FALLIBILITY OF MEMORY, SOCIAL DESIRABILITY BIASES, AND THE LIMITED FREQUENCY OF EVALUATION, NEGATING MORE NUANCED UNDERSTANDING OF BEHAVIORAL CHANGE IN RESPONSE TO COMMON FLUCTUATIONS IN ENVIRONMENTAL AND INDIVIDUAL FACTORS. OUR TEAM AT OREGON HEALTH & SCIENCE UNIVERSITY HAS VALIDATED THE COLLABORATIVE AGING RESEARCH USING TECHNOLOGY (CART) PLATFORM, WHICH IS COMPRISED OF AN INTEGRATED NETWORK OF IN-HOME MONITORING DEVICES THAT CAPTURE HIGH-DENSITY MULTI-MODAL DATA AND ARE COUPLED WITH ALGORITHMS TO DERIVE ACTIVITY PATTERNS THAT PREDICT COGNITIVE DECLINE. THROUGH A PARTNERSHIP WITH THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO, WE HAVE EXTENDED THE TECHNOLOGY TO THE HOMES OF 5 MEXICAN AMERICAN OLDER ADULTS. WE NOW PROPOSE TO EXPAND UPON THIS LINE OF RESEARCH AND LEVERAGE THE CART PLATFORM TO CONTINUOUSLY MONITOR REAL-WORLD PHYSICAL, COGNITIVE, AND SOCIAL ACTIVITY PATTERNS ACROSS A THREE-YEAR PERIOD IN A COHORT OF 120 OLDER MEXICAN AMERICANS ADULTS (AIM 1A). WE WILL FURTHER EVALUATE THE MODIFYING EFFECTS OF SOCIOECONOMIC STATUS, ACCULTURATION, SEX, DEPRESSION, CARDIOVASCULAR BURDEN, AND APOLIPOPROTEIN E4 STATUS (AIM 1B). NEXT, WE WILL EXPLORE THE ASSOCIATIONS BETWEEN ACTIVITY ENGAGEMENT AND TRADITIONAL AND NOVEL NEUROIMAGING INDICES OF BRAIN AGING AND ADRD (AIM 2). FINALLY, WE WILL EXAMINE THE INFLAMMATORY PROFILE ASSOCIATED WITH ACTIVITY ENGAGEMENT, AS WELL AS THEIR ASSOCIATIONS WITH COGNITIVE DECLINE AND NEUROIMAGING OUTCOMES (AIM 3). LEVERAGING THE INNOVATIVE CART TECHNOLOGY PLATFORM, WE WILL IDENTIFY THE ACTIVITY ENGAGEMENT PATTERNS THAT PROMOTE RISK AND RESILIENCE OF COGNITIVE DECLINE IN A HIGH-RISK, UNDERSTUDIED ETHNIC GROUP. RESULTS OF THE STUDY WILL IDENTIFY MULTIDIMENSIONAL HEALTH DETERMINANTS AND INFLAMMATORY PATHWAYS THAT SHAPE COGNITIVE TRAJECTORIES, PROVIDING INSIGHTS INTO TARGETED ADRD PREVENTION AND TREATMENT STRATEGIES WITHIN THIS GROWING POPULATION.

GENETICS OF DIABETIC RETINOPATHY IN HISPANICS

THERAPEUTIC CONTROL OF HSK BY CD80

WOMEN'S ISCHEMIA SYNDROME EVALUATION (WISE) - MECHANISMS OF CORONARY MICROVASCULAR DYSFUNCTION LEADING TO PRE-HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFPEF)

THE ROLE OF CHLAMYDIA PNEUMONIAE INFECTION IN ALZHEIMER'S DISEASE - LATE ONSET ALZHEIMER'S DISEASE (AD), A PROGRESSIVE IRREVERSIBLE SENILE DEMENTIA, IS THE SIXTH LEADING CAUSE OF DEATH IN THE ELDERLY, WITH AN ESTIMATED 5.7 MILLION AMERICANS AFFLICTED BY THIS DEBILITATING DISORDER. THESE NUMBERS ARE EXPECTED TO DOUBLE IN THE NEXT 20 YEARS, PRESENTING A SIGNIFICANT EMOTIONAL AND ECONOMIC BURDEN. WHILE AD RESEARCH CONTINUES TO BE A PRIORITY, LITTLE HEADWAY HAS BEEN MADE IN SLOWING DISEASE PROGRESSION, LET ALONE CURING IT. EARLY HYPOTHESES REGARDING THE CAUSE OF AD INCLUDED INFECTIOUS PARADIGMS, BUT THESE IDEAS WERE LARGELY DISCARDED AS THE UNDERSTANDING OF THE PATHOGENIC ROLE OF AMYLOID SS (ASS) GREW AND THE GENETIC UNDERPINNINGS OF EARLY ONSET AD WERE IDENTIFIED. HOWEVER, NEW DATA HAS LED RESEARCHERS TO ONCE AGAIN SUGGEST THAT INFECTIONS MAY PLAY A DEVELOPMENTAL AND/OR ACCELERATING ROLE IN AD PROGRESSION. AMONG INFECTIOUS ORGANISMS, CHLAMYDIA PNEUMONIAE (CP) HAS BEEN IDENTIFIED AS THE LEADING CANDIDATE FOR A PATHOGENIC ROLE IN AD. CP, A COMMON CAUSE OF COMMUNITY-ACQUIRED PNEUMONIA, HAS BEEN LINKED TO MANY CHRONIC INFLAMMATORY DISEASES, INCLUDING ATHEROSCLEROSIS, ASTHMA, LUNG CANCER, AND AD. IN ADDITION TO AN ASSOCIATION BETWEEN ANTI-CP ANTIBODY TITER AND AD, SEVERAL STUDIES HAVE IDENTIFIED CP IN THE BRAINS OF AD PATIENTS. HOWEVER, THE MECHANISMS BY WHICH CP INFECTION MAY ALTER AD PATHOGENESIS ARE UNKNOWN, AND NO DEFINITIVE MOUSE STUDIES HAVE BEEN PERFORMED. INFLAMMATORY CYTOKINES LIKE NLRP3/IL-1SS AND IL17, BOTH INVOLVED IN CP INFECTION INDUCED PATHOLOGY, MAY BE THE KEY DRIVERS FOR INFECTION –MEDIATED ACCELERATION OF AD, AND WILL BE TARGETED IN THIS APPLICATION. IN A PRELIMINARY STUDY WE FOUND CP ANTIGENS COLOCALIZING WITH ACTIVATED MICROGLIA IN THE BRAINS OF CP INFECTED APPSWE/PS1E9 MICE, CLEARLY PLACING CP IN THE RIGHT LOCATION TO INFLUENCE AD PROGRESSION. WE WERE ALSO ABLE TO IDENTIFY ASC SPECKS (ACTIVE INFLAMMASOME) IN THE BRAINS OF THESE MICE. OUR EXPERTISE IN CP INFECTION AND IMMUNE RESPONSES, IN COMBINATION WITH OUR CO-PI'S EXPERTISE IN AD, PUTS US IN A UNIQUELY STRONG POSITION TO INVESTIGATE THE RELATIONSHIP BETWEEN CP INFECTION AND AD, AND THE POTENTIAL OF ANTIBIOTIC THERAPY IN CP-ACCELERATED AD. BASED ON THESE DATA, WE HYPOTHESIZE THAT CP INFECTION PLAYS A ROLE IN PROGRESSION AND/OR DEVELOPMENT OF ALZHEIMER'S DISEASE, WHICH IS PREVENTABLE BY EARLY ANTIBIOTIC TREATMENT, AND THAT CP EFFECTS ARE AT LEAST PARTIALLY MEDIATED THROUGH ACTIVATION OF THE NLRP3 INFLAMMASOME AND IL-17A. IN ORDER TO TEST THESE HYPOTHESES, WE WILL INVESTIGATE THE FOLLOWING AIMS: 1) DETERMINE THE EFFECT OF CP INFECTION ON DISEASE PROGRESSION IN APPSWE/PS1E9 (ADTG) MICE AND 2) DETERMINE THE ROLE OF THE NLRP3 INFLAMMASOME IN CP INFECTION- MODULATED AD PATHOLOGY IN ADTG MICE AND IN PATIENTS WITH AD OR MILD COGNITIVE IMPAIRMENT (MCI) AND 3) DETERMINE THE ROLE OF IL-17A IN CP INFECTION-MODULATED AD-LIKE PATHOLOGY IN ADTG MICE. THE COMPLETION OF OUR PROPOSAL WILL LAY THE GROUNDWORK FOR UNDERSTANDING WHAT POSSIBLE ROLE CP INFECTION PLAYS IN AD. FURTHERMORE, THESE DATA WILL BE USED AS THE BASIS FOR FUTURE RESEARCH UNDERSTANDING THE MECHANISMS INVOLVED CP INFECTION ROLE IN AD WITH THE ULTIMATE GOAL LEADING TO NEW THERAPEUTIC APPROACHES FOR THIS DEVASTATING DISEASE.

ADVANCING ANALYSIS AND INTERPRETATION OFADVERSE EVENTS AND PROS IN CANCER CLINICAL TRIALS

HOST IMMUNITY TO COMMENSAL GUT FUNGI

TUMOR TARGETED CORROLES FOR DETECTION AND INTERVENTION

GAP JUNCTION TRAFFICKING TO AND WITHIN THE PLASMA MEMBRANE

WOMEN'S ISCHEMIA SYNDROME EVALUATION (WISE) CORONARY VASCULAR DYSFUNCTION

NEURONAL MECHANISMS OF HUMAN EPISODIC MEMORY

EVALUATING ENVIRONMENTAL CONTROL (AVOID) AND INHIBITORY CONTROL (RESIST) STRATEGIES TO IMPROVE WEIGHT MANAGEMENT OUTCOMES - ABSTRACT EVIDENCE-BASED WEIGHT MANAGEMENT PROGRAMS ARE EFFECTIVE WHEN INDIVIDUALS ARE ABLE TO CONSISTENTLY ADHERE TO RECOMMENDATIONS. HOWEVER, A LARGE PROPORTION OF TREATMENT-SEEKING INDIVIDUALS DO NOT EXPERIENCE CLINICALLY SIGNIFICANT WEIGHT LOSS. INNOVATIVE STRATEGIES ARE NEEDED TO OPTIMIZE BEHAVIOR CHANGE IN WEIGHT MANAGEMENT INTERVENTIONS. THE PROPOSED RANDOMIZED CONTROLLED TRIAL TESTS TWO SELF-REGULATORY APPROACHES TO IMPROVE INTENTIONAL WEIGHT LOSS AND DIET QUALITY IN INDIVIDUALS WITH OVERWEIGHT OR OBESITY: (1) AN ENVIRONMENTAL CONTROL STRATEGY (AVOID) AND (2) AN IMPULSE CONTROL TRAINING STRATEGY (RESIST). SPECIFICALLY, 500 WOMEN AND MEN (BMI BETWEEN 25-39.9 KG/M2) WILL BE RECRUITED FROM THE CEDARS-SINAI MEDICAL CENTER NETWORK OF HOSPITALS AND CLINICS. ALL PARTICIPANTS WILL BE ENROLLED IN A 12-MONTH WEIGHT-MANAGEMENT PROGRAM (WW, FORMERLY WEIGHT WATCHERS©) FOCUSING ON DIET, PHYSICAL ACTIVITY AND MINDSET SKILLS, AND RANDOMIZED TO ONE OF FOUR STUDY ARMS: (1) WW ONLY, (2) WW + MODIFICATION OF HOME FOOD ENVIRONMENT AND ONLINE GROCERY DELIVERY (AVOID), (3) WW + GAMIFIED INHIBITORY CONTROL TRAINING (RESIST), (4) WW + AVOID + RESIST. BASELINE, 6- AND 12-MONTH ASSESSMENTS WILL BE COMPLETED BY EXPERIENCED, ENGLISH AND SPANISH SPEAKING STUDY STAFF. AIM 1 (OUTCOMES). (A) TESTS HOW AVOID AND RESIST AFFECT WEIGHT LOSS AND WAIST CIRCUMFERENCE (PRIMARY) AND DIET QUALITY (SECONDARY). H1A: AVOID AND/OR RESIST (ARMS 2, 3, 4) WILL RESULT IN GREATER WEIGHT LOSS AT 6-MONTH AND 12-MONTH TIMEPOINTS COMPARED TO WW ALONE. (B) TESTS POTENTIAL RIPPLE EFFECTS OF AVOID AND RESIST ON AVAILABLE HOUSEHOLD MEMBERS' DIET QUALITY (PRIMARY) AND WEIGHT (SECONDARY). H1B: WE PREDICT THAT AVOID (ARMS 2 AND 4) WILL PRODUCE GREATER DIETARY CHANGES IN HOUSEHOLD MEMBERS THAN WW ALONE AND RESIST (ARMS 1 AND 3). AIM 2 (MECHANISMS). TESTS THE MECHANISTIC PATHWAYS OF AVOID AND RESIST BY (A) COMPARING LONGITUDINAL CHANGES IN INHIBITORY CONTROL AND HOME FOOD ENVIRONMENT ACROSS STUDY ARMS; AND (B) WHETHER INHIBITORY CONTROL AND THE HOME FOOD ENVIRONMENT MEDIATE THE RELATIONSHIPS BETWEEN STUDY ARMS AND ANTHROPOMETRIC AND DIETARY OUTCOMES. H2: AVOID WILL PRODUCE CHANGES IN THE HOME FOOD ENVIRONMENT AND RESIST WILL OPERATE ON INHIBITORY CONTROL. AIM 3 (MODERATORS). EXAMINES HOW (A) INDIVIDUAL CHARACTERISTICS (AGE, SEX, ETHNICITY, SOCIOECONOMIC STATUS, HOUSEHOLD COMPOSITION, PHYSICAL ACTIVITY, BASELINE BMI AND EXECUTIVE FUNCTIONING), AND (B) PROCESS DATA (FREQUENCY OF GROCERY DELIVERY, DINING OUT AND TAKE OUT, IMPULSE CONTROL TRAINING AND WW APP USE) MODERATE THE RELATIONSHIP BETWEEN STUDY ARMS AND ANTHROPOMETRIC AND DIETARY OUTCOMES. THESE CONSIDERATIONS ARE IMPORTANT TO HELP EXPLAIN HETEROGENEITY IN INTERVENTION OUTCOMES AND TO UNDERSTAND WHO BENEFITS FROM AVOID AND/OR RESIST.

AI METHODS FOR LARGE SCALE EPIDEMIOLOGICAL STUDIES USING PATIENT REPORTS OF MEDICATION ADHERENCE AND TOLERABILITY - PROJECT SUMMARY ADHERENCE TO PRESCRIBED MEDICATIONS IS A CRITICAL ASPECT OF EFFECTIVE MEDICAL TREATMENT, ESPECIALLY FOR CHRONIC CON- DITIONS; HOWEVER, THE WORLD HEALTH ORGANIZATION (WHO) ESTIMATES THAT MORE THAN 50% OF PATIENTS WITH CHRONIC CONDITIONS IN THE UNITED STATES DO NOT TAKE THEIR MEDICATIONS AS PRESCRIBED. MEDICATION NON-ADHERENCE IS ASSOCI- ATED WITH WORSENING HEALTH CONDITIONS AND INCREASED COMORBIDITIES, AND IS ESTIMATED TO ANNUALLY ACCOUNT FOR 25% OF HOSPITALIZATIONS, MORE THAN 100,000 PREVENTABLE DEATHS, AND UP TO $500 BILLION IN HEALTHCARE COSTS IN THE UNITED STATES. THE WHO AFFIRMS THAT “INCREASING THE EFFECTIVENESS OF ADHERENCE INTERVENTIONS MAY HAVE A FAR GREATER IMPACT ON THE HEALTH OF THE POPULATION THAN ANY IMPROVEMENT IN SPECIFIC MEDICAL TREATMENTS.” THE CHALLENGE OF INCREASING THE EFFECTIVENESS OF ADHERENCE INTERVENTIONS HAS LIKELY BEEN DUE IN PART TO THE FACT THAT THE MAJORITY OF MEDICATION NON-ADHERENCE IS INTENTIONAL (IN CONTRAST TO UNINTENTIONAL, SUCH AS FORGETFULNESS) AND SOURCES OF DATA FOR UNDERSTANDING THE FACTORS THAT INFLUENCE INTENTIONAL NON-ADHERENCE REMAIN LIMITED. AS ENCOURAGED BY THE UNITED STATES FOOD AND DRUG ADMINISTRATION AND CENTERS FOR DISEASE CONTROL AND PREVENTION, OUR PRIOR WORK—FUNDED FOR THE PAST 10 YEARS BY THE NATIONAL LIBRARY OF MEDICINE (R01LM011176)—HAS DEMONSTRATED THAT PATIENT REPORTS IN REAL-WORLD, NON-TRADITIONAL SOURCES OF DATA CAN BE USED AS A NOVEL, COMPLEMENTARY APPROACH TO POST-MARKETING PHARMACOVIGILANCE. BECAUSE ONLINE PATIENT REPORTS ARE NOT BIASED BY SURVEY QUESTIONS OR INTERVIEWERS, ARE AVAIL- ABLE ON A LARGE SCALE, AND MAY INCLUDE PARTICIPANTS WHO ARE UNDER-REPRESENTED IN TRADITIONAL SOURCES OF DATA, IN A PRELIMINARY QUALITATIVE CONTENT ANALYSIS, WE WERE ABLE TO GAIN NOVEL INSIGHTS ABOUT MEDICATION NON-ADHERENCE THAT WERE NOT WELL-REPRESENTED IN OTHER STUDIES, SUCH AS PATIENTS REPORTING DECHALLENGE (I.E., AN ADVERSE EFFECT STOPPING WHEN THE MEDICATION WAS STOPPED) AND RECHALLENGE (I.E., THE ADVERSE EFFECT RESUMING WHEN THE MEDICATION WAS STARTED AGAIN). VALIDATING OUR APPROACH THROUGH FIVE DISEASE-SPECIFIC CASE STUDIES IN COLLABORATION WITH DOMAIN EXPERTS IN CARDIOVASCULAR DISEASES, GASTROINTESTINAL DISEASES, CANCER, HIV, AND DIABETES (AIM 3), WE PROPOSE TO DEVELOP NOVEL NATURAL LANGUAGE PROCESSING AND ARTIFICIAL INTELLIGENCE METHODS (AN INTELLIGENT AGENT WITH A SPECIAL- IZED LARGE LANGUAGE MODEL AT ITS CORE) TO CAPTURE MEDICATION USE NARRATIVES FROM ONLINE PATIENT REPORTS (AIM 1) AND TO ELUCIDATE ADDITIONAL FACTORS CONTRIBUTING TO MEDICATION NON-ADHERENCE FROM SPONTANEOUS REPORTING SYSTEMS (SRS, E.G., FAERS), SUCH AS DRUG INDICATIONS, THE MAGNITUDE OF ADVERSE EVENTS, AND DRUG-DRUG INTERACTIONS (AIM 2). WE INCORPORATE FINDINGS FROM OTHER SOURCES INTO OUR CASE STUDIES THROUGH SYSTEMATIC REVIEWS (AIM 3), SYNTHE- SIZING AND COMPARING PUBLISHED STUDIES TO WHAT WE LEARN FROM PATIENT REPORTS POSTED ONLINE AND IN SRS. THIS IS THE MOST COMPREHENSIVE STUDY OF ITS KIND EVER ATTEMPTED, BRINGING THE VOICE OF THE PATIENTS DIRECTLY TO RESEARCHERS IN A REPRODUCIBLE, COST-EFFECTIVE MANNER. THIS CAN INFORM ADHERENCE INTERVENTIONS AND REDUCE THE MORBIDITY, MORTALITY, AND FINANCIAL BURDEN ASSOCIATED WITH INTENTIONAL NON-ADHERENCE, ALIGNING WITH THE NLM’S GOAL OF CREATING A FUTURE IN WHICH DATA AND INFORMATION TRANSFORM AND ACCELERATE BIOMEDICAL DISCOVERY AND IMPROVE HEALTH AND HEALTHCARE.

4D SSFP MRI FOR DETECTING FUNCTIONALLY IMPORTANT CORONARY ARTERY STENOSIS AT REST

BLADDER FIDUCIAL MARKERS AND DIFFUSION-MRI TO OPTIMIZE BLADDER CHEMO-RADIOTHERAPY

ADVERSE OUTCOMES OF ASSISTED REPRODUCTIVE TECHNOLOGIES: GENETICS OR EPIGENETICS

METHIONINE ADENOSYLTRANSFERASE ALPHA1 IN ALCOHOLIC LIVER DISEASE

DNA INVERTED REPEATS AS AN AT-RISK MOTIF FOR PALINDROMIC GENE AMPLIFICATION

NOVEL BIOMARKERS FOR CANCER-RELATED FATIGUE: INTEGRATING METABOLOMICS, GENOMICS AND BEHAVIORS

AN ACCURATE NON-CONTRAST-ENHANCED CARDIAC MRI METHOD FOR IMAGING CHRONIC MYOCARDIAL INFARCTIONS: TECHNICAL DEVELOPMENTS TO RAPID CLINICAL VALIDATION

OCULAR HSV: MECHANISM OF VIRUS REACTIVATION

SINGLE NUCLEI RNA-SEQ TO MAP ADIPOSE CELLULAR POPULATIONS AND SENESCET CELLS IN OLDER SUBJECTS - AGING IS CHARACTERIZED BY AN EXPANSION IN ADIPOSE TISSUE (I.E. OBESITY), WHICH PLAYS A KEY ROLE IN THE PATHOPHYSIOLOGY OF MANY AGING-DISEASES, INCLUDING TYPE 2 DIABETES, ATHEROSCLEROTIC VASCULAR DISEASE, ALZHEIMER’S DISEASE, AND SOME CANCERS. ADIPOSE TISSUE IS COMPOSED OF ADIPOCYTES, IMMUNE CELLS, ENDOTHELIAL CELLS, STEM/STROMAL CELLS, AND PREVIOUSLY UNCHARACTERIZED CELLULAR POPULATIONS. ADIPOSE TISSUE ALSO CONTAINS CELLS THAT HAVE UNDERGONE CELLULAR SENESCENCE, A STATE CHARACTERIZED BY THE ARREST OF THE CELL CYCLE AND A SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP), WHICH INDUCES INFLAMMATION, CYTOTOXICITY, AND METABOLIC DYSFUNCTION IN OTHER CELLS AND TISSUES. RECENT RESEARCH SUGGESTS THAT AGING IS ASSOCIATED WITH CHANGES IN ADIPOSE CELLULAR POPULATIONS AND SUBPOPULATIONS, AND THAT THESE VARIATIONS MAY BE INVOLVED IN THE BIOLOGY OF AGING AND ETIOLOGY OF AGING-RELATED DISEASES. YET, THE PRECISE PROFILING OF ADIPOSE TISSUE CELLULAR COMPOSITION HAS BEEN LIMITED DUE TO A LACK OF ROBUST CELL SURFACE MARKERS FOR THE NUMEROUS CELLULAR SUBPOPULATIONS. SINGLE-CELL (SC) RNA SEQ IS A NOVEL HIGH-RESOLUTION METHODOLOGY THAT ENABLES GLOBAL IDENTIFICATION OF CELLULAR POPULATIONS AND SUBPOPULATIONS (KNOWN AND NEWLY IDENTIFIED) IN TISSUES. WE HAVE DEVELOPED A SINGLE NUCLEI (SN)RNA-SEQ BASED METHOD (A VARIATION OF SCRNA-SEQ) THAT ALLOWS EXCELLENT IDENTIFICATION, SEPARATION AND CLUSTERING OF ADIPOSE CELLULAR POPULATIONS, INCLUDING MATURE ADIPOCYTES, IMMUNE CELLS, ENDOTHELIAL CELLS, AND MESENCHYMAL STEM CELLS. ALTHOUGH SNRNA-SEQ ALSO IS A PROMISING TOOL FOR IDENTIFICATION AND CHARACTERIZATION OF CELLS UNDERGOING SENESCENCE, IT HAS NOT BEEN USED TO MORE FULLY ELUCIDATE THE IMPORTANCE OF SUCH CELLS IN THE BIOLOGY OF AGING AND THE ETIOLOGY OF AGING-RELATED METABOLIC DISEASES. IN AIM 1 WE WILL CONDUCT ADIPOSE TISSUE MOLECULAR PROFILING VIA SNRNA-SEQ IN THREE COHORTS AT BASELINE: YOUNGER LEAN, OLDER LEAN, AND OLDER OBESE INDIVIDUALS. WE WILL DEVELOP MOLECULAR ATLASES IN THESE SUBJECTS TO TEST THE HYPOTHESIS THAT BOTH AGING AND AGING PLUS OBESITY WILL HAVE DISTINCT ADIPOSE TISSUE MOLECULAR PROFILES. IN A SUBGROUP OF OLDER OBESE SUBJECTS WE WILL ALSO TEST WHETHER A LIFESTYLE INTERVENTION CHANGES THE GLOBAL MOLECULAR PROFILE IN ADIPOSE TISSUE TO A PROFILE CLOSER TO THAT IN YOUNGER AND OLDER LEAN INDIVIDUALS. IN AIM 2 WE WILL FOCUS ON THE IDENTIFICATION, QUANTIFICATION, AND FUNCTIONAL CHARACTERIZATION OF ADIPOSE TISSUE SENESCENT CELLS. SUB AIM 2A WILL TEST THE HYPOTHESES THAT THE AMOUNT AND FUNCTION (I.E. SASP) OF ADIPOSE TISSUE SENESCENT CELLS WILL BE ELEVATED WITH AGING AND FURTHER ENHANCED BY OBESITY, AND THAT THE LIFESTYLE INTERVENTION (FROM AIM 1) WILL REDUCE SENESCENT CELL BURDEN IN OLDER OBESE SUBJECTS. IN SUB AIM 2B WE WILL ADMINISTER SENOLYTIC AGENTS TO A SUBGROUP OF OLDER OBESE SUBJECTS (FROM AIM 1) TO DETERMINE WHETHER CLEARANCE OF SENESCENT CELLS IMPROVES METABOLIC OUTCOMES. THIS SUB AIM WILL DIRECTLY TEST THE CELLULAR SENESCENCE THEORY AND WILL SERVE AS A POSITIVE CONTROL FOR THE LIFESTYLE INTERVENTION REGARDING ITS POTENTIAL ANTI-SENESCENCE EFFECT.

WHOLE-HEART MYOCARDIAL BLOOD FLOW QUANTIFICATION USING MRI

THERAPEUTIC TARGETING OF BREAST CANCER AND HOST IMMUNE RESPONSES AT INFLECTION POINTS IN THE DISEASE TRAJECTORY

EXOSOME THERAPEUTICS TO DISSECT HFPEF MECHANISMS - PROJECT SUMMARY NO EFFECTIVE PHARMACOLOGICAL OR MEDICAL DEVICE INTERVENTIONS ARE AVAILABLE TO TREAT HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFPEF). WE HAVE PIONEERED THE CONCEPT OF CELL THERAPY FOR HFPEF: CARDIOSPHERE-DERIVED CELLS (CDCS) DRAMATICALLY IMPROVE DIASTOLIC FUNCTION AND REDUCE ARRHYTHMIAS, WHILE ATTENUATING FIBROSIS AND INFLAMMATION. MOST, IF NOT ALL, OF THESE BENEFICIAL EFFECTS ARE MEDIATED BY EXOSOMES SECRETED BY CDCS (CDCEXO). HERE WE SEEK TO ESTABLISH DETAILED MOLECULAR SIGNATURES OF HFPEF; TO USE THOSE MOLECULAR SIGNATURES AS ROADMAPS TO IDENTIFY KEY, POTENTIALLY CAUSAL PATHWAYS BY DISSECTING THE RESPONSES TO CDCEXO; AND TO DISCOVER NOVEL DEFINED MOLECULAR ENTITIES, BASED ON CDCEXO CARGO, WITH DISEASE-MODIFYING BIOACTIVITY IN HFPEF. OUR HYPOTHESES, BACKED BY STRONG PRELIMINARY DATA, ARE: - UNDERLYING HFPEF ARE BEWILDERINGLY EXTENSIVE CHANGES IN MYOCARDIAL TRANSCRIPTOMICS AND PROTEOMICS. SORTING CAUSAL FROM ASSOCIATIVE CHANGES PRESENTS A MAJOR CHALLENGE, BUT IT IS DOABLE. - A SUBSET OF THESE HFPEF-RELATED PROTEOME CHANGES ARE REVERSED BY CDCS OR CDCEXO AND SOME CORRELATED TO THE REVERSAL OF THE KEY FUNCTIONAL ABNORMALITIES OF HFPEF. WE POSIT THAT FOCUSING ON CDCEXO-RESPONSIVE PATHWAYS WILL FACILITATE THE SEARCH FOR CAUSAL ABNORMALITIES, ENABLING TARGETED HYPOTHESIS TESTING. - BY MINING THE RNA AND PROTEIN CONTENTS OF CDCEXO, WE HAVE THE POTENTIAL TO PINPOINT DEFINED FACTORS WHICH HAVE DISEASE-MODIFYING BIOACTIVITY IN HFPEF. SUCH DEFINED FACTORS MAY THEMSELVES BE VIABLE THERAPEUTIC CANDIDATES, OR CAN INSPIRE THE CREATION OF NEW CHEMICAL ENTITIES AS THERAPEUTIC CANDIDATES. THE OVERALL GOAL OF THIS PROPOSAL IS TO UNDERSTAND BETTER THE PATHOGENESIS OF HFPEF, AND TO DEVELOP NOVEL CELL- FREE APPROACHES TO TREAT THIS DISEASE. THREE AIMS ARE PROPOSED. IN AIM 1 WE WILL PERFORM AND ANALYZE TISSUE AND SINGLE CELL TRANSCRIPTOMICS AND PROTEOMICS (INCLUDING NUMEROUS PROTEIN POST-TRANSLATIONAL MODIFICATIONS) OF HFPEF, IN THREE DIFFERENT MODELS (PIG, MOUSE AND RAT) THAT REPRESENT DIFFERENT COMORBIDITIES AND COMPARE THEIR DISEASE SIGNATURE TO THOSE IN HUMAN HFPEF HEART TISSUE. COMMONALITIES IN THE OMICS RESPONSES AMONG SPECIES WILL HELP DISTINGUISH CAUSAL VERSUS ASSOCIATIVE PATHWAYS IN HFPEF PATHOGENESIS. AIM 2 WILL ANALYZE MOLECULAR SIGNATURES OF THERAPEUTIC EFFICACY BY COMPARING TRANSCRIPTOMICS AND PROTEOMICS WITH AND WITHOUT EXPOSURE TO CDCEXO. BECAUSE CDCS AND THEIR EXOSOMES STRIKINGLY REVERSE THE HFPEF PHENOTYPE, IDENTIFICATION OF CDCEXO-INDUCED MOLECULAR CHANGES WILL FURTHER REFINE PATHWAY PRIORITIZATION IN TERMS OF CAUSAL VERSUS ASSOCIATIVE. HERE WE WILL STUDY VENTRICULAR TISSUE AND SINGLE CELLS FROM RAT, MOUSE AND PIG MODELS OF HFPEF (AND CONTROLS), WITH AND WITHOUT IN VIVO EXPOSURE TO CDCEXO. IN AIM 3 WE WILL MINE CDCEXO CARGO TO IDENTIFY CRITICAL FACTORS UNDERLYING DISEASE-MODIFYING BIOACTIVITY IN A RAT MODEL OF HFPEF. THIS WILL ALLOW US TO DEFINE AND/OR CREATE SPECIFIC MOLECULAR ENTITIES (EITHER RNA SPECIES OR PROTEINS) THAT MAY BE PREFERABLE TO COMPLEX BIOLOGICALS (CELLS, EXOSOMES) IN TERMS OF MECHANISTIC DISCRETENESS, EASE OF MANUFACTURING, AND THERAPEUTIC CONSISTENCY.

MEDIATORS OF SYSTEMIC INFLAMMATION AND HEART FAILURE RISK IN THE COMMUNITY

CHARACTERIZING NON-CODING SOMATIC AND GERMLINE VARIANT INTERACTIONS IN OVARIAN CANCER

MULTIPARAMETRIC PET/MRI ASSESSMENT OF MAST CELL STABILIZATION EFFECTS ON INFLAMMAGING AND GLUCOSE UTILIZATION IN INFARCTED MYOCARDIUM - PROJECT SUMMARY INSULIN RESISTANCE (IR) IN AGING HEARTS OF NONDIABETICS IS KNOWN TO BE PROMOTED BY FAT ACCUMULATION WITHIN SENESCENT MYOCARDIUM IN THE ABSENCE OF OBESITY OR PHYSICAL INACTIVITY. IMPORTANTLY, THESE CHANGES MAKE THE AGED MYOCARDIUM MORE SUSCEPTIBLE TO HEART FAILURE AND SUDDEN DEATH. SIMILARLY, AGING OF INFARCTED MYOCARDIUM IN NONDIABETIC SUBJECTS IS COMMONLY ACCOMPANIED BY FAT ACCUMULATION IN MYOCARDIAL SCAR TISSUE (LIPOMATOUS METAPLASIA, LM). HOWEVER, WHETHER LM INFLUENCES MYOCARDIAL IR, REMAINS UNKNOWN. RECENT STUDIES USING A NONDIABETIC RAT MODEL HAVE DEMONSTRATED DIRECT EVIDENCE OF SELECTIVE MYOCARDIAL IR IN CHRONIC MIS WITH HEART FAILURE. HOWEVER, IT REMAINS UNKNOWN WHETHER THESE MIS ALSO HAD LM. CARDIAC INFLAMMAGING POST-MI IS A STATE OF CHRONIC LOW-GRADE STERILE INFLAMMATION THAT PLAYS A KEY ROLE IN THE ONSET AND PROGRESSION OF HEART FAILURE. IT IS A MAST CELL (MC)- AND MACROPHAGE (MF)-DRIVEN PROCESS CHARACTERIZED BY A COMPLEX BALANCE BETWEEN PRO- AND ANTI-INFLAMMATORY RESPONSES. EQUALLY IMPORTANT, THE PREPONDERANCE OF MC AND PROINFLAMMATORY M1 MF WITHIN ADIPOSE TISSUE (AT) IS NOW RECOGNIZED AS A HALLMARK OF OBESITY- ASSOCIATED LOW-GRADE INFLAMMAGING WHICH LEADS TO REDUCED EXPRESSION OF ADIPOCYTE GLUCOSE TRANSPORTER (GLUT4) AND SYSTEMIC IR. SYSTEMIC IR HAS BEEN COMMONLY OBSERVED IN NONDIABETIC PATIENTS WITH ISCHEMIC POST-MI CARDIOMYOPATHY. HOWEVER, WHETHER THESE SUBJECTS ALSO EXHIBIT MYOCARDIAL IR AND/OR LM, IS UNKNOWN. METABOLIC STATE AND THE PHENOTYPE OF MC AND MF THROUGHOUT THE INFLAMMATORY PROCESS ARE TIGHTLY LINKED. WHILE ACTIVATED MC AND M1 MF ARE HIGHLY DEPENDENT ON GLUCOSE AS AN ENERGY SUBSTRATE, ANTI-INFLAMMATORY M2 MF ARE PREFERENTIALLY FUELED BY FATTY ACID SS-OXIDATION. LIPID-OVERLOADING AND INSULIN (HYPER) STIMULATION HAVE EACH BEEN DEMONSTRATED TO PROMOTE MC ACTIVATION, M1 POLARIZATION, AND MF FOAM CELL FORMATION, THUS INITIATING THE PROCESS OF ATHEROGENESIS. MOREOVER, THE PRO-ATHEROGENIC EFFECTS OF MCS WERE SHOWN TO BE SUCCESSFULLY ABOLISHED VIA MC MEMBRANE STABILIZATION. NOTABLY, MC AND LIPID-LADEN M1 MF HAVE EACH BEEN DEMONSTRATED IN INFARCTED TERRITORY BEYOND SUBACUTE PHASE OF MI. HOWEVER, THEIR LONG-TERM FATE, THE INTERACTION BETWEEN THE TWO, AND THEIR RESPECTIVE ROLES IN LM AND/OR IR REMAIN UNKNOWN. WHILE 18F-FLUORODEOXYGLUCOSE (18FDG) PET HAS EMERGED AS A NON-INVASIVE IMAGING OF CHOICE TO ASSESS MYOCARDIAL IMMUNOMETABOLIC STATE AND TO DIAGNOSE MYOCARDIUM-SPECIFIC IR, QUANTITATIVE CARDIAC MR (QCMR) IS NOW WIDELY ACCEPTED AS THE GOLD STANDARD FOR THE QUANTITATIVE ESTIMATION OF INFARCT SIZE AND TISSUE COMPOSITION. HEREIN, WE PROPOSE TO USE A COMBINED 18FDG-PET/QCMR IMAGING TO EVALUATE THE EFFECTS OF MC STABILIZATION ON METABOLIC PHENOTYPE AND REMODELING OF MI, IN A PORCINE MODEL.

ASSESSMENT OF MAST CELL DEGRANULATION IN INFARCTED MYOCARDIUM USING QUANTITATIVE MULTIPARAMETRIC MRI - PROJECT SUMMARY THE OVERALL OBJECTIVE OF THE PROPOSED PROJECT IS TO EVALUATE THE EFFECTIVENESS OF A NOVEL PHARMACOLOGICAL TREATMENT OF MYOCARDIAL INFARCTION (MI) USING QUANTITATIVE MULTIPARAMETRIC MAGNETIC RESONANCE IMAGING (QMRI). MI IS A MAJOR CAUSE OF DEATH AND DISABILITY WORLDWIDE. URGENT REPERFUSION OF THE OCCLUDED ARTERY TO RESTORE MYOCARDIAL BLOOD FLOW IS CENTRAL TO THE CLINICAL MANAGEMENT OF ACUTE THROMBOTIC MI (AMI). HOWEVER, RECANALIZATION OF THE CULPRIT ARTERY MAY ALSO RESULT IN UNINTENDED INJURY BY CAUSING MICROVASCULAR OBSTRUCTION (MVO), INTRAMYOCARDIAL HEMORRHAGE (IMH), AND EDEMA DURING THE ACUTE PHASE. IN THE SETTING OF CHRONIC MI, IRON DEPOSITION AND FAT ACCUMULATION (LIPOMATOUS METAPLASIA, LM) ARE FREQUENTLY OBSERVED IN INFARCTED MYOCARDIUM. ALL THESE BIOMARKERS ARE STRONG PREDICTORS OF MAJOR ADVERSE CARDIOVASCULAR EVENTS SUCH AS HEART FAILURE. TO DATE, HOWEVER, THERE HAVE BEEN NO EFFECTIVE THERAPEUTIC STRATEGIES FOR ATTENUATING EITHER MVO, IMH, CHRONIC IRON DEPOSITION, OR LM POST-REPERFUSION. MAST CELLS (MC) ARE DERIVED FROM BLOOD-BORNE, MULTIPOTENT HEMATOPOIETIC PROGENITOR CELLS THAT, ONCE LOCATED IN TISSUE, DIFFERENTIATE TO A FINAL PHENOTYPE UNDER THE INFLUENCE OF THE LOCAL MICROENVIRONMENT. IN GENERAL, MC EXERT THEIR PHYSIOLOGICAL AND PATHOLOGICAL FUNCTIONS BY RELEASING CYTOPLASMIC GRANULES (DEGRANULATION) CONTAINING A VARIETY OF BIOLOGICALLY ACTIVE MEDIATORS. RECENT EXPERIMENTAL STUDIES HAVE SHOWN THAT HEMATOMA GROWTH, EDEMA EXPANSION AND OVERALL NEUROLOGICAL DAMAGE AFTER CEREBRAL ISCHEMIA- REPERFUSION CAN BE REDUCED BY EARLY TREATMENT WITH MC STABILIZERS, WHICH ARE KNOWN TO SUPPRESS MC DEGRANULATION. EQUALLY IMPORTANT, ATHEROSCLEROSIS RESEARCH OVER THE LAST TWO DECADES HAS PROVIDED STRONG EVIDENCE FOR MC INVOLVEMENT IN FOAM CELL FORMATION AND PLAQUE DEVELOPMENT. BASED ON THESE STUDIES, WE HYPOTHESIZED THAT MC STABILIZATION VIA THE ADMINISTRATION OF OVER-THE-COUNTER ANTI-ALLERGY MEDICATION LORATADINE REDUCES MYOCARDIAL EDEMA, IMH VOLUME AND IMPROVES MYOCARDIAL MICROCIRCULATION IN THE ACUTE MI SETTING; AND ATTENUATES LM OF INFARCTED MYOCARDIUM IN THE CHRONIC PHASE. QUANTITATIVE CARDIOVASCULAR MR (QCMR) IMAGING HAS BEEN WIDELY USED TO CHARACTERIZE MYOCARDIAL ISCHEMIA, HEMORRHAGE, EDEMA, INFLAMMATION, IRON DEPOSITION, FAT ACCUMULATION AND OTHER PATHOLOGICAL CONDITIONS. IN THIS PROPOSAL, WE AIM TO VALIDATE THE EFFECTIVENESS OF MC STABILIZER LORATADINE ON STRUCTURAL AND FUNCTIONAL CARDIAC REMODELING POST-PHARMACOTHERAPY IN A PORCINE MODEL OF MI BY TEMPORALLY FOLLOWING IMAGING BIOMARKERS OF ACUTE AND CHRONIC MI USING WELL-ESTABLISHED QCMR TECHNIQUES. SUCCESSFUL COMPLETION OF THE PROJECT WILL PROVIDE INITIAL VALIDATION THAT EARLY LORATADINE INTERVENTION HAS THE POTENTIAL TO BE A NOVEL THERAPEUTIC STRATEGY FOR PREVENTION OF HEART FAILURE POST-MI AS EVALUATED BY OUR QUANTITATIVE MULTIPARAMETRIC MRI APPROACH.

FUNCTIONAL EFFECTS OF OVARIAN CANCER RISK VARIANTS

IL-27R SIGNALING AS A NEGATIVE REGULATOR OF INNATE AND ADAPTIVE ANTI-CANCER IMMUNITY IN HEPATOCELLULAR CARCINOMA - PROJECT SUMMARY LIVER CANCER RANKS FIFTH IN FREQUENCY AND THIRD IN MORTALITY, WITH ESTIMATED NUMBERS OF OVER 700,000 NEW CASES EVERY YEAR WORLDWIDE. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON FORM OF LIVER CANCER THAT ORIGINATES FROM VIRAL INFECTION (E.G., HEPATITIS B, C) OR INJURY-DRIVEN CHRONIC INFLAMMATION (E.G., CIRRHOSIS FROM EXCESSIVE ALCOHOL CONSUMPTION OR OBESITY-INDUCED STEATOHEPATITIS) IN THE LIVER. ALTHOUGH HBV AND HCV INCIDENCE ARE ON THE DECLINE, THE OBESITY EPIDEMIC HAS RESULTED IN AN INCREASE IN THE NUMBER OF NEW CASES OF HCC IN DEVELOPED COUNTRIES INCLUDING THE US. THUS, IDENTIFYING TARGETABLE MEDIATORS OF HCC REPRESENTS AN IMPORTANT UNMET MEDICAL NEED. INTERLEUKIN (IL)-27 IS A CYTOKINE THAT PLAYS IMMUNOMODULATORY ROLES IN INFECTION AND AUTOIMMUNITY. IL27R SIGNALING REDUCES INFLAMMATION IN INFECTIOUS AND INFLAMMATORY MODELS OSTENSIBLY BY SUPPRESSING A PRO- INFLAMMATORY IMMUNE RESPONSE. THESE FINDINGS LED US TO SPECULATE THAT IL27 MIGHT FUNCTION SIMILARLY TO LIMIT LIVER INFLAMMATION AND HALT HCC DEVELOPMENT. SURPRISINGLY, HOWEVER, WE HAVE DISCOVERED THAT ELIMINATING IL27R SIGNALING SUPPRESSES TUMOR DEVELOPMENT IN TWO IN VIVO MOUSE MODELS OF HCC WHICH WAS ACCOMPANIED BY THE INCREASED ACCUMULATION AND ACTIVATION OF INNATE AND ADAPTIVE CYTOTOXIC IMMUNE CELLS, SUGGESTING A NEW, PRO- TUMORIGENIC ROLE FOR THIS OTHERWISE ANTI-INFLAMMATORY CYTOKINE. HERE WE PROPOSE TO INVESTIGATE CELLULAR AND MOLECULAR MECHANISMS OF HOW IL27R SIGNALING SUPPRESSES ANTI-CANCER CYTOTOXIC IMMUNE RESPONSE USING HIGHLY RELEVANT TO HUMAN HCC MUP-UPA MOUSE MODEL COMBINED WITH CELL TYPE SPECIFIC ABLATION OF IL27R AND INTEGRATED ARRAY OF CUTTING-EDGE TRANSCRIPTOMICS, HISTOLOGICAL, IMMUNOLOGICAL, AND MOLECULAR BIOLOGY ANALYSES. FINALLY, WE WILL TEST THE EFFICACY AND IDENTIFY CELLULAR AND MOLECULAR MECHANISMS OF IL27 SIGNALING BLOCKADE EITHER ALONE OR IN COMBINATION WITH OTHER IMMUNOTHERAPIES, AS A NEW THERAPEUTIC AVENUE FOR HCC. OVERALL, THE PROPOSED RESEARCH WILL UNCOVER THE ROLE OF IL27R SIGNALING IN HCC DEVELOPMENT AND DETERMINE THE BENEFICIAL MECHANISMS OF ITS BLOCKADE. THIS WORK HAS STRONG TRANSLATIONAL POTENTIAL WITH GAME- CHANGING RAMIFICATIONS FOR HCC.

ROLE OF NEUTROPHILS AND EOSINOPHILS IN BACTERIAL LIGAND-INDUCED VASCULITIS

MYOCARDIAL STEATOSIS IN WOMEN WITH CORONARY MICROVASCULAR DYSFUNCTION: DEFINING THE PATHWAY TO HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFPEF) - PROJECT SUMMARY HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFPEF) CONTINUES TO POSE A MAJOR BURDEN TO THE HEALTHCARE SYSTEM, WOMEN ARE TWICE AS LIKELY AS MEN TO DEVELOP HFPEF, AND NO TARGETED THERAPIES FOR HFPEF EXIST. CORONARY MICROVASCULAR DYSFUNCTION (CMD), DEFINED AS IMPAIRED FUNCTION OF THE SMALL MICROVESSELS WITHIN THE HEART, IS A WIDELY PREVALENT YET POORLY UNDERSTOOD CONDITION THAT ALSO PREDOMINANTLY AFFECTS WOMEN. HFPEF IS THE MOST FREQUENTLY EXPERIENCED MORBID OUTCOME IN WOMEN WITH CMD, WHO ARE OFTEN YOUNGER THAN THOSE WITH OTHER HFPEF PHENOTYPES. WHILE WE AND OTHERS HAVE SHOWN THAT HFPEF IS PRESENT IN UP TO A THIRD OF WOMEN WITH CMD, THE PATHOBIOLOGY OF CMD-RELATED HFPEF REMAINS UNCLEAR. CMD LEADS TO CHRONIC MYOCARDIAL ISCHEMIA, WHICH RESULTS IN AN INTRA-CARDIOMYOCYTE METABOLIC SHIFT TOWARDS INCREASED GLUCOSE UTILIZATION, REDUCED FREE FATTY ACID OXIDATION, AND TRIGLYCERIDE (TG) ACCUMULATION IN THE MYOCARDIUM – LEADING TO MYOCARDIAL STEATOSIS, WHICH WE HAVE ASSOCIATED WITH DIASTOLIC DYSFUNCTION, A PRE-HFPEF TRAIT. BECAUSE WOMEN WITH CMD ARE MORE LIKELY THAN MEN TO SUFFER CHRONIC ISCHEMIA FOR LONGER DURATIONS, OUR CENTRAL HYPOTHESIS IS THAT CMD-RELATED CHRONIC ISCHEMIA AND SUBSEQUENT MYOCARDIAL STEATOSIS ARE KEY CONTRIBUTORS TO THE DEVELOPMENT OF HFPEF IN WOMEN WITH CMD. EMERGING DATA FROM OUR GROUP UNDERSCORES THE IMPORTANCE OF CHRONIC INFLAMMATORY (I.E. EICOSANOID) PATHWAYS IN GOVERNING RESPONSES TO THE ISCHEMIC, INTRA-CARDIOMYOCYTE METABOLIC SHIFTS, AND CARDIAC MECHANICAL STRESSORS THAT HAVE BEEN IMPLICATED IN CMD AND HFPEF PATHOPHYSIOLOGY. THEREFORE, THE AIMS OF THIS EARLY STAGE INVESTIGATOR R01 APPLICATION ARE TO: (1) DETERMINE THE RELATIONSHIP BETWEEN CHRONIC ISCHEMIA AND MYOCARDIAL STEATOSIS AND THE EXTENT TO WHICH MYOCARDIAL STEATOSIS MEDIATES ASSOCIATIONS BETWEEN ISCHEMIA AND PRE-CLINICAL HFPEF IN CMD; AND, (2) IDENTIFY SPECIFIC EICOSANOID MOLECULES THAT UNDERLIE RISK FOR CMD-RELATED MYOCARDIAL STEATOSIS, PRE-CLINICAL HFPEF TRAITS, AND CLINICAL HFPEF. IN A PROSPECTIVE COHORT OF 220 CMD WOMEN UNDERGOING COMPREHENSIVE CARDIAC MAGNETIC RESONANCE (CMR) IMAGING AND SPECTROSCOPY, WE WILL DETERMINE CLINICAL HFPEF STATUS AND QUANTIFY: (I) MYOCARDIAL TG CONTENT AND STEATOSIS; (II) CHRONIC ISCHEMIA BURDEN, AND (III) PRE-CLINICAL CMR HFPEF TRAITS TO RELATE CHRONIC ISCHEMIA WITH MYOCARDIAL STEATOSIS. PLASMA BIOSAMPLES FROM THE COHORT WILL UNDERGO HIGH-THROUGHPUT ANALYSES TO IDENTIFY DISTINCT EICOSANOID PROFILES ASSOCIATED WITH MYOCARDIAL STEATOSIS. AN EXPLORATORY ANALYSIS WITH 18F-FDG PET WILL RELATE THE EICOSANOID PROFILES TO MYOCARDIAL-SPECIFIC INFLAMMATION. THE EICOSANOID PROFILES WILL ALSO BE TESTED FOR INCIDENT HFPEF IN A LARGE COMMUNITY COHORT WITH OVER A DECADE OF HFPEF OUTCOMES. UNDERSTANDING THE ROLE OF CARDIAC STEATOSIS WITH RESPECT TO CMD-RELATED ISCHEMIA, INFLAMMATION, AND HFPEF TRAITS PROMISES TO REVEAL NOVEL TARGETS FOR PREVENTING AND TREATING HFPEF, ESPECIALLY IN WOMEN.

ROLE OF SAME IN LIVER FUNCTION AND INJURY

PREDICTION OF IMMINENT SUDDEN CARDIAC DEATH BASED ON WARNING SIGNS

FLOW SENSITIVE SSFP FOR NON-CONTRAST MRA AND VESSEL WALL IMAGING

RANDOMIZED CONTROLLED TRIAL OF VIRTUAL REALITY FOR GI CANCER PAIN TO IMPROVE PATIENT REPORTED OUTCOMES - PROJECT SUMMARY PATIENTS WITH DIGESTIVE TRACT MALIGNANCY OFTEN EXPERIENCE SEVERE AND UNREMITTING ABDOMINAL PAIN THAT NEGATIVELY AFFECTS PHYSICAL, EMOTIONAL, AND SOCIAL FUNCTION, AS WELL AS HEALTH RELATED QUALITY OF LIFE (HRQOL). DESPITE THE SUBSTANTIAL BURDEN OF VISCERAL CANCER PAIN, AVAILABLE THERAPIES ARE LIMITED IN THEIR ABILITY TO OFFER SAFE AND EFFECTIVE ANALGESIA. PATIENTS FREQUENTLY TURN TO OPIOIDS WHEN OTHER TREATMENTS FAIL TO PROVIDE ADEQUATE ANALGESIA, YET OFTEN DISCOVER THAT OPIOIDS ALSO FALL SHORT IN DELIVERING MEANINGFUL PAIN REDUCTION OR IMPROVING HRQOL. FOR THOSE WHO DO ACHIEVE EFFECTIVE ANALGESIA FROM OPIOIDS, THEY NONETHELESS ASSUME A SUBSTANTIAL RISK OF OPIOID-RELATED MORBIDITY AND MORTALITY. FURTHER, IN MANY CASES, OPIOIDS IMPAIR BOWEL FUNCTION AND CAN WORSEN— NOT ALLEVIATE—ABDOMINAL PAIN. HENCE, THERE IS A CRITICAL GAP IN MANAGING VISCERAL PAIN FROM DIGESTIVE TRACT MALIGNANCIES; IT IS VITAL TO ADDRESS THIS EVIDENCE GAP IN A WAY THAT MAXIMIZES BENEFITS FOR PATIENTS WHILE MINIMIZING THE RISK OF HARM. THERAPEUTIC VIRTUAL REALITY (VR) HAS EMERGED AS A PROMISING AND EVIDENCE-BASED TREATMENT MODALITY FOR CANCER PAIN. USERS OF VR WEAR A PAIR OF GOGGLES WITH A CLOSE-PROXIMITY SCREEN IN FRONT OF THE EYES THAT CREATES A SENSATION OF BEING TRANSPORTED INTO LIFELIKE, THREE-DIMENSIONAL WORLDS. TO DATE, VR HAS BEEN LIMITED TO SHORT-TERM CLINICAL TRIALS FOR CANCER PAIN. MOREOVER, LIMITED RESEARCH EXISTS ON THEORY-BASED VR MODALITIES BEYOND MERE DISTRACTION, SUCH AS VR THAT EMPLOYS ACCEPTANCE AND COMMITMENT THERAPY (ACT) WITH COMPONENTS OF BIOFEEDBACK AND MINDFULNESS. TO BRIDGE THESE GAPS, THIS STUDY SEEKS TO: (1) ASSESS THE IMPACT OF IMMERSIVE VR ON PATIENT-REPORTED OUTCOMES (PROS), INCLUDING PAIN, ACTIVITY METRICS, AND OPIOID USE AMONG PATIENTS WITH VISCERAL PAIN FROM A DIGESTIVE TRACT MALIGNANCY; (2) ASSESS DIFFERENCES IN PROS, ACTIVITY METRICS, AND OPIOID USE BETWEEN SKILLS-BASED VR THERAPY VS. DISTRACTION VR THERAPY; AND (3) DETERMINE PATIENT-LEVEL PREDICTORS OF VR TREATMENT RESPONSE IN VISCERAL CANCER PAIN. TO ADDRESS THESE AIMS, THE STUDY WILL MEASURE PROS AND OPIOID USE IN 360 PATIENTS RANDOMIZED AMONG 3 GROUPS AND FOLLOW THEM FOR 60 DAYS AFTER ENROLLMENT: (1) AN ENHANCED VR GROUP RECEIVING SKILLS-BASED VR; (2) A DISTRACTION-BASED VR GROUP RECEIVING PATIENT-SELECTED VR VIDEOS; AND (3) A VR SHAM CONTROL GROUP USING A VR HEADSET WITH 2-D CONTENT. THE RESULTS WILL INFORM BEST PRACTICES FOR THE IMPLEMENTATION OF VR FOR VISCERAL CANCER PAIN MANAGEMENT AND GUIDE SELECTION OF PATIENT-TAILORED EXPERIENCES.

BIOLOGICAL PACEMAKER FROM PROOF-OF-CONCEPT TO CLINIC

DESIGN AND VALIDATION OF EASY-TO-ADOPT MASS SPECTROMETRY ASSAYS OF IMPORTANCE TO OBESITY

ACE AND MYELOID CELL METABOLISM - A LONG SOUGHT GOAL OF MEDICAL RESEARCH IS TO IDENTIFY WAYS TO INCREASE THE EFFECTIVENESS OF THE IMMUNE RESPONSE. HERE, WE PRESENT A MEANS OF INCREASING MYELOID CELL FUNCTION BY INCREASING CELL EXPRESSION OF ANGIOTENSIN CONVERTING ENZYME (ACE). WE SHOW THAT 1) UNDER NATURAL CIRCUMSTANCES IN BOTH HUMANS AND MICE, MYELOID CELLS INCREASE THEIR PRODUCTION OF ACE IN RESPONSE TO IMMUNE CHALLENGE. THIS IS AN ADAPTIVE RESPONSE THAT ALLOWS THE CELLS TO BETTER RESPOND TO THE CHALLENGE. 2) WHEN THIS PROCESS IS EXAGGERATED BY USING GENETIC MEANS TO AUGMENT ACE EXPRESSION IN EITHER MACROPHAGES OR NEUTROPHILS, THE RESULT IS A MARKED INCREASE IN THE ABILITY OF MICE TO MOUNT BOTH AN INNATE AND ADAPTIVE IMMUNE RESPONSE AGAINST A VARIETY OF IMMUNE CHALLENGES. THIS INCREASE IN RESPONSE IS DIRECTLY DUE TO THE CATALYTIC ACTIVITY OF THE OVER-EXPRESSED ACE PROTEIN. 3) THE ENHANCED IMMUNE RESPONSE IS THE RESULT OF ACE-INDUCED METABOLIC CHANGES THAT INCREASE OXIDATIVE PHOSPHORYLATION AND INCREASE MYELOID CELL ATP. THIS IS QUITE DIFFERENT FROM THE WELL DESCRIBED MYELOID METABOLIC EFFECTS OF LPS. THAT ACE AFFECTS CELL LEVELS OF ATP IS A VERY NEW FINDING BASED ON MASS SPECTROMETRY AND CHEMICAL ANALYSIS OF ATP LEVELS IN TWO LINES OF MICE. IN CONTRAST, MYELOID CELLS GENETICALLY LACKING ACE HAVE REDUCED ATP AND REDUCED IMMUNE FUNCTION. 4) SIMILAR TO THE GENETIC ACE KO, ACE INHIBITORS (ACEI) REDUCE NEUTROPHIL SUPEROXIDE AND ANTI-BACTERIAL RESPONSE IN BOTH HUMANS AND MICE. THUS, THERE IS A DIRECT RELATIONSHIP BETWEEN THE LEVEL OF ACE EXPRESSION BY MYELOID CELLS, MYELOID CELL ATP CONTENT, AND EFFECTIVENESS OF THE IMMUNE RESPONSE. UNDERSTANDING HOW ACE AFFECTS MYELOID CELL IMMUNOMETABOLISM WILL REVEAL A TOTALLY NEW BIOCHEMICAL MEANS OF ENHANCING MYELOID FUNCTION THAT MIGHT ULTIMATELY BE MANIPULATED TO ENHANCE HUMAN RESPONSE. IN AIM 1, WE EXAMINE THE DETAILED METABOLISM OF MYELOID CELLS WITH INCREASED ACE EXPRESSION TO IDENTIFY CHANGES AFFECTING IMMUNE FUNCTION. IN AIM 2, WE WILL STUDY THE ROLE OF THE TRANSCRIPTION FACTOR PPARA IN INDUCING THE IMMUNE PHENOTYPE OF MYELOID CELLS EXPRESSING INCREASED ACE. WE ALSO ASK HOW ACE ACTIVITY INDUCES INCREASED CELL PPARA. IN AIM 3, WE STUDY WHETHER ACE ACTS AS AN AUTOCRINE OR PARACRINE FACTOR AND WHETHER WE CAN CHARACTERIZE THE PEPTIDE PRODUCT OF ACE RESPONSIBLE FOR AFFECTING CELL METABOLISM AND INCREASING THE IMMUNE RESPONSE OF MYELOID CELLS.

PUSH-BUTTON CARDIAC MRI FOR NON-INVASIVE QUANTIFICATION OF MYOCARDIAL ENERGY CONSUMPTION IN HEART FAILURE - ABSTRACT CARDIAC ENERGY CONSUMPTION IS THE CENTRAL DETERMINANT OF CARDIAC FUNCTION. ITS IMPAIRMENT IS THE HALLMARK OF HEART FAILURE (HF), WHICH ACCOUNTS FOR NEARLY $40 BILLION IN MEDICAL COSTS EVERY YEAR AND IS THE MOST FREQUENT CAUSE OF HOSPITALIZATION. IN HF PATHOPHYSIOLOGY, THE DEPRESSION OF CONTRACTILE FORCE OF THE MYOCARDIUM IS NOT MATCHED BY A CONCOMITANT DEPRESSION OF ENERGY CONSUMPTION. THIS RESULTS IN THE UNCOUPLING BETWEEN MECHANICAL CONTRACTION AND ENERGY EXPENDITURE OF THE HEART, WHICH DRIVES SYSTOLIC OR DIASTOLIC DYSFUNCTION OF THE HEART. THUS, THE DETECTION OF EARLY ALTERATIONS IN CARDIAC ENERGETICS IN HF PATIENTS CAN PROVIDE CRITICAL INFORMATION ON HEART HEALTH AND GUIDE NOVEL THERAPEUTIC INTERVENTIONS FOR HF WHICH ARE UNDER DEVELOPMENT. SINCE THE HEART RELIES ALMOST EXCLUSIVELY ON AEROBIC OXIDATION, THE GOLD STANDARD FOR STAGING ALTERATIONS IN CARDIAC ENERGETICS IS FROM INVASIVELY MEASURED WHOLE HEART MYOCARDIAL OXYGEN CONSUMPTION (MVO2). HOWEVER, INVASIVE CATHETERIZATION IS NOT A PRACTICAL WAY FOR REPEAT SURVEILLANCE OF THE DISEASE IN THE SUSPECT POPULATION OR THE MONITORING OF THERAPEUTIC EFFICACY. HENCE THERE IS AN UNMET NEED FOR A NONINVASIVE APPROACH THAT CAN ENABLE REPEATABLE QUANTITATIVE ASSESSMENT OF CARDIAC ENERGETICS. SIGNIFICANT EFFORT HAS BEEN MADE TOWARDS DEVELOPING NONINVASIVE TECHNIQUES FOR MVO2 MEASUREMENT, PARTICULARLY BASED ON POSITRON EMISSION TOMOGRAPHY (PET) AND MAGNETIC RESONANCE SPECTROSCOPY (MRS). HOWEVER, THEY HAVE NOT MADE IT INTO THE CLINICAL ARENA DUE TO MAJOR TECHNICAL/PRACTICAL LIMITATIONS. AN ALTERNATIVE APPROACH, WHICH OVERCOMES KEY LIMITATIONS OF PET AND LONGSTANDING TECHNICAL CHALLENGES OF MRS FOR ESTIMATING MVO2, EMPLOYS MAGNETIC RESONANCE OXIMETRY. NONETHELESS, THIS REQUIRES SIMULTANEOUS AND RELIABLE MAPPING OF QUANTITATIVE MR PARAMETERS IN THE RAPIDLY MOVING CORONARY SINUS, WHICH IS NEARLY IMPOSSIBLE FOR THE CMR TECHNIQUES TODAY. HERE, WE PROPOSE TO DEVELOP AND VALIDATE A SINGLE, FAST, FREE-BREATHING, MOTION-INSENSITIVE ACQUISITION TO SIMULTANEOUSLY DERIVE CORONARY SINUS OXYGEN SATURATION AND MYOCARDIAL BLOOD FLOW FOR MVO2 MEASUREMENT. WE WILL TEST THE DEVELOPED METHOD IN DETECTING THE IMPAIRED CARDIAC ENERGY CONSUMPTION LEVEL IN AN ANIMAL MODEL WITH HEART FAILURE. THE PROPOSED METHOD IS EXPECTED TO QUANTIFY CARDIAC ENERGY CONSUMPTION NONINVASIVELY, WITHOUT IONIZING RADIATION, AND EXOGENOUS CONTRAST AGENTS. ACCORDINGLY, FORMING THE FOUNDATION TOWARD (1) EARLY DETECTION AND CLASSIFICATION OF HF FOR TARGET TREATMENTS, (2) PROGNOSIS OF HF WITHOUT INVASIVE PROCEDURES, AND (3) LONGITUDINAL MONITORING OF HF PROGRESSION TO GUIDE THE DEVELOPMENT OF NOVEL HF THERAPIES.

A NOVEL ESSENTIAL INFLAMMASOME COMPONENT PROPAGATING INFLAMMATORY RESPONSES

RACIAL DIFFERENCES IN PROSTATE CANCER MOLECULAR SUBTYPING

IMPACT OF THE GUT MICROBIOME AND DIET ON CHANGE IN INSULIN HOMEOSTASIS AND CARDIOMETABOLIC RISK

MAGNETOFLUORESCENT NANOPLATFORM FOR GLIOBLASTOMA THERAPY

EVALUATION OF SHORT- AND LONG-TERM SYSTEMIC ANTI-TUMOR IMMUNITY FOLLOWING COMBINED RADIATION AND IMMUNOTHERAPY IN TRIPLE-NEGATIVE BREAST CANCER

QUANTITATIVE STUDIES OF METABOLIC ORGAN DYNAMICS

AUTOMATED ASSESSMENT FOR ROBOTIC SUTURING UTILIZING DEEP LEARNING ALGORITHMS - ABSTRACT MEDICAL ERRORS ARE THE THIRD LEADING CAUSE OF DEATH IN THE US AT A COST OF $20 BILLION ANNUALLY. SURGICAL COMPLICATIONS ACCOUNT FOR A THIRD OF THESE DEATHS AND COST. SURGICAL PERFORMANCE DIRECTLY IMPACTS PATIENT OUTCOMES. PROSTATE CANCER, THE MOST COMMON CANCER IN MEN, IS TREATED WITH SURGERY (ROBOT-ASSISTED RADICAL PROSTATECTOMY (RARP)) THAT CAN LEAD TO IMPOTENCE, INCONTINENCE, AND EVEN DEATH. RELIABLE MEANS OF OBJECTIVELY ASSESSING TECHNIQUE ARE REQUIRED. IN THIS PROJECT WE WILL FOCUS ON ASSESSING SURGEON SUTURING SKILLS DURING RARP THROUGH VIRTUAL REALITY (VR) SIMULATION. SUTURING IS A COMMON SKILL IN MANY TYPES OF SURGERIES, CAN BE TRACKED WITH PERFORMANCE METRICS, AND HAS BEEN CORRELATED WITH PATIENT OUTCOMES AFTER RARP. IN THIS PROPOSAL WE SEEK TO FIRST DETERMINE THE CRITICAL SUB-STEP MANEUVERS OF SUTURING AND THE TECHNICAL SKILLS NECESSARY TO ACHIEVE THEM SUCCESSFULLY (AIM 1A). FURTHER, WE INTEND TO DEVELOP AN AUTOMATED SKILLS ASSESSMENT PIPELINE THROUGH THE ANALYSIS OF RAW KINEMATIC DATA (AIM 1B), VIDEO (AIM 2B), AND BOTH KINEMATIC/VIDEO (AIM 2C), FROM VR SIMULATION PERFORMANCE BY INNOVATIVE MACHINE LEARNING STRATEGIES AND DEEP-LEARNING-BASED COMPUTER VISION. THE PRIMARY DIFFERENTIATOR OF THE PROPOSED WORK IS DETERMINING HOW WELL GRANULAR SUB-STEP MANEUVERS IN SUTURING ARE PERFORMED. SURGEONS PARTICIPATING IN THIS STUDY WILL NOT ONLY PROVIDE DATA THROUGH THEIR VR SIMULATION PERFORMANCE, BUT WILL ALSO CONTRIBUTE REAL PATIENT DATA FROM THE RARP TO ESTABLISH THE RELATIONSHIP BETWEEN SURGEON SKILL, PATIENT FACTORS, AND SURGICAL OUTCOMES. STATISTICAL MODELING WILL MEASURE THE DIFFERENTIAL IMPACT OF SURGEON SKILL AND PATIENT FACTORS TO PATIENT OUTCOMES (AIM 3). WE HYPOTHESIZE THAT INNOVATIVE APPLICATION OF MACHINE LEARNING ALGORITHMS CAN ACCURATELY ASSESS SURGEON TECHNICAL SKILLS, AND CAN FURTHER ANTICIPATE LIKELIHOOD OF RELEVANT CLINICAL OUTCOMES. THE PROPOSED WORK WILL ENABLE SCALABLE AND ACTIONABLE FEEDBACK IN VR, EMPOWERING SURGEONS WITH VALUABLE KNOWLEDGE TO MINIMIZE SURGICAL RISK IN LIVE SURGERY.

THE CONTRIBUTION OF RARE ALLELES TO OVARIAN CANCER IN THE POPULATION

A BLOOD TEST TO IDENTIFY PROSTATE CANCER PATIENTS AT RISK FOR VISCERAL METASTASIS

VACCINE INDUCED IMMUNE-INFLAMMATORY RESPONSE AND CARDIOVASCULAR RISK - PROJECT SUMMARY IN THE MIDST OF EMERGING THREATS FROM SPORADIC VIRAL ENTITIES, THE PERENNIAL INFLUENZA VIRAL STRAINS CONTINUE TO IMPOSE A SUBSTANTIAL BURDEN OF MORBIDITY AND MORTALITY THAT COMPOUNDS TOTAL ANNUAL RISKS TO THE POPULATION AT LARGE. LAST SEASON (2018-19), INFLUENZA AFFECTED 35.5 MILLION AND LED TO 490,600 HOSPITALIZATIONS AND 34,200 DEATHS IN THE U.S. THESE VITAL STATISTICS HAVE BEEN STEADILY RISING EACH YEAR. INDIVIDUALS WITH CARDIOVASCULAR DISEASE ARE ESPECIALLY SUSCEPTIBLE TO THE MORBIDITY AND MORTALITY ASSOCIATED COMMUNITY-ACQUIRED VIRAL INFECTIONS SUCH AS INFLUENZA. VACCINATION SIGNIFICANTLY REDUCES THE INCIDENCE OF CARDIOVASCULAR EVENTS AT THE POPULATION LEVEL; HOWEVER, ADMINISTRATION OF INFLUENZA VACCINATION AT THE INDIVIDUAL LEVEL IS EXTREMELY VARIABLE WITH RESPECT TO (I) THE EXTENT OF HUMORAL ANTIBODY RESPONSE ACHIEVED, AND (II) THE DEGREE OF CARDIOPROTECTION CONFERRED. INTRIGUINGLY, THE DEGREE OF CARDIOPROTECTION CONFERRED DOES NOT DEPEND ENTIRELY ON THE LEVEL OF HUMORAL IMMUNITY ACHIEVED, HIGHLIGHTING FURTHER OPPORTUNITIES TO DISCOVER AND DERIVE CLINICAL BENEFIT FROM A PREVENTIVE THERAPY WITH BOTH COMPLEX AND NON- UNIFORM EFFECTS. ACCUMULATING EVIDENCE NOW INDICATES THAT UPSTREAM MEDIATORS OF ENDOGENOUS IMMUNE- INFLAMMATORY PATHWAYS ARE LIKELY KEY DETERMINANTS OF THE INDIVIDUAL-LEVEL RESPONSE TO AND BENEFIT FROM AN ADMINISTERED VACCINATION. THESE MOLECULAR MEDIATORS OF SYSTEMIC IMMUNE-INFLAMMATORY ACTIVITY, TERMED EICOSANOIDS, INCLUDE A DIVERSE FAMILY OF SMALL BIOACTIVE LIPIDS THAT ARE ENZYMATICALLY DERIVED FROM POLYUNSATURATED FATTY ACIDS. BASED ON RESULTS FROM PRELIMINARY STUDIES, WE HYPOTHESIZE THAT SPECIFIC EICOSANOIDS NOT ONLY PREDICT THE IMMUNOLOGIC RESPONSE TO INFLUENZA VACCINATION BUT ALSO PREDICT ITS CONFERRED PROTECTION FROM ADVERSE CARDIOVASCULAR EVENTS, IRRESPECTIVE OF INFECTION STATUS. THEREFORE, WE PROPOSE AN ANCILLARY STUDY FOR THE NHLBI-FUNDED INFLUENZA VACCINE TO EFFECTIVELY STOP CARDIOTHORACIC EVENTS AND DECOMPENSATED HEART FAILURE (INVESTED) TRIAL, THAT AIMS TO: (1) IDENTIFY EICOSANOIDS THAT PREDICT THE CLASSIC HUMORAL ANTIBODY RESPONSE TO INFLUENZA VACCINATION IN PATIENTS WITH CHRONIC CARDIOVASCULAR DISEASE, WHO REPRESENT THE POPULATION SUBSET MOST AT-RISK FOR ADVERSE EVENTS; AND, (2) IDENTIFY EICOSANOIDS GENERATED IN RESPONSE TO VACCINATION THAT CORRESPOND WITH REDUCED RISK FOR CARDIOVASCULAR EVENTS, IRRESPECTIVE OF HUMORAL IMMUNITY AND INFECTION STATUS. THE EXISTING INFRASTRUCTURE OF THE INVESTED TRIAL OFFERS A COST-EFFECTIVE WAY TO REACH INDIVIDUALS WHO ARE AT THE HIGHEST RISK FOR INFLUENZA- ASSOCIATED EVENTS AND ENABLE A RIGOROUS STUDY DESIGN FOR INVESTIGATING HETEROGENEITY IN THE RESPONSE TO AND BENEFIT FROM VACCINATION.

CALCIUM REGULATION IN HEART FAILURE WITH PRESERVED VERSUS REDUCED EJECTION FRACTION

INTEGRATED PREDICTION OF CARDIOVASCULAR EVENTS BY AUTOMATED CORONARY PLAQUE AND PERICORONARY ADIPOSE TISSUE QUANTIFICATION FROM CT ANGIOGRAPHY

MECHANISMS FOR GH ACTION ON EPITHELIAL CELLS

TRANSCENDING COVID-19 BARRIERS TO PAIN CARE IN RURAL AMERICA: PRAGMATIC COMPARATIVE EFFECTIVENESS TRIAL OF EVIDENCE-BASED, ON-DEMAND, DIGITAL BEHAVIORAL TREATMENTS FOR CHRONIC PAIN - PROJECT SUMMARY THE COVID-19 PANDEMIC HAS AFFECTED EVERYONE IN DIFFERENT WAYS. FOR PEOPLE FROM THE RURAL AMERICA WITH CHRONIC DISEASES, PARTICULARLY THOSE WHO EXPERIENCE PAIN, THE PANDEMIC CAN NOT ONLY WORSEN PAIN, BUT ALSO IT CAN TRIGGER ANXIETY, DEPRESSION, TROUBLE SLEEPING, AND SUBSTANCE USE. THIS PSYCHOLOGICAL DISTRESS IS EXACERBATED BY PHYSICAL AND SOCIAL ISOLATION, FEAR OF SEEKING IN-PERSON VISITS, AND DIMINISHED ABILITY TO ACCESS CLINICAL CARE DURING THE PANDEMIC. ONE WAY DOCTORS AND HEALTH SYSTEMS ARE REACHING OUT IS BY VIDEO VISITS, WHERE PATIENTS AND THEIR PROVIDERS COMMUNICATE ONLINE VIA THE INTERNET. HOWEVER, VIDEO VISITS STILL HAVE LIMITS. THEREFORE, WE CAN HELP SUPPORT THEM WITH OTHER TECHNIQUES. BEYOND VIDEO VISITS, THERE ARE HOME-BASED PROGRAMS THAT PATIENTS CAN ADMINISTER THEMSELVES TO HELP MANAGE THEIR PAIN. THESE PROVEN PROGRAMS CAN OVERCOME STAFFING SHORTFALLS, BE USED ACROSS LONG DISTANCE TO REACH ANYONE IN THE WORLD AND CAN BE USED AT THE TIME AND PLACE OF THE PATIENTS' CHOOSING. IN THIS STUDY, WE WILL COMPARE TWO AVAILABLE, EVIDENCE-BASED, DIGITAL TREATMENT PROGRAMS THAT PATIENTS CAN USE AT HOME. THE GOAL IS TO SEE IF ONE APPROACH IS BETTER THAN THE OTHER, AND WHETHER CERTAIN PATIENTS RESPOND TO ONE MORE THAN THE OTHER. THE FIRST PROGRAM IS AN APP THAT CAN RUN ON ANY SMARTPHONE OR COMPUTER. THE PROGRAM OFFERS AN 8-WEEK, AT-HOME CURRICULUM TO LEARN AND PRACTICE NEW SKILLS THAT CAN HELP MANAGE PAIN. THE PROGRAM RUNS ON A STANDARD SCREEN ON YOUR PHONE OR COMPUTER. THE SECOND PROGRAM IS ALSO A PROVEN, 8-WEEK PROGRAM, BUT IT USES A TECHNOLOGY CALLED VIRTUAL REALITY, OR VR. VR INVOLVES WEARING SPECIALIZED GOGGLES THAT CREATE A SENSATION OF BEING IN A 3D WORLD. EVIDENCE SHOWS THAT VIRTUAL WORLDS CAN HELP PEOPLE LEARN AND RETAIN NEW SKILLS THAT HELP REDUCE PAIN. THE STUDY WILL RECRUIT 300 PEOPLE FROM RURAL COMMUNITIES IN CALIFORNIA, LOUISIANA, AND ALABAMA AND RANDOMIZE THEM INTO EITHER THE 2D OR 3D PROGRAMS. WE WILL THEN FOLLOW PATIENTS FOR 8 WEEKS DAYS AND MEASURE THEIR PAIN LEVELS. WE WILL ALSO MEASURE SIGNS OF DISTRESS, INCLUDING CORONAVIRUS-RELATED ANXIETY, ALONG WITH MEASURING MEDICATIONS USED FOR PAIN, SUCH AS OPIOIDS, AND THE IMPACT OF PAIN ON OVERALL QUALITY OF LIFE. TO CONDUCT THE STUDY, WE WILL ASK PATIENTS TO PERIODICALLY COMPLETE SHORT SURVEYS ONLINE AND ALLOW PERMISSION FOR THE RESEARCH TEAM TO COLLECT INFORMATION FROM THE ELECTRONIC HEALTH RECORD. WE DEVELOPED THIS STUDY WORKING WITH PATIENT PARTNERS FROM THE AMERICAN CHRONIC PAIN ASSOCIATION (ACPA), AND THEY WILL BE PART OF THE RESEARCH TEAM THROUGHOUT THE CONDUCT, ANALYSIS, AND REPORTING OF THE STUDY. THE RESULTS WILL HELP PATIENTS, DOCTORS, AND HEALTH SYSTEM DECIDE HOW BEST TO ADMINISTER HOME-BASED, PATIENT-ADMINISTERED, DIGITAL TREATMENT PROGRAMS FOR PAIN, AND WILL OFFER RECOMMENDATION ON HOW TO SELECT THE RIGHT TREATMENT FOR THE RIGHT PATIENT.

PROTEIN-DNA DRUG CARRIERS FOR TUMOR TARGETING

STAT3, G6PD AND TRXR AS UNDERLYING MECHANISMS FOR ANTITUMOR RESPONSES TO HIRSUTINOLIDES

BIOLOGICAL SUBSTRATE MODIFICATION TO SUPPRESS VENTRICULAR ARRHYTHMIAS IN A PORCINE MODEL OF CHRONIC ISCHEMIC CARDIOMYOPATHY - PROJECT SUMMARY/ABSTRACT CARDIOMYOPATHY PATIENTS ARE PRONE TO VENTRICULAR ARRHYTHMIAS (VA) AND SUDDEN DEATH. CURRENT THERAPIES TO PREVENT VA INCLUDE RADIOFREQUENCY ABLATION TO DESTROY SLOWLY CONDUCTING PATHWAYS OF VIABLE MYOCARDIUM WHICH SUPPORT RE-ENTRY. HERE WE PROPOSE TO TEST THE REVERSE CONCEPT, NAMELY THAT BOOSTING LOCAL TISSUE VIABILITY IN ZONES OF SLOW CONDUCTION MIGHT ELIMINATE SLOW CONDUCTION AND SUPPRESS VA. WE SEEK TO DO SO BY LOCAL INJECTION, INTO MAPPED AREAS OF SLOW CONDUCTION, OF EXOSOMES SECRETED BY CARDIOSPHERE-DERIVED CELLS (CDCS), A STROMAL/PROGENITOR CELL TYPE FROM THE HUMAN HEART. EXOSOMES ARE EXTRACELLULAR VESICLES LADEN WITH BIOACTIVE CARGO. THOSE SECRETED BY CDCS (CDCEXO) REDUCE SCAR AND IMPROVE HEART FUNCTION AFTER INTRAMYOCARDIAL DELIVERY. IN A VA-PRONE PORCINE MODEL OF ISCHEMIC CARDIOMYOPATHY, WE PRESENT PRELIMINARY DATA IN WHICH WE INJECTED CDCEXO OR VEHICLE INTO ZONES OF DELAYED CONDUCTION DEFINED BY ELECTROANATOMIC MAPPING. UP TO ONE MONTH POST- INJECTION, CDCEXO, BUT NOT VEHICLE, DECREASED MYOCARDIAL SCAR, SUPPRESSED SLOWLY CONDUCTING ELECTRICAL PATHWAYS, AND INHIBITED VA INDUCTION BY PROGRAMMED STIMULATION. IN SILICO RECONSTRUCTION OF ELECTRICAL ACTIVITY BASED ON MAGNETIC RESONANCE IMAGES ACCURATELY REPRODUCED THE SUPPRESSION OF VA INDUCIBILITY BY CDCEXO. HERE WE WILL EXPLORE ALTERNATIVE INTRACORONARY DELIVERY METHODS WHICH WOULD BE MORE READILY TRANSLATABLE CLINICALLY THAN THE INTRAMYOCARDIAL INJECTION APPROACH, WHICH REQUIRES NON-APPROVED CATHETERS. WE WILL ALSO EXPLORE MECHANISM OF THE ANTI-VA EFFECTS HISTOLOGICALLY AND BY RNA SEQUENCING, AS WELL AS IN A CO-CULTURE ASSAY OF CARDIOMYOCYTES AND FIBROBLASTS. WE WILL ALSO COMPARE DIRECTLY THE EFFICACY OF EXOSOMES VERSUS CONVENTIONAL RF ABLATION. IN CONCLUSION, WE SEEK TO ESTABLISH BIOLOGICAL SUBSTRATE MODIFICATION BY EXOSOME INJECTION AS A NONDESTRUCTIVE ALTERNATIVE TO CONVENTIONAL ABLATION FOR THE PREVENTION OF RECURRENT VENTRICULAR TACHYARRHYTHMIAS.

ROLES OF ENDOTHELIAL AND SMOOTH MUSCLE KATP CHANNELS IN MYOCARDIAL ISCHEMIC INJURY

CARD-ONLY PROTEIN REGULATION OF CYTOSOLIC PATTERN RECOGNITION RECEPTOR SIGNALING

INTEGRATING ARTIFICIAL INTELLIGENCE FOR OPTIMAL ANALYSIS OF CARDIACPET/CT - PROJECT SUMMARY CORONARY ARTERY DISEASE (CAD) IS THE LEADING CAUSE OF DEATH AND DISABILITY IN THE US AND GLOBALLY. THE EPIDEMIC OF OBESITY, DIABETES, AND CARDIOMETABOLIC DISEASE IS CHANGING THE NATURE OF CAD, WITH DIFFUSE AND MICROVASCULAR DISEASE EMERGING AS KEY DRIVERS OF ADVERSE OUTCOMES. RADIONUCLIDE MYOCARDIAL PERFUSION IMAGING IS THE MOST WIDELY USED MODALITY FOR CAD ASSESSMENT AND IS STILL PRIMARILY PERFORMED WITH SPECT. BUT SPECT EVALUATES ONLY RELATIVE PERFUSION AND IS INHERENTLY INSENSITIVE IN THE SETTING OF DIFFUSE OR MICROVASCULAR DISEASE. PET, WITH ITS UNIQUE ABILITY TO ACCURATELY QUANTIFY ABSOLUTE MYOCARDIAL BLOOD FLOW, ALLOWS ROBUST DETECTION OF OBSTRUCTIVE CAD, DIFFUSE ATHEROSCLEROSIS, BALANCED ISCHEMIA, AND CORONARY MICROVASCULAR DYSFUNCTION. CARDIAC PET IS ALSO ALWAYS OBTAINED WITH ADDITIONAL CHEST CT FOR ATTENUATION CORRECTION PURPOSES. HOWEVER, THIS MODALITY REQUIRES A HIGH LEVEL OF ON-SITE TECHNICAL EXPERTISE TO MAXIMIZE ITS BROAD CAPABILITIES. WE HAVE APPLIED HIGHLY EFFICIENT, IMAGE-BASED ARTIFICIAL INTELLIGENCE (AI) APPROACHES EXTENSIVELY TO SPECT AND CT, DEMONSTRATING IMPROVED DIAGNOSTIC ACCURACY AND RISK STRATIFICATION. THESE TOOLS CAN BE HARNESSED TO ENHANCE THE UTILITY OF CARDIAC PET/CT. WE PROPOSE TO EFFICIENTLY TRANSLATE THE LATEST AI ADVANCES AND OUR RECENT SPECT DEVELOPMENTS TO FULLY AUTOMATE CARDIAC PET/CT ANALYSIS, INCLUDING NOVEL TOOLS FOR QUALITY CONTROL, HIGH- PERFORMANCE IMAGE SEGMENTATION, NEW QUANTITATIVE VARIABLES, AND DIRECT OUTCOME PREDICTION FROM IMAGES, USING PET/CT DATA FROM MULTIPLE CENTERS. THE OVERALL AIM IS TO DEVELOP IS TO DEVELOP PRACTICAL AI ALGORITHMS FOR COMPREHENSIVE CARDIAC PET/CT ANALYSIS AND TO VALIDATE THEM IN A MULTI-CENTER SETTING. FOR THIS WORK, WE PROPOSE THE FOLLOWING 3 SPECIFIC AIMS: (1) TO DEVELOP AND TEST AUTOMATED END-TO-END PET QUANTIFICATION, (2) TO DEVELOP AND TEST AUTOMATED END-TO-END CHEST CT QUANTIFICATION, (3) TO DEVELOP AND VALIDATE EXPLAINABLE AI MODELS FOR ENHANCED PATIENT ASSESSMENT FROM IMAGES AND CLINICAL DATA, EMPLOYING LATEST ADVANCES IN SURVIVAL ANALYSIS, SUPERVISED AND UNSUPERVISED LEARNING, AND KNOWLEDGE TRANSFER. THIS RESEARCH WILL RESULT IN PERSONALIZED TOOLS, WHICH WILL IMPROVE THE ACCURACY OF PATIENT ASSESSMENT BY PET/CT BEYOND WHAT IS POSSIBLE BY THE CURRENT PRACTICE OF SUBJECTIVE INTERPRETATION AND MENTAL INTEGRATION OF DIVERSE DATA. EXPLAINABLE METHODS COMBINING IMAGE AND CLINICAL DATA TO MAKE AI CONCLUSIONS MORE TANGIBLE WILL ALLOW CLINICAL ADOPTION OF THIS TECHNOLOGY. THE NEW TOOLS CAN DRAMATICALLY SIMPLIFY PET/CT PROTOCOLS, REDUCE SUBJECTIVITY, REDUCE BURDEN ON THE PHYSICIANS, AND MAXIMIZE THE INFORMATION DERIVED FROM THE MULTIMODAL SCANS. THEY WILL FIT DIRECTLY INTO EXISTING WORKFLOWS, FACILITATING DEPLOYMENT IN DIVERSE CLINICAL SETTINGS. THE NEW AI METHODS FOR IMAGE ANALYSIS AND EXPLAINABLE INTEGRATION OF MULTIMODALITY DATA WILL GENERALIZE TO OTHER DISEASES AND PROBLEMS IN BIOMEDICAL IMAGING.

PHENYLPROPANOID ANALOGS TO TREAT STROKE

INTEGRATED ANALYSIS OF CORONARY ANATOMY AND BIOLOGY WITH 18F-FLUORIDE PET AND CT ANGIOGRAPHY

PRESERVING ERECTILE FUNCTION BY QUANTIFYING THE NERVE-SPARING STEP OF THE ROBOTIC PROSTATECTOMY - ABSTRACT VARIATION IN PERFORMANCE BETWEEN SURGEONS LEADS TO DIFFERENCES IN PATIENT OUTCOMES, BUT SURGEONS CANNOT IMPROVE IF THEY ARE NOT AWARE OF THE TECHNICAL CONSIDERATIONS FOR A SURGICAL PROCEDURE THAT WILL ALLOW THEM TO IMPROVE OUTCOMES. AS A PRIME EXAMPLE, ROBOT-ASSISTED RADICAL PROSTATECTOMY (RARP) FOR PROSTATE CANCER CAN LEAD TO HIGHLY VARIABLE RATES OF PATIENT ERECTILE FUNCTION (EF) RECOVERY (10-50%). YET RELIABLE MEANS OF OBJECTIVELY ASSESSING SURGEON PERFORMANCE, THAT STRONGLY ASSOCIATE WITH PATIENT OUTCOMES, ARE GENERALLY LACKING. IN THIS PROJECT, AS A TEST CASE FOR QUANTIFYING SURGEON PERFORMANCE TO IMPROVE A PATIENT OUTCOME, WE WILL FOCUS ON ASSESSING A SURGEON’S NERVE-SPARING (NS) DISSECTION QUALITY DURING RARP THROUGH THE EVALUATION OF SURGICAL VIDEO AND PATIENT OUTCOMES. THE NUANCED NS STEP IS A GOOD TEST CASE BECAUSE IT IS THE PRIMARY DETERMINANT OF THE QUANTIFIABLE EF OUTCOME, RARP IS A COMMON PROCEDURE (~145,000 CASES/YEAR), AND SURGICAL VIDEO IS READILY AVAILABLE FOR ANALYSIS. WE WILL ACCOMPLISH OUR OBJECTIVE WITH THREE INDEPENDENT, YET COMPLEMENTARY AIMS. AIM 1: WE SEEK TO DETERMINE THROUGH EXPERT CONSENSUS THE COMMON TECHNICAL CONSIDERATIONS NECESSARY TO OPTIMALLY PERFORM THE NS STEP FOR EF RECOVERY. AIM 2: WE WILL DEVELOP AN AUTOMATED PERFORMANCE ASSESSMENT PIPELINE THROUGH COMPUTER VISION ANALYSIS OF SURGICAL VIDEO. AIM 3: WE WILL DEVELOP AND VALIDATE A SKILLS FEEDBACK ASSESSMENT TOOL FOR A PROOF-OF- CONCEPT NS-SPECIFIC VR SIMULATION. THE PRIMARY DIFFERENTIATOR OF THE PROPOSED WORK IS WE WILL QUANTIFY THE MOST RELEVANT TECHNICAL CONSIDERATIONS FOR TISSUE DISSECTION DRIVING A PATIENT REPORTED OUTCOME. SURGEONS PARTICIPATING IN THIS STUDY WILL NOT ONLY PROVIDE DATA THROUGH SURGICAL VIDEOS OF THEM PERFORMING THE NS STEP, BUT THEY WILL ALSO CONTRIBUTE REAL PATIENT EF OUTCOME DATA FROM THE RARP TO ESTABLISH THE RELATIONSHIP BETWEEN SURGEON SKILL, PATIENT FACTORS, AND EF OUTCOME. STATISTICAL MODELING WILL DELINEATE THE DIFFERENTIAL IMPACT OF SURGEON SKILL AND PATIENT FACTORS TO EF OUTCOME. FURTHER, WE WILL HARNESS DEEP LEARNING-BASED COMPUTER VISION TO HOLISTICALLY CAPTURE ALL THE NUMEROUS FACETS OF NS TECHNIQUE AND SKILL TO HELP DETERMINE HOW THEY CONTRIBUTE TO THE ULTIMATE EF OUTCOME. THE PROPOSED WORK WILL ENABLE SCALABLE AND ACTIONABLE FEEDBACK, EMPOWERING SURGEONS WITH VALUABLE KNOWLEDGE TO MAXIMIZE SURGICAL OUTCOME. THE NS STEP AND EF RECOVERY AFTER RARP WILL SERVE AS OUR TEST CASE FOR FUTURE AUTOMATED ASSESSMENTS TO IMPROVE OUTCOMES IN ANY SURGICAL PROCEDURE.

ANIMAL MODELS OF HYPERTHYROIDISM

DAP12 AND THE HOST RESPONSE TO CRYPTOCOCCOSIS - PROJECT SUMMARY CRYPTOCOCCUS NEOFORMANS IS AN OPPORTUNISTIC FUNGAL PATHOGEN THAT IS INHALED INTO THE LUNGS AND CAN DISSEMINATE TO THE BRAIN, CAUSING A HIGHLY FATAL MENINGOENCEPHALITIS IN IMMUNOCOMPROMISED PATIENTS, PARTICULARLY THOSE WITH HIV/AIDS, SOLID ORGAN TRANSPLANTATION, AND CANCER. EVEN WITH CONTEMPORARY COMBINATION ANTIFUNGAL THERAPY, THE MORTALITY RATE FOR CRYPTOCOCCOSIS APPROXIMATES 25%, AND THE AT-RISK POPULATION IS EXPANDING WITH THE DEVELOPMENT OF NEW IMMUNOSUPPRESSIVE REGIMENS FOR AUTOIMMUNITY AND CANCER. OUR ABILITY TO DEVELOP NEW TREATMENTS FOR CRYPTOCOCCOSIS REMAINS LIMITED BECAUSE WE DO NOT YET FULLY UNDERSTAND HOW THE FUNGUS EVADES HOST IMMUNITY. WE RECENTLY DISCOVERED THAT C. NEOFORMANS IS ABLE TO SUPPRESS THE RESPONSE OF INFLAMMATORY MONOCYTES, INNATE IMMUNE CELLS THAT GIVE RISE TO MACROPHAGES AND DENDRITIC CELLS AND TYPICALLY AID IN FUNGAL RECOGNITION AND CLEARANCE BY THE HOST. C. NEOFORMANS DIRECTS INFLAMMATORY MONOCYTES TO DIFFERENTIATE INTO ALTERNATIVELY ACTIVATED (M2) MACROPHAGES THAT ARE PERMISSIVE FOR FUNGAL PROLIFERATION AND DISSEMINATION, LEADING TO INCREASED MORTALITY FROM THE INFECTION. WE HAVE IDENTIFIED A SIGNALING ADAPTER DNAX- ACTIVATING PROTEIN OF 12 KDA (DAP12) THAT MAY PLAY A CRUCIAL ROLE IN SUPPRESSING THE INFLAMMATORY MONOCYTE RESPONSE TO C. NEOFORMANS. THE DELETION OF DAP12 IMPROVES FUNGAL CLEARANCE AND SURVIVAL IN A MURINE MODEL OF CRYPTOCOCCOSIS, AND DAP12-DEFICIENT MONOCYTE-DERIVED MACROPHAGES HAVE BETTER UPTAKE AND KILLING OF THE FUNGUS. ADDITIONALLY, THE LUNGS OF DAP12-/- MICE HAVE INCREASED NUMBERS OF CD8+ T CELLS, CYTOTOXIC ADAPTIVE IMMUNE CELLS THAT CAN BE RECRUITED AND ACTIVATED BY MACROPHAGES AND ARE IMPORTANT FOR THE CLEARANCE OF C. NEOFORMANS. THUS, DAP12 MAY BE AN IMPORTANT TARGET FOR REVERSING THE SUPPRESSIVE EFFECTS OF C. NEOFORMANS ON THE FUNGICIDAL ACTIVITY OF INFLAMMATORY MONOCYTES AND THEIR ABILITY TO PRIME CD8+ T CELLS. OUR PRELIMINARY DATA INDICATE THAT THIS REPRESSIVE DAP12 ACTIVITY MAY BE REGULATED BY THE BINDING OF C. NEOFORMANS TO THE CELL SURFACE RECEPTOR TRIGGERING RECEPTOR EXPRESSED ON MYELOID CELLS 2 (TREM2) ON MONOCYTE-DERIVED MACROPHAGES. THE GOAL OF THIS PROPOSAL IS TO FURTHER DEFINE THIS NOVEL DAP12 SIGNALING PATHWAY. WE HYPOTHESIZE THAT C. NEOFORMANS INDUCES FORMATION OF A TREM2-DAP12 SIGNALING COMPLEX THAT COORDINATES EFFECTOR MOLECULES TO INHIBIT THE ANTI-CRYPTOCOCCAL DEFENSES OF INFLAMMATORY MONOCYTES AND CD8+ T CELLS, THEREBY SUBVERTING THE HOST RESPONSE TO INFECTION. THE SPECIFIC AIMS ARE TO 1) DETERMINE THE MECHANISM BY WHICH DAP12 SIGNALING IS INITIATED BY C. NEOFORMANS, 2) DEFINE THE SIGNALING CASCADE THAT MEDIATES THE SUPPRESSIVE EFFECTS OF DAP12 DURING INFECTION, AND 3) ASCERTAIN THE ROLE OF INFLAMMATORY MONOCYTE-INTRINSIC DAP12 IN THE REGULATION OF CD8+ T CELL RESPONSES TO C. NEOFORMANS. DEFINING THESE MECHANISMS WILL DEEPEN OUR UNDERSTANDING OF HOST IMMUNITY TO OPPORTUNISTIC FUNGI AND INFORM NEW OPPORTUNITIES FOR IMMUNOMODULATORY INTERVENTIONS AGAINST C. NEOFORMANS IN VULNERABLE HOSTS.

ELECTROPHYSIOLOGY AND CELL BIOLOGY OF CARDIAC STEM CELLS

ROLE OF INTESTINAL MICROBIOME AND GUT PERMEABILITY IN THE DEVELOPMENT OF KAWASAKI DISEASE VASCULITIS

ULTRASOUND-GUIDED DNA DELIVERY FOR REGENERATIVE MEDICINE

REGULATION OF THE DYNAMIC PROTEOME AFTER ISCHEMIC INJURY

GENERATING PROTECTIVE IMMUNITY TO STAPHYLOCOCCUS AUREUS

QUALIFYING MULTI-TRANSCRIPT SIGNATURES FOR ACTIVE SURVEILLANCE OF PROSTATE CANCER

DATA-DRIVEN DRUG DISCOVERY: INVESTIGATING THE MOLECULAR MECHANISMS OF SAFETY AND EFFICACY

PATHOGENIC AND PROTECTIVE ROLES OF STRAIN-SPECIFIC P. ACNES HYALURONIDASES IN ACNE

ZIP8-DEPENDENT ZINC METABOLIC REGULATION IN ALVEOLAR PROGENITOR CELL AGING AND FIBROSIS - ABSTRACT WITH THE RAPID GROWTH OF AN AGING POPULATION WORLDWIDE, THE ANNUAL INCIDENCES OF AGING-ASSOCIATED LUNG DISEASES SUCH AS IDIOPATHIC PULMONARY FIBROSIS (IPF), ARE INCREASING. THEREFORE, THERE IS A GREAT NEED TO COMPREHENSIVELY INVESTIGATE THE COMPLEX PROCESS OF LUNG AGING AND DEVELOP INTERVENTIONS TO EXTEND THE HEALTH SPAN OF THE ELDERLY POPULATION. TYPE 2 ALVEOLAR EPITHELIAL CELLS (AEC2S) FUNCTION AS PROGENITOR CELLS THAT MAINTAIN EPITHELIUM HOMEOSTASIS AND REPAIR THE LUNG AFTER INJURY. A CHARACTERISTIC OF THE AGING LUNG IS PROGENITOR CELL EXHAUSTION AND, IN TURN, IMPAIRS ALVEOLAR REGENERATION. PERSISTENT EPITHELIAL CELL INJURY COUPLED WITH INADEQUATE ALVEOLAR EPITHELIAL REPAIR DUE TO PROGENITOR CELL FAILURE RESULTS IN A PROTOTYPE OF AGE-ASSOCIATED LUNG DISEASE, IPF. IN FACT, IT HAS BEEN ARGUED THAT IPF IS A DISEASE OF PREMATURE AGING OF AEC2S. HENCE, STUDIES FOCUSING ON RE-ACTIVATING AND/OR EXPANDING AEC2 PROGENITOR CELLS IN LUNG AGING ARE NEEDED. AS WE REPORTED, AEC2 PROGENITOR CELLS ARE EXHAUSTED IN HUMAN IPF LUNGS. IPF AEC2S FAIL TO REGENERATE IN ORGANOID ASSAYS RELATIVE TO NORMAL AEC2S. IN OUR PRELIMINARY STUDIES FOR THIS APPLICATION, WE FOUND A DECREASE IN AEC2 RENEWAL CAPACITY AND A LOSS OF AEC2 POPULATION OCCUR DURING LUNG AGING. WE AIMED TO UNCOVER THE MOLECULAR MECHANISMS THAT CONTRIBUTE TO IMPAIRED AEC2 RENEWAL DURING AGING, WITH THE LONG-TERM GOAL OF POINTING THE WAY TO NOVEL INTERVENTIONS THAT CAN REJUVENATE AGED AEC2S. WE HAVE FOUND THAT: 1) THE RENEWAL CAPACITY OF AEC2S IN 18-20 MONTHS OLD AGED MOUSE LUNGS ARE REDUCED JUST AS WHAT WE OBSERVED WITH IPF LUNGS; 2) USING SINGLE CELL RNA-SEQ AND FLOW CYTOMETRY, WE IDENTIFIED A DEFICIENCY OF A SPECIFIC ZINC TRANSPORTER SLC39A8 (ENCODING ZIP8) IN AEC2S FROM 18-20 MONTHS OLD AGED MOUSE LUNGS AND IPF LUNGS; 3) SIRTUIN SIGNALING PATHWAY WAS DOWNREGULATED IN AEC2S FROM BLEOMYCIN-INJURED OLD MOUSE LUNGS AND IPF LUNGS; 4) ZIP8 REGULATES AEC2 PROGENITOR FUNCTION THROUGH SIRT1 AND ZIP8/SIRT1 AXIS IS REQUIRED FOR AEC2 RENEWAL. IN ADDITION, WE HAVE GENERATED A NOVEL MOUSE MODEL OF ZIP8 DEFICIENCY IN AEC2 CELLS THAT REVEALS PHENOTYPES OF PREMATURE AEC2 AGING. BASED ON THESE NOVEL FINDINGS, WE HYPOTHESIZE THAT ZIP8 DEFICIENCY OCCURS IN AEC2S WITH AGING AND DOWNREGULATES SIRT1, THEREBY IMPAIRING AEC2 PROGENITOR CELL RENEWAL. FURTHERMORE, WE PROPOSE THAT RESTORING CRITICAL COMPONENTS OF THE ZIP8/ZINC/SIRT1 PATHWAY WILL IMPROVE AEC2 PROGENITOR ACTIVITY AND, THUS MAINTAIN LUNG EPITHELIAL INTEGRITY AND PREVENT AGE-ASSOCIATED LUNG DISEASES.

NANOCONJUGATE BASED ON POLYMALIC ACID FOR BRAIN TUMOR TREATMENT

THE THYROTHROPIN RECEPTOR IN HEALTH AND DISEASE

SPATIALLY RESOLVED, SINGLE CELL BIOMARKERS OF B CELL LYMPHOMA - PROJECT SUMMARY/ABSTRACT DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) IS THE MOST COMMON FORM OF NON-HODGKIN LYMPHOMA (NHL). DLBCL TUMORS ARE HIGHLY HETEROGENEOUS AND MOLECULAR PROFILING HAS REVEALED UP TO SIX DISTINCT PROGNOSTICALLY RELEVANT SUB-GROUPS, HOWEVER THESE CLASSIFICATIONS ARE PRIMARILY BASED ON PROFILES OF THE MALIGNANT CELLS. NON-MALIGNANT CELLS IN THE TUMOR IMMUNE MICROENVIRONMENT (TME) CAN BE POWERFUL MODULATORS OF TUMOR GROWTH AND CAN BE TARGETED FOR CANCER THERAPY, YET BIOMARKERS THAT INCLUDE TME ELEMENTS HAVE NOT BEEN DEVELOPED. WE HYPOTHESIZE THAT SUCCESSFUL DEVELOPMENT OF NEXT GENERATION IMMUNE TARGETING THERAPIES FOR LYMPHOMA WILL REQUIRE SPATIALLY RESOLVED, HIGHLY MULTIPLEXED SINGLE CELL BASED BIOMARKERS OF TME COMPOSITION AND STRUCTURE. IN THIS STUDY WE PROPOSE TO PERFORM IMAGING MASS CYTOMETRY ANALYSIS (IMC) ON OVER 2000 CASES OF AGGRESSIVE B CELL LYMPHOMA WITH THE FOLLOWING AIMS: SPECIFIC AIM 1: VALIDATE SPATIALLY-DERIVED PROTEIN BIOMARKERS OF DLBCL OUTCOMES (N-830 PATIENTS). SPECIFIC AIM 2: ANALYZE THE SINGLE CELL TOPOLOGY OF HISTOLOGICALLY DIVERSE AGGRESSIVE B CELL LYMPHOMAS (N=1380) TO IDENTIFY SHARED TME BASED BIOMARKERS ACROSS ALL AGGRESSIVE B CELL LYMPHOMA. SPECIFIC AIM 3: DETERMINE WHICH TME ELEMENTS MODULATE CHEMORESISTANCE AND MEDIATE RESPONSE TO IMMUNE THERAPIES IN LYMPHOMA THROUGH IN VITRO MODEL SYSTEMS. IN THE FIRST TWO AIMS, WE WILL APPLY OUR NOVEL ABUNDANCE WEIGHTED SCORE (M-SCORE), DEVELOPED SPECIFICALLY FOR IMC ANALYSIS, TO VALIDATE CANDIDATE BIOMARKERS (SUCH AS PD-L1+/CCR4+/TIM-3+) AND IDENTIFY NEW BIOMARKERS. WE WILL ALSO APPLY OUR SINGLE CELL SPATIAL CLUSTERING ALGORITHM, REGIONS OF IMMUNE CELL ORGANIZATION (RICO), TO IDENTIFY TUMOR-IMMUNE SPATIAL CLUSTERS THAT ARE ASSOCIATED WITH CLINICAL OUTCOME. THE SPATIAL RESOLVED, SINGLE CELL, HIGHLY MULTIPLEXED, DIGITAL IMAGE ANALYSIS PROPOSED HERE WILL HAVE CLINICAL IMPACT FOR THE ~80,000 NEW US CASES OF NHL. SPECIFIC AIM 1 WILL VALIDATE AND DISCOVER PROTEIN BIOMARKERS IN A IMAGE FORMAT FAMILIAR TO PATHOLOGISTS ALLOWING FOR SEAMLESS CLINICAL ADOPTION, SPECIFIC AIM 2 WILL REFINE METHODS FOR SPATIAL SYSTEMS BIOLOGY APPLIED TO CHALLENGING LYMPHOMA TYPES, AND SPECIFIC AIM 3 WILL ALLOW PRE-CLINICAL VALIDATION OF PROGNOSTIC AND PREDICTIVE BIOMARKERS.

SYNDECAN-1 SUPPRESSION OF LUNG INFLAMMATION - DIVERSITY SUPPLEMENT - PROJECT SUMMARY/ABSTRACT ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) IS INITIATED BY A NUMBER OF PULMONARY AND EXTRA-PULMONARY INSULTS. HOWEVER, THE LUNG DAMAGE BECOMES PERSISTENT DESPITE TREATMENT OF THE UNDERLYING ETIOLOGY. THEREFORE, FAILURE OF INFLAMMATION RESOLUTION IS AN UNDERLYING ABNORMALITY THAT DRIVES THE DEVELOPMENT OF ARDS. MULTIPLE PATHWAYS HAVE BEEN ESTABLISHED THAT DRIVE INFLAMMATORY CELL DEATH. HOWEVER, APOPTOSIS IS UNDER RECOGNIZED IN ITS ABILITY TO CAUSE INFLAMMATION. INDEED, APOPTOTIC DEATH OF THE LUNG EPITHELIUM IS A PROMINENT FEATURE IN ARDS AND BLOCKING APOPTOSIS HAS PROVEN BENEFICIAL IN VARIOUS MODELS OF ARDS. APOPTOTIC CELLS MUST BE EFFICIENTLY CLEARED BY PHAGOCYTES TO PREVENT SECONDARY NECROSIS OF THE DYING CELL. THUS, APOPTOTIC DEATH IS QUIESCENT ONLY WHEN THE CELL IS REMOVED BY A PROCESS CALLED EFFEROCYTOSIS. INEFFICIENT CLEARANCE AUGMENTS INFLAMMATION DAMAGES TISSUE LEADING TO FURTHER APOPTOTIC DEATH CREATING A POSITIVE FEEDBACK LOOP OF UNRELENTING INFLAMMATION, SUCH AS WE SEE IN ARDS. WE HAVE FOUND THAT SYNDECAN-1 REGULATES LUNG INFLAMMATION AFTER INFLUENZA INFECTION BY PROMOTING EFFEROCYTOSIS OF APOPTOTIC EPITHELIUM. THEREFORE, THE CENTRAL HYPOTHESIS OF THIS PROPOSAL IS THAT SYNDECAN-1 EXPRESSION BY THE LUNG EPITHELIUM FACILITATES APOPTOTIC CELLS CLEARANCE BY MACROPHAGES THEREBY PROMOTING THE RESOLUTION OF LUNG INFLAMMATION AFTER INFLUENZA INJURY. THIS MULTI-PI PROPOSAL BRINGS TOGETHER TWO LONGSTANDING COLLABORATORS THAT HAVE STUDIED THE ROLE OF SYNDECAN-1 IN LUNG INJURY. DR. CHEN HAS A RESEARCH PROGRAM PRIMARILY BASED ON UNDERSTANDING THE EPITHELIAL IMMUNE RESPONSE IN THE LUNGS AFTER INJURY WHEREAS DR. PARKS' PROGRAM FOCUSES ON MACROPHAGE BIOLOGY. MERGING THE EXPERTISE FROM THESE TWO PIS WILL PROVIDE AN UNIQUE OPPORTUNITY TO CONDUCT HIGH IMPACT STUDIES ON EPITHELIAL:MACROPHAGE INTERACTIONS IN LUNG INJURY. SPECIFICALLY, THE INVESTIGATIVE TEAM WILL EVALUATE HOW SYNDECAN- 1 EXPRESSION IN LUNG EPITHELIUM PROMOTES MACROPHAGE CLEARANCE OF APOPTOTIC CELLS (I.E., EFFEROCYTOSIS) TO RESOLVE LUNG INFLAMMATION AFTER INFLUENZA INFECTION.

DEFINING HUMAN CORRELATES OF SUPER-EVASIVE DISSEMINATED TUMOR CELLS, THEIR PATHOLOGICAL RELEVANCE AND HOW TO ERADICATE THEM

BARBER AND PHARMACIST COORDINATION TO IMPROVE BLOOD PRESSURE MANAGEMENT - HYPERTENSION (HTN) IS A MAJOR RISK FACTOR FOR MULTIPLE MORBID CONDITIONS. DURING THE FIRST GRANT PERIOD, OUR TEAM SUCCESSFULLY CONDUCTED A CLUSTER-RANDOMIZED TRIAL OF A COMMUNITY-CENTERED BLOOD PRESSURE (BP) REDUCTION PROGRAM OF 319 NON-HISPANIC (NH) BLACK MEN WITHIN 52 BLACK-OWNED BARBERSHOPS IN LOS ANGELES, CA (LOS ANGELES BARBERSHOP BP STUDY [LABBPS] R01HL117983). THE INTERVENTION WAS HIGHLY EFFECTIVE CONFERRING MARKED REDUCTIONS IN SYSTOLIC BP OF 21.6 MMHG IN 6-MONTHS THAT WERE SUSTAINED AT 1 YEAR; HOWEVER, CRITICAL DATA ON LONGER TERM BP CONTROL ARE NEEDED TO JUSTIFY THE COSTS OF SCALING THIS SUCCESSFUL INTERVENTION. ADDITIONALLY, WHILE HIGHLY EFFECTIVE, THE CURRENT LABBPS MODEL, WHICH INVOLVED IN-PERSON VISITS WITH CLINICAL PHARMACISTS IN BARBERSHOPS, IS NOT ONLY RESOURCE INTENSIVE BUT ALSO HAS CONSTRAINED SCALABILITY DUE TO THE INEFFICIENCIES OF PHARMACIST TRAVEL TO AND BETWEEN SHOPS ACROSS WIDE GEOGRAPHIC REGIONS. THESE LIMITATIONS HAVE RESULTED IN STUNTED TRANSLATION OF THIS EVIDENCE-BASED INTERVENTION INTO CLINICAL PRACTICE. IN THIS RENEWAL APPLICATION, WE WILL LEVERAGE THE EXISTING, ONE-OF-A-KIND LABBPS COHORT AND BARBERSHOP COMMUNITY TO ADDRESS BOTH BARRIERS TO WIDESPREAD ADOPTION BY: 1) ASSESSING THE LONG-TERM IMPACT OF THE 1-YEAR LABBPS INTERVENTION ON BP AND ADVERSE HTN-RELATED OUTCOMES IN THE ORIGINAL LABBPS POPULATION - AND - 2) ADAPTING THE INTERVENTION IN THE LABBPS BARBERSHOPS TO BE MORE COST-EFFECTIVE AND LESS RESOURCE INTENSIVE BY TRANSITIONING THE IN- PERSON CLINICAL PHARMACIST’S HTN MANAGEMENT TO A TELEMEDICINE PLATFORM BASED IN THE BARBERSHOPS. IN AIMS 1 AND 2, TO ASSESS LONG-TERM BP CONTROL AND OUTCOMES, WE WILL PERFORM IN-PERSON FOLLOW-UP VISITS WITH THE ORIGINAL LABBPS PARTICIPANTS IN THE BARBERSHOPS AND ASCERTAIN/REVIEW UPDATED MEDICAL RECORDS TO CONFIRM HTN- RELATED CARDIOVASCULAR, RENAL, AND MORTALITY OUTCOMES. IN AIM 3, TO ADAPT THE IN-PERSON LABBPS MODEL TO A BARBERSHOP-ROOTED, TELEMEDICINE HTN MANAGEMENT PROGRAM, WE WILL USE RIGOROUS IMPLEMENTATION SCIENCE METHODS ALONG WITH INPUT FROM OUR ESTABLISHED COMMUNITY STAKEHOLDER ADVISORY BOARD. THE ADAPT-ITT AND RE- AIM IMPLEMENTATION SCIENCE FRAMEWORKS WILL BE USED TO THEATER TEST AND ASSESS THE FEASIBILITY AND ACCEPTABILITY OF MODIFYING THE LABBPS CLINICAL PHARMACIST’S ROLE FROM IN-PERSON WITHIN THE BARBERSHOPS TO A TELEMEDICINE VIDEO PLATFORM ALSO LOCATED IN THE BARBERSHOPS. THIS ADAPTATION STUDY WILL BE CONDUCTED IN 10 OF THE ORIGINAL LABBPS BARBERSHOPS WHERE 50 NEW NH BLACK PATRONS WITH HTN WILL BE ENROLLED. FOLLOWING IMPLEMENTATION, EFFECTIVENESS OF THE ADAPTED INTERVENTION WILL BE ASSESSED BY COMPARING THE ACHIEVED REDUCTION IN SYSTOLIC BP AT 6 MONTHS TO THAT OBTAINED IN THE ORIGINAL IN-PERSON LABBPS INTERVENTION. ACHIEVEMENT OF THESE AIMS WILL PROVIDE CRITICAL DATA NEEDED TO SUPPORT THE BROADER ADOPTION OF AN EVIDENCE-BASED COMMUNITY-CENTERED HTN CONTROL PROGRAM FOR NH BLACK MEN WHO ARE AT HIGH RISK OF HTN-ASSOCIATED MORBIDITY AND MORTALITY.

IDENTIFYING PATHWAYS OF PROGRESSION OF ACUTE PANCREATITIS TO RECURRING ACUTE PANCREATITIS AND CHRONIC PANCREATITIS

INTERROGATING A WHITE MATTER DEGENERATION-SPECIFIC ASTROCYTE REACTIVITY STATE AND ITS ROLE IN GOVERNING REPAIR-ASSOCIATED MICROGLIA SPECIFICATION AND FUNCTION. - PROJECT SUMMARY CLEARANCE OF CELLULAR DEBRIS FROM THE DEGENERATING CENTRAL NERVOUS SYSTEM (CNS) WHITE MATTER IS INEFFICIENT. DEBRIS ACCUMULATION, ESPECIALLY FROM MYELIN, PRECIPITATES MALADAPTIVE NEUROINFLAMMATION WHICH FURTHERS DISEASE PROGRESSION AND PREVENTS REPAIR. CHRONIC WHITE MATTER DEGENERATION THAT PRODUCES CELLULAR DEBRIS AND PROTRACTED INNATE IMMUNE INFLAMMATION IS A HALLMARK OF DIVERSE DISORDERS, INCLUDING TRAUMATIC AND ISCHEMIC CNS INJURY AND MULTIPLE SCLEROSIS (MS). THE DEVELOPMENT OF THERAPIES AIMED ENHANCING DEBRIS CLEARANCE TO PROMOTE REPAIR IS THEREBY OF BROAD TRANSLATIONAL RELEVANCE. RESEARCH AIMED AT UNCOVERING CENTRAL REGULATORY MECHANISMS UNDERLYING THE INFLAMMATORY RESPONSE THAT FACILITATES DEBRIS CLEARANCE AFTER WHITE MATTER INSULT IS THEREFORE PRUDENT AND NECESSARY. THE OVERARCHING OBJECTIVE OF THIS RESEARCH IS TO DISSECT MOLECULAR PATHWAYS OF ASTROCYTE- MICROGLIA INTERACTION THAT GOVERN PRO-RESTORATIVE CNS INNATE IMMUNE RESPONSES TO WHITE MATTER DEGENERATION. THE PRESENT RESEARCH WILL INVESTIGATE A NEWLY IDENTIFIED MECHANISM OF INTERCELLULAR COMMUNICATION, THROUGH WHICH A DISTINCT SUBPOPULATION OF WHITE MATTER DEGENERATION-REACTIVE ASTROCYTES REGULATE MICROGLIA SPECIFICATION AND FUNCTION REQUIRED FOR THE REMOVAL OF INFLAMMATORY MYELIN DEBRIS AND TISSUE REPAIR. IN AIM 1, WE WILL USE A TRANSGENIC, CELL TYPE-SPECIFIC LOSS-OF-FUNCTION SYSTEM, SINGLE-NUCLEUS RNA-SEQUENCING (SNRNA-SEQ) AND MOUSE MODELS OF ACUTE AND CHRONIC WHITE MATTER DEGENERATION TO ASSESS THE INVOLVEMENT OF THIS UNIQUE ASTROCYTE- MEDIATED SIGNALING PATHWAY IN REGULATING DAMAGE-RESPONSIVE MICROGLIA SPECIFICATION REQUIRED FOR MYELIN DEBRIS CLEARANCE AND REMYELINATION. IN AIM 2, WE WILL DISSECT THE DIRECT EFFECTS AND RECEPTOR DEPENDENT MECHANISM OF ACTION FOR A NOVEL ASTROCYTE-DERIVED MOLECULAR CUE ON MICROGLIA MOLECULAR PROFILE, MOTILITY, AND CAPACITY FOR MYELIN DEBRIS PHAGOCYTOSIS USING CULTURES OF MOUSE PRIMARY AND HUMAN IPSC-DERIVED MICROGLIA. IN AIM 3, WE WILL DETERMINE CELL-INTRINSIC REGULATORY PATHWAYS UNDERLYING MOLECULARLY AND FUNCTIONALLY DISTINCT STATES OF WHITE MATTER ASTROCYTE REACTIVITY USING CELL-PAIRED SNRNA-SEQ AND SINGLE-NUCLEUS ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN USING SEQUENCING (SNATAC-SEQ), OVER TIME, IN A MOUSE MODEL OF CHRONIC WHITE MATTER DEGENERATION. AN INTEGRATIVE ANALYSIS PIPELINE WILL BE USED TO GENERATE GENE REGULATORY PROGRAMS OF ASTROCYTE REACTIVITY, INCLUDING DYNAMIC CHANGES IN CHROMATIN STRUCTURE AND CONTEXT-SPECIFIC COMBINATIONS OF TRANSCRIPTIONAL REGULATORS (TR), WHICH TOGETHER GOVERN GENETIC ACCESSIBILITY AND DISTINCT REACTIVE CHANGES IN TRANSCRIPTOMIC PROFILE. SELECT TR OF MOLECULARLY DISTINCT STATES OF WHITE MATTER ASTROCYTE REACTIVITY WILL BE FUNCTIONALLY INTERROGATED IN VIVO BY LOSS-OF-FUNCTION STUDIES. TOGETHER, THIS RESEARCH WILL ENHANCE THE UNDERSTANDING OF HOW ASTROCYTE-MICROGLIA INTERACTIONS SHAPE CNS INNATE IMMUNE RESPONSES THAT ENABLE WHITE MATTER REPAIR. THESE DATA MAY ALSO INFORM NEW THERAPEUTIC AVENUES FOR HARNESSING RESTORATIVE INNATE IMMUNE RESPONSES, INVOLVING ASTROCYTES AND MICROGLIA, TO PREVENT OR ATTENUATE MALADAPTIVE WHITE MATTER INFLAMMATION, AS WELL AS IMPROVE OUTCOME AND PROMOTE RECOVERY AFTER CNS INJURY AND IN DISEASE.

ROLE OF PTPN2 IN RHEUMATOID ARTHRITIS

EPITHELIAL PROGENITOR CELLS FOR LUNG REPAIR AND REGENERATION

GCDH ADDICTION IN MELANOMA - PROJECT SUMMARY IN THIS REVISED R01 APPLICATION WE PROPOSE TO CHARACTERIZE A NOVEL MECHANISM UNDERLYING THE CONTROL OF APOPTOSIS BY THE MITOCHONDRIAL ENZYME GCDH, AND TO EXTEND THE DEVELOPMENT OF SMALL MOLECULE GCDH INHIBITORS TO TREAT MELANOMA. IN OUR PRELIMINARY RESULTS WE DISCOVERED THAT ADDICTION TO GCDH ACTIVITY IS CRITICAL FOR CELL SURVIVAL IN MELANOMA, BUT NOT LIVER, BREAST OR PROSTATE TUMOR CELLS, A DISCOVERY THAT WAS CONFIRMED IN PATIENT SPECIMENS WHERE INVERSE CORRELATION BETWEEN GCDH EXPRESSION AND SURVIVAL IS SEEN IN MELANOMA. OUR STUDIES REVEAL INDUCTION OF APOPTOSIS IN MELANOMA CELL LINES FOLLOWING GCDH INHIBITION, A PHENOTYPE DEPENDENT ON THE UPSTREAM DHTKD1 ENZYME. KEY IN MEDIATING GCDH ACTIVITIES IN MELANOMA IS NRF2, WHICH IS SUBJECTED TO GLUTARYLATION UPON INHIBITION OF GCDH. NRF2 GLUTARYLATION PROMOTES ITS STABILITY AND TRANSACTIVATION OF AN APOPTOTIC UPR SIGNALING CONSISTING OF ATF4, ATF3, CHOP AND CHAC1, THE LATTER BEING COMPONENTS OF THE UNFOLDED PROTEIN RESPONSE (UPR). INHIBITION OF GCDH EFFECTIVELY INDUCES APOPTOTIC UPR SIGNALING IN MELANOMA BUT NOT IN LIVER OR BREAST CANCER CELLS, SUBSTANTIATING THE SELECTIVITY OF THE PATHWAY AS MAPPED IN CELL LINES AND PATIENT TUMOR SAMPLES. THESE OBSERVATIONS PROVIDE THE FOUNDATION FOR OUR HYPOTHESIS THAT GCDH-MEDIATED REGULATION OF NRF2-UPR SIGNALING CONSTITUTES A NOVEL PATHWAY CONTROLLING MELANOMA CELL SURVIVAL. OUR STUDIES WILL (I) MAP THE NRF2 GLUTARYLATION PATHWAY IN MELANOMA, GENERATE ANTIBODIES SPECIFIC TO GLUTARYLATED NRF2, MONITOR NRF2 GLUTARYLATION IN SPECIMENS FROM MELANOMA PATIENTS BOTH RESPONSIVE AND NON-RESPONSIVE TO THERAPY (II) ASSESS HOW GCDH IMPACTS TUMOR DEVELOPMENT, PROGRESSION AND RESPONSE TO TARGETED AND IMMUNO THERAPY IN GENETIC MOUSE MODELS. YUMM1.7, MARAS, B16F10 LINES WILL BE MODIFIED TO EXPRESS INDUCIBLE KD OF GCDH BEFORE THEIR INOCULATION INTO SYNGENEIC WT OR GCDH KO MOUSE MODELS WHICH WILL BE MONITORED PRIOR AND FOLLOWING THERAPY (III) ADVANCE DEVELOPMENT GCDH INHIBITORS AS NOVEL THERAPEUTIC MODALITIES. SBI-0690564 WAS CONFIRMED IN VITRO AND IN CULTURED MELANOMA CELLS, WHERE IT PHENOCOPIES GENETIC INACTIVATION OF GCDH AND INHIBITS MELANOMA TUMORS IN MICE. WE WILL CHARACTERIZE AND FURTHER DEVELOP A NOVEL CLASS OF INHIBITORS TO TARGET GCDH AND DETERMINE THEIR EFFECTIVENESS IN CULTURE AND IN VIVO USING MOUSE MODELS. OUR STUDIES WILL ESTABLISH NOVEL PARADIGM FOR GCDH SIGNALING AS WE DEFINE MECHANISMS UNDERLYING GCDH CONTROL MELANOMA TUMOR FATE. UNDERSTANDING THE ADDICTION TO GCDH IN MELANOMA PROVIDES THE FOUNDATION FOR THE DEVELOPMENT AND EVALUATION OF NOVEL GCDH INHIBITORS TO SELECTIVELY TARGET THESE AND POSSIBLY OTHER SELECT CANCERS.

A RANDOMIZED CONTROLLED PHASE 2 STUDY OF THE KETOGENIC DIET FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA IN COMBINATION WITH STANDARD-OF-CARE TREATMENT - ABSTRACT MEDIAN GLIOBLASTOMA (GBM) SURVIVAL IS ~15 MONTHS AND IS LITTLE CHANGED THE PAST 50 YEARS. BETTER THERAPIES ARE NEEDED. PRECLINICAL WORK FROM US AND OTHERS HAS SHOWN THAT A HIGH-FAT / LOW-CARBOHYDRATE KETOGENIC DIET (KD) CAN SLOW CANCER GROWTH IN MULTIPLE MODELS INCLUDING GBM. LIKE MANY CANCERS, GBM DEPENDS ON GLYCOLYSIS FOR THE BIOSYNTHETIC, BIOENERGETIC, AND SIGNALING NEEDS OF ONCOGENESIS. BY LIMITING GLYCOLYTIC FLUX AND ALTERING METABOLISM, KD MAY HAVE ANTI-CANCER EFFECTS, INCLUDING ABROGATING DYSREGULATED INSULIN-PI3K SIGNALING, SUPPRESSING THE PRO-INFLAMMATORY TUMOR ENVIRONMENT, AND FACILITATING AN ANTI-TUMOR IMMUNE RESPONSE. GIVEN THE DISMAL PROGNOSIS, MANY GBM PATIENTS ADOPT A QUASI-KD DESPITE THE LACK OF HIGH-QUALITY DATA SUPPORTING ITS USE. TO FILL THIS GAP, WE CONDUCTED A PILOT KD STUDY FOR BRAIN TUMOR PATIENTS, WHEREIN WE SAW IMPROVEMENTS IN FATIGUE, MOOD, COGNITIVE FUNCTION, AND SEIZURE CONTROL, AS WELL AS RADIOGRAPHIC RESPONSES. WE RECENTLY COMPLETED A PHASE 1 KD TRIAL FOR PATIENTS WITH NEWLY DIAGNOSED GBM. THE PRIMARY OBJECTIVES OF THE PHASE 1 STUDY - SAFETY AND FEASIBILITY – WERE MET. IMPORTANTLY, WE FOUND AN IMPRESSIVE MEDIAN OVERALL SURVIVAL (OS) OF 29.1 MONTHS, A 99% IMPROVEMENT VS. HISTORIC CONTROL FROM THE PHASE 3 TRIAL THAT ESTABLISHED THE CURRENT STANDARD OF CARE (SOC). WE ARE NOW POISED TO CONDUCT THE FIRST EVER WELL-POWERED RANDOMIZED CONTROLLED PHASE 2 STUDY OF KD + SOC VS. SOC FOR PATIENTS WITH NEWLY DIAGNOSED GBM. WE PROPOSE A 170-PERSON MULTICENTER RANDOMIZED CONTROLLED PHASE 2 STUDY OF KD PLUS SOC VS. SOC FOR PATIENTS NEWLY DIAGNOSED WITH GBM. OUR PRIMARY OBJECTIVE IS TO TEST EFFICACY BETWEEN KD + SOC VS. SOC AS ASSESSED BY IMPROVED OS. WE WILL ASSESS QUALITY OF LIFE (QOL), COGNITION, AND PHYSICAL FUNCTION, AS BENEFITS IN ANY OF THESE WOULD BE IMPACTFUL TO PATIENTS’ LIVES. WE WILL TAKE FULL ADVANTAGE OF TUMOR, BLOOD, AND STOOL SAMPLES THAT WE WILL BE COLLECTING TO UNDERSTAND THE EFFECTS OF KD ON TUMOR AND HOST METABOLISM AND IMMUNE RESPONSE. DESPERATE PATIENTS ARE NOT WAITING. WE THUS HAVE AN URGENT RESPONSIBILITY TO PROSPECTIVELY AND COMPREHENSIVELY EVALUATE KD AND UNDERSTAND ITS EFFECTS, GOOD OR BAD. IF NEGATIVE, PATIENTS CAN BE COUNSELED ACCORDINGLY, AND SPEND THEIR PRECIOUS TIME AND ENERGY ON OTHER ENDEAVORS, THOUGH QOL BENEFITS (IF SEEN) MAY STILL PERSUADE SOME TO GO ON A KD. IF POSITIVE, WE HAVE THE POTENTIAL TO ESTABLISH A NEW SOC THAT CAN BE BROADLY APPLIED WITHOUT THE COST OR TOXICITY OF MOST NEW CANCER THERAPIES. WE WILL SEIZE THE OPPORTUNITY TO GAIN A GREATER MECHANISTIC UNDERSTANDING OF THE EFFECTS OF KD ON GBM, WHICH MAY SHAPE FUTURE EFFORTS TO IDENTIFY EARLY MARKERS/PREDICTORS OF RESPONSE AND OPTIMIZE THERAPEUTIC COMBINATIONS. THESE DATA CAN ALSO HELP MANAGE GBM PATIENTS WHO CHOOSE TO GO ON A KD EITHER FOR OS OR QOL BENEFITS (IF SEEN). THUS, REGARDLESS OF OUTCOME, THIS STUDY WILL SHAPE CLINICAL PRACTICE.

IBD: MUCOSA SPECIFIC REGULATION OF IFN-GAMMA PRODUCTION

CARDIOPROTECTIVE MECHANISMS OF NOVEL NONCODING RNA IN MYOCARDIAL INFARCTION - PROJECT SUMMARY/ABSTRACT THIS PROPOSAL SEEKS TO UNDERSTAND THE CARDIOPROTECTIVE EFFECTS OF A NEW NONCODING RNA (NCRNA) ENTITY, TY4, THAT IS BIOINSPIRED BY THE CONTENTS OF EXOSOMES. OUR FOCUS IS ON ONE CLASS OF SMALL NCRNA, NOT PREVIOUSLY RECOGNIZED AS PARTICULARLY RELEVANT TO CARDIAC DISEASE. Y RNAS CAPTURED OUR ATTENTION BECAUSE MOLECULES ENCODED BY THE YRNA4 GENE ARE EXCEPTIONALLY PLENTIFUL IN EXOSOMES SECRETED BY CARDIOSPHERE-DERIVED CELLS. THE PREDOMINANT SUCH NCRNA, EV-YF1, HAS SALUTARY PROPERTIES WHEN DELIVERED ON ITS OWN: EV-YF1 INCREASES IL-10 SECRETION, IS CARDIOPROTECTIVE AND ANTI-HYPERTROPHIC. HERE WE PRESENT PRELIMINARY DATA ON TY4, A NEW CHEMICAL ENTITY (NCE) BIOINSPIRED BY EV-YF1. TY4 EXERTS GLOBAL TRANSCRIPTOMIC CHANGES INVOLVING INFLAMMATORY AND FIBROTIC PATHWAYS, AND EXERTS DISEASE-MODIFYING BIOACTIVITY IN MURINE MODELS OF HEART FAILURE WITH PRESERVED EJECTION FRACTION, DUCHENNE MUSCULAR DYSTROPHY, AND MI. REMARKABLY, TY4, WHEN FORMULATED WITH THE BREAST MILK PROTEIN CASEIN, WORKS ORALLY IN ALL THREE MODELS. IN TERMS OF MECHANISM, PRELIMINARY DATA SHOW THAT TY4 BINDS TO TPR, A NUCLEAR PORE COMPLEX PROTEIN THAT ACTS AS A GATEKEEPER FOR MESSENGER RNA EXPORT FROM THE NUCLEUS. WE HAVE ALSO FOUND THAT MACROPHAGE DEPLETION ABROGATES TY4-MEDIATED CARDIOPROTECTION. AS A SMALL CHEMICALLY- MODIFIED MUTANT NCE, TY4 HAS KEY FEATURES DESIRABLE IN A SYNTHETIC RNA DRUG. BUT OTHER RNA DRUGS, WHETHER FDA-APPROVED OR IN DEVELOPMENT, ALL HAVE KNOWN MECHANISMS OF ACTION: THEY ARE ANTISENSE OLIGOS, SMALL INTERFERING RNAS, APTAMERS, OR MIR-MODIFIERS. TY4 FITS INTO NONE OF THOSE CLASSES AND THUS IS THE PROTOTYPE FOR A NEW CLASS OF RNA DRUGS. THE FOCUS HERE IS ON UNDERSTANDING THE MECHANISM WHEREBY TY4 LIMITS INFARCT SIZE. WE WILL TEST THE FOLLOWING MECHANISTIC HYPOTHESIS: TY4 IS CARDIOPROTECTIVE AGAINST MI BY BINDING TO TPR AND ALTERING GENE EXPRESSION IN TARGET CELLS (AND SPECIFICALLY, IN MACROPHAGES). WE WILL PURSUE THE FOLLOWING AIMS: 1: INVESTIGATE THE MECHANISM(S) WHEREBY TY4 ALTERS GENE EXPRESSION IN MACROPHAGES. SUB-AIMS SEEK TO IDENTIFY TY4 BINDING PARTNERS, CHARACTERIZE THE TRANSCRIPTOMIC CHANGES INDUCED BY TY4, AND PRIORITIZE BIOLOGICAL TARGETS FOR FURTHER INTERROGATION. 2: OPTIMIZE IN VIVO EFFICACY OF ORAL TY4 IN MURINE MI. SUB-AIMS SEEK TO OPTIMIZE THE DOSAGE PARADIGM FOR ORAL TY4 IN ACUTE MI, MEASURE BIODISTRIBUTION OF TY4 AFTER ORAL DELIVERY IN MICE PRE- AND POST- ACUTE MI, DETERMINE THE WINDOW OF OPPORTUNITY FOR TY4 EFFICACY POST-MI IN ACUTE MI, TEST TY4 CARDIOPROTECTIVE EFFICACY IN AGED MICE, AND CHARACTERIZE THE EFFECTS OF OPTIMIZED ORAL TY4 DELIVERY IN A CHRONIC MI MODEL. 3: TEST WHETHER MACROPHAGES ARE NECESSARY AND SUFFICIENT TO EXPLAIN TY4 EFFICACY IN ACUTE MI. SUB-AIMS SEEK TO COMPARE MI OUTCOMES +/- TY4 WITH AND WITHOUT PRIOR MACROPHAGE DEPLETION, PROBE THE RELATIVE ROLES OF TISSUE-RESIDENT VERSUS CIRCULATING MACROPHAGES, AND DETERMINE WHETHER POST-MI ADOPTIVE TRANSFER OF EX VIVO TY4-CONDITIONED MACROPHAGES REDUCES INFARCT SIZE IN MACROPHAGE-DEPLETED MICE. WHILE HIGHLY MECHANISTIC, OUR PROPOSAL, FOCUSING ON A SYNTHETIC NCRNA NCE BIOINSPIRED BY EXOSOMAL CARGO, ALSO OFFERS TRANSLATIONAL VALUE IN ITS DEVELOPMENT OF A NOVEL CARDIOPROTECTIVE AGENT THAT IS EFFECTIVE EVEN WHEN GIVEN AFTER REPERFUSION.

REGULATION OF LIMBAL NICHE IN NORMAL AND DIABETIC CORNEA BY EXTRACELLULAR VESICLES

AUTOMATED QUANTITATIVE CT IMAGING OF EPICARDIAL ADIPOSE TISSUE AND RISK OF CARDIAC EVENTS

REGULATION OF CELLULAR CALCIUM BY CARDIAC SODIUM-CALCIUM EXCHANGE

ROLE OF AMPK IN MELANOMA BRAIN METASTASIS - PROJECT SUMMARY: AMP ACTIVATED PROTEIN KINASE (AMPK) IS A CRITICAL EVOLUTIONARILY CONSERVED ENERGY SENSOR THAT REGULATES ENERGY HOMEOSTASIS BY MONITORING CHANGES IN THE INTRACELLULAR AMP OR ADP TO ATP RATIOS. MOUNTING EVIDENCE SUPPORTS THAT THE AMPK PATHWAY IS ONE OF THE MAJOR SIGNALING PLAYERS AT THE INTERFACE OF METABOLISM AND CANCER. HOWEVER, THE ROLE OF AMPK IN TUMOR PROGRESSION AND METASTASIS REMAINS OBSCURE. OUR RECENT ANALYSIS ON MELANOMA CANCER GENOMICS DATA HAS REVEALED THAT THE MUTATIONS IN THE PRKAA2 GENE, WHICH ENCODES THE ALPHA 2 CATALYTIC SUBUNIT OF AMPK, OCCUR IN 8-10% OF CUTANEOUS MELANOMAS AND TEND TO CO-OCCUR WITH NF1 MUTATIONS. IN OUR PRELIMINARY STUDIES, WE FOUND THAT KNOCKOUT OF AMPKA2 PROMOTED ANCHORAGE-INDEPENDENT GROWTH OF MUTANT NF1-MELANOMA CELLS IN SOFT AGAR ASSAYS AND THEIR GROWTH AS XENOGRAFTED TUMORS IN NUDE MICE. IMPORTANTLY, WE FOUND THAT EXPRESSION OF AMPKA2 IS SIGNIFICANTLY DOWNREGULATED IN HUMAN MELANOMA BRAIN METASTASIS SAMPLES COMPARED TO PATIENT-MATCHED EXTRACRANIAL METASTASIS SAMPLES. FURTHERMORE, KNOCKOUT OF AMPKA2 PROMOTED BRAIN METASTASIS OF NF1-MUTANT MEWO MELANOMA CELLS IN NUDE MICE. BASED ON THESE PRELIMINARY RESULTS, WE HYPOTHESIZE THAT INACTIVATION OF AMPKA2 IN MELANOMA PROMOTES TUMOR PROGRESSION TO MELANOMA BRAIN METASTASIS. IN AIM 1, WE WILL ESTABLISH THE ROLE OF AMPKA2 IN MELANOMA BRAIN METASTASIS USING MOUSE MODELS AND HUMAN SAMPLES. WE PLAN TO CHARACTERIZE THE EFFECTS OF AMPKA2 LOSS IN BOTH SYNGENEIC AND GENETICALLY ENGINEERED MOUSE MODELS. HUMAN MELANOMA BRAIN METASTASIS SAMPLES WILL BE USED TO EXPLORE THE CONTRIBUTION OF AMPKA2 LOSS THROUGH SPATIAL SINGLE CELL RNA-SEQ ANALYSES. IN AIM 2, WE WILL CHARACTERIZE DOWNSTREAM TARGETS OF AMPK INVOLVED IN THE METABOLIC REGULATION OF MELANOMA BRAIN METASTASIS. WE WILL INVESTIGATE THE CONTRIBUTION OF A NOVEL PUTATIVE SUBSTRATE OF AMPKA2 INVOLVED IN DE NOVO LIPOGENESIS, IDENTIFIED IN OUR PRELIMINARY STUDIES, TO MELANOMA BRAIN METASTASIS, AND EXPLORE ADDITIONAL NEW AMPKA2 TARGETS THROUGH COMPREHENSIVE METABOLOMICS AND RPPA ANALYSES OF TUMOR SAMPLES FROM MOUSE MODELS. IN AIM 3, WE WILL ASSESS THE THERAPEUTIC EFFECTS OF METABOLIC DRUGS TARGETING THE AMPK PATHWAY ON ENHANCING THE EFFICACIES OF TARGETED- AND IMMUNE- THERAPIES IN MELANOMA BRAIN METASTASIS USING HUMAN MELANOMA XENOGRAFTS, SYNGENEIC AND GENETICALLY ENGINEERED MOUSE MODELS. TO ACHIEVE THESE AIMS, WE HAVE ASSEMBLED A TEAM OF INVESTIGATORS WITH VARIOUS EXPERTISE INCLUDING CANCER CELL METABOLISM, MELANOMA BRAIN METASTASIS BIOLOGY, MELANOMA ONCOLOGISTS/SURGEON AND COMPUTATIONAL BIOLOGY. OUR STUDY WILL NOT ONLY PROVIDE CRITICAL INSIGHTS INTO THE ROLE OF AMPK METABOLIC SIGNALING IN MELANOMA BRAIN METASTASIS ADDRESSING A SIGNIFICANT KNOWLEDGE GAP IN THE FIELD, BUT ALSO IDENTIFY NOVEL THERAPEUTIC APPROACHES TO TARGET MELANOMA BRAIN METASTASIS.

HYPOTHALAMIC PATHWAYS OF AGE RELATED HOMEOSTATIC DYSREGULATION - PROJECT SUMMARY THIS PROJECT IS DESIGNED TO DETERMINE THE ROLE OF HYPOTHALAMIC NEURONS IN THE PROGRESSION OF PHYSIOLOGICAL DECLINE WITH AGE. DURING SUMMER HEAT WAVES, OLDER ADULTS ARE EXTREMELY VULNERABLE TO HYPERTHERMIA AND DEHYDRATION LEADING TO HIGHER RISK OF MORBIDITY AND MORTALITY. UNDERSTANDING THE CELLULAR MECHANISMS RESPONSIBLE FOR INCREASED FRAILTY WITH AGE IS CRITICAL FOR IMPROVING HEATHSPAN IN OLDER ADULTS. THE GOAL OF THIS PROPOSAL IS TO ESTABLISH A NOVEL ROLE FOR SUPRAOPTIC HYPOTHALAMIC NEURONS IN CAUSING AGE-DEPENDENT PHYSIOLOGICAL DISTURBANCES WHICH DISRUPT NEUROENDOCRINE HOMEOSTASIS. GUIDED BY OUR RECENT FINDING THAT ARGININE-VASOPRESSIN (AVP) TRANSCRIPTION IN SUPRAOPTIC HYPOTHALAMIC NEURONS IS DRAMATICALLY INCREASED IN AGED MICE, THE PROPOSED EXPERIMENTS LEVERAGE STATE-OF-THE-ART METHODS FOR MONITORING AND MANIPULATING VASOPRESSIN NEURONS IN MICE WITH THE GOAL TO ELUCIDATE THEIR ROLE IN THERMOREGULATION AND FLUID BALANCE. THIS PROPOSAL WILL ALSO EXPLORE THE ROLE OF BRAIN INFLAMMATION IN ALTERING PHYSIOLOGICAL HOMEOSTASIS THROUGH DYSREGULATION OF VASOPRESSIN NEURONAL FUNCTION. FINALLY, THE THERAPEUTIC POTENTIAL OF GENE THERAPIES FOCUSING ON VASOPRESSIN NEURONS WILL BE INVESTIGATED IN THE CONTEXT OF BEHAVIORAL AND PHYSIOLOGICAL FRAILTY WITH AGE. THE PROPOSED STUDIES WILL LAY THE GROUNDWORK FOR IMPUTING A CAUSAL ROLE OF SUPRAOPTIC VASOPRESSIN NEURONS IN THE ONSET OF AGE-DEPENDENT FRAILTY.

SUDDEN CARDIAC DEATH WITH PRESERVED LEFT VENTRICULAR EJECTION FRACTION

MITIGATION OF RADIATION INJURY VIA VASCULAR REGENERATION AND REMODELING

MOTION-RESOLVED, COMPREHENSIVE QUANTITATIVE TISSUE CHARACTERIZATION USING MR MULTITASKING

OVERCOMING IMMUNOTHERAPY RESISTANCE IN BREAST CANCER USING RT-MEDIATED IMMUNOMODULATION

RETINAL IMAGING OF ALZHEIMER'S DISEASE PATHOLOGY

THE ROLE OF INTERLEUKIN 17RB SIGNALING IN COLORECTAL CANCER PROGRESSION

TARGETING THE MYCOBIOME IN GENETICALLY DEFINED PATIENTS WITH CROHNS DISEASE - ABSTRACT INFLAMMATORY BOWEL DISEASE (IBD), DIVIDED LARGELY INTO CROHN’S DISEASE (CD) AND ULCERATIVE COLITIS, IS A CHRONIC AND SERIOUS DISEASE THAT RESULTS FROM DYSREGULATED INFLAMMATORY IMMUNE ACTIVITY IN THE MUCOSA OF THE GASTROINTESTINAL TRACT. THERE HAS BEEN MUCH PROGRESS DEFINING GENETIC, INTESTINAL MICROBIOME, HOST PATHWAY, AND ENVIRONMENTAL ROLES IN DISEASE, AND A MAJOR GOAL IN IBD RESEARCH AND CARE IS TO TRANSLATE THESE OBSERVATIONS INTO STRATEGIES TO IMPROVE OUTCOMES BY BETTER MATCHING DISEASE TREATMENT WITH PATIENTS’ SPECIFIC UNDERLYING MECHANISMS OF DISEASE. STUDIES ON THE ROLE OF THE MICROBIOME IN INFLUENCING IBD HAVE FOCUSED LARGELY ON THE BACTERIAL MICROBIOTA, WHILE THE POTENTIAL ROLE FOR COMMENSAL FUNGAL MICROBIOTA TO INFLUENCE DISEASE HAS BEEN LARGELY OVERLOOKED. WE RECENTLY REPORTED A STRONG ASSOCIATION OF THE YEAST MALASSEZIA WITH CROHN’S DISEASE. SPECIFICALLY, INTESTINAL MUCOSA- ASSOCIATED MALASSEZIA ARE ELEVATED IN PATIENTS CARRYING A PREVIOUSLY DESCRIBED IBD RISK POLYMORPHISM (S12N) IN THE GENE FOR CARD9, A SIGNALING MOLECULE REQUIRE FOR ANTIFUNGAL INFLAMMATORY IMMUNE RESPONSES. IN MOUSE MODELS, MALASSEZIA EXACERBATES COLITIS VIA A MECHANISM REQUIRING CARD9. THIS PROJECT IS DESIGNED TO TEST THE HYPOTHESIS THAT ORAL ANTIFUNGAL TREATMENT CAN REDUCE THE BURDEN OF MALASSEZIA SPP. IN CD PATIENTS WITH THE CARD9 S12N ALLELE AND IMPROVE DISEASE SYMPTOMS. THE APPROACH INCLUDES A TWO-CENTER RANDOMIZED, DOUBLE- BLIND, PLACEBO-CONTROLLED STUDY OF ANTIFUNGAL DRUG TREATMENT IN GENETICALLY DEFINED PATIENTS WITH ACTIVE CROHN’S DISEASE. WE WILL EVALUATE THE CONSEQUENCES OF ANTIFUNGAL DRUG TREATMENT ON THE OVERALL MICROBIOME AND METABOLITES IT PRODUCES AS WELL AS REGULATION OF IMMUNE CELL FUNCTION IN THE MUCOSA.

INNATE NLRC4 SIGNALING CONTROLS ADAPTIVE IMMUNE RESPONSES - PROJECT SUMMARY NLRC4 IS A MEMBER OF THE NUCLEOTIDE-BINDING DOMAIN AND LEUCINE-RICH REPEAT RECEPTOR (NLR) FAMILY OF CYTOSOLIC PATTERN RECOGNITION RECEPTORS AND IS PRIMARILY EXPRESSED IN INNATE IMMUNE CELLS. THE CANONICAL NLRC4 PATHWAY IS ACTIVATED FOLLOWING THE RECOGNITION OF COMPONENTS OF GRAM-NEGATIVE BACTERIA BY NAIP PROTEINS RESULTING IN NLRC4 OLIGOMERIZATION AND ASSEMBLY OF THE INFLAMMASOME COMPLEX. ACTIVATION OF THE NLRC4 INFLAMMASOME CULMINATES IN CASPASE-1-MEDIATED PROCESSING AND RELEASE OF THE PRO-INFLAMMATORY CYTOKINE IL- 1. WE HAVE FOUND THAT NLRC4 PLAYS A PROTECTIVE ROLE IN MICE CHALLENGED SUBCUTANEOUSLY WITH EITHER B16F10 MELANOMA CELLS OR IN A MODEL OF INFLUENZA A VIRUS INFECTION. IN BOTH MODELS, NLRC4-DEFICIENT (NLRC4-/-) MICE HAD A LOSS OF EFFECTOR CD4+ T CELLS. GENERATION AND MAINTENANCE OF ROBUST T CELL RESPONSES RELIES ON T CELL INTERACTIONS WITH ANTIGEN PRESENTING CELLS. EVALUATION OF NLRC4-/- MACROPHAGES AND DENDRITIC CELLS (DC) REVEALED A DOWNREGULATION OF AKT1 AND FOXO3A PHOSPHORYLATION, WHICH IN TURN RESULTED IN THE UPREGULATION OF THE APOPTOSIS- INDUCING LIGAND FASL ON NLRC4-/- MYELOID CELLS THAT TRIGGERED CELL DEATH IN CO-CULTURED T CELLS. IMPORTANTLY, UNLIKE THE CANONICAL NLRC4 PATHWAY, THE ANTI-TUMOR AND ANTI-VIRAL ROLES OF NLRC4 WERE INFLAMMASOME-INDEPENDENT, SUGGESTING A NOVEL NON-CANONICAL NLRC4 SIGNALING PATHWAY. IN THIS PROPOSAL WE WILL EXPAND ON THESE NOVEL FINDINGS AND UTILIZE INNOVATE TECHNOLOGIES TO PROBE UNANSWERED QUESTIONS. WE HYPOTHESIZE THAT ENDOGENOUS DANGER SIGNALS ACTIVATE NLRC4 IN MYELOID CELL, WHICH IN TURN MAINTAINS EFFECTOR T CELL RESPONSES BY PREVENTING FASL UPREGULATION. WE WILL DEFINE THE MECHANISM BY WHICH NLRC4 IS ACTIVATED IN ANTIGEN PRESENTING CELLS AND THE NOVEL NON-CANONICAL PATHWAY THROUGH WHICH NLRC4 MODIFIES SUBSEQUENT T CELL RESPONSES. WE WILL ALSO DETERMINE WHAT FACTORS DOWNREGULATE NLRC4 EXPRESSION AND HOW THIS DOWNREGULATION CAN BE EXPLOITED BY PATHOGENS AND TUMORS. THESE STUDIES WILL IDENTIFY NOVEL PATHWAYS IN INNATE IMMUNE CELLS THAT CAN BE TARGETED TO EITHER AUGMENT SPECIFIC ANTI-TUMOR OR ANTI-VIRAL RESPONSES OR INHIBIT PATHOGENIC T CELL RESPONSES.

DEEP LEARNING BASED PHENOTYPING AND OUTCOMES PREDICTION FOR VALVULAR HEART DISEASE - ABSTRACT MITRAL VALVE DISEASE IS A COMMON UNDERRECOGNIZED DISORDER AFFECTING OVER 170 MILLION INDIVIDUALS WORLDWIDE, HOWEVER A SIZABLE PROPORTION OF INDIVIDUALS WILL EXPERIENCE ADVERSE MYOCARDIAL RESPONSE LEADING TO DEGENERATIVE MITRAL REGURGITATION, HEART FAILURE, CARDIAC ARREST, OR EVEN SUDDEN CARDIAC DEATH. MYOCARDIAL REMODELING RESPONDING TO MITRAL REGURGITATION CAN LEAD TO CHANGES IN CARDIOVASCULAR STRUCTURE AND FUNCTION, BUT GENERAL PATTERNS OF CHANGE DURING EARLY DISEASE (SUCH AS DIASTOLIC DYSFUNCTION AND INCREASED SPHERICITY) ARE INSUFFICIENT TO DISTINGUISH BETWEEN APPROPRIATE COMPENSATED MYOCARDIAL RESPONSE TO INNOCENT MITRAL VALVE PROLAPSE VS. EARLY MANIFESTATIONS OF FUTURE SYMPTOMATIC DEGENERATIVE MITRAL REGURGITATION ASSOCIATED WITH ADVERSE OUTCOMES. RECENT ADVANCES IN ARTIFICIAL INTELLIGENCE (AI), WHEN APPLIED TO BIOMEDICAL IMAGES, INDICATE THAT DEEP LEARNING ALGORITHMS CAN BOTH OFFER PRECISE MEASUREMENTS BEYOND HUMAN FIDELITY AND ALSO IDENTIFY SUBTLE TRAITS IN IMAGING THAT ARE UNRECOGNIZED BY THE HUMAN EYE. OUR PRIOR WORK APPLYING AI TO ECHOCARDIOGRAPHY AS WELL AS OTHERS APPLYING AI TO OTHER FORMS OF MEDICAL IMAGING, HAVE SHOWN DEEP LEARNING CAN NOT ONLY REPRODUCE STANDARD MEASURES OF CARDIAC STRUCTURAL AND FUNCTION BUT IS ALSO IDENTIFY CVD RISK FEATURES INCLUDING CHRONOLOGIC AGE, BIOLOGICAL SEX, DIABETES, HYPERTENSION, AND SMOKING. IN EFFECT, AI APPLIED TO ECHOCARDIOGRAPHY NOW OFFERS THE POTENTIAL TO CAPTURE A PRECISE PHENOTYPING OF MITRAL VALVE DISEASE, CHARACTERIZE MYOCARDIAL RESPONSE, AGGREGATE RISK OF FUTURE COMORBIDITY AND, IN TURN, IDENTIFY INTERVENABLE TARGET FOR MITIGATING FUTURE CVD RISK. THUS, WE HYPOTHESIZE THAT AI METHODS APPLIED TO ECHOCARDIOGRAPHY CAN BE USED TO NOT ONLY PRECISELY CHARACTERISTICS MITRAL VALVE DISEASE BY (I) AUTOMATING THE PHENOTYPING OF MITRAL REGURGITATION SEVERITY, SYSTOLIC DYSFUNCTION, DIASTOLIC PARAMETERS, AND OTHER MEASURES OF ADVERSE MYOCARDIAL RESPONSE THAT DEMONSTRATE TRAJECTORIES OF ACCELERATED VERSUS DELAYED CARDIOVASCULAR RISK, (II) DISCERN KEY CONTRIBUTORS TO ACCELERATED CARDIOVASCULAR RISK IN MITRAL VALVE DISEASE, AND (III) BE USED ON LARGE CLINICAL COHORTS TO IDENTIFY CLINICAL UNDERDIAGNOSIS. TO TEST THESE HYPOTHESES, WE WILL LEVERAGE ECHOCARDIOGRAPHY IMAGES THAT ARE ACQUIRED AS A PART OF ROUTINE CLINICAL CARE IN ADDITION TO SERIAL IMAGING FREQUENTLY OBTAINED IN LARGE COHORT STUDIES OF AGING ADULTS. BECAUSE HEALTHCARE COHORTS ARE ENRICHED FOR PATIENTS WITH ACCELERATED AND HIGH RISK TRAJECTORIES, WHILE EPIDEMIOLOGIC COHORTS ARE ENRICHED FOR INDIVIDUALS WITH DELAYED AND LOW RISK TRAJECTORIES, WE PLAN TO ANALYZE IMAGING AND OUTCOMES DATA COLLECTED FROM BOTH TYPES OF COHORTS. ACCORDINGLY, OUR AIMS ARE TO TRAIN AND VALIDATE AI MODELS ON PHENOTYPING MITRAL VALVE DISEASE FROM CARDIAC IMAGING AND IDENTIFY ITS COMPONENT CONTRIBUTORS TO EXCESS CARDIOVASCULAR RISK IN BOTH THE HEALTHCARE SETTING AND IN THE COMMUNITY SETTING.

MONOCYTE PRODUCTION BY BONE MARROW PROGENITORS

COMMUNITY-BASED EVALUATION OF SUDDEN CARDIAC DEATH IN HISPANICS/LATINOS

ROLE OF LMPTP IN CARDIAC FIBROSIS

COMMUNITY CHILD HEALTH NETWORK-LOS ANGELES

MUSCLE-DERIVED GDNF: A GENE THERAPEUTIC APPROACH FOR PRESERVING MOTOR NEURON FUNCTION IN ALS

DIFFERENTIAL MRI IMAGING FOR BRAIN TUMOR METASTASES DIAGNOSIS AND TREATMENT MONITORING

ROLE OF PTP4A1 IN SYSTEMIC SCLEROSIS

A HYPERCHOLESTEROLEMIA-INDUCED IMMUNOMETABOLITE IN ATHEROSCLEROSIS - PROJECT ABSTRACT A MALADAPTIVE INFLAMMATORY RESPONSE TO LIPID IMBALANCE UNDERLIES THE CHRONIC VASCULAR INFLAMMATION IN ATHEROSCLEROSIS. PERSISTENT ACTIVATION OF THE INTEGRATED STRESS RESPONSE (ISR) SIGNALING IS ALSO OBSERVED IN BOTH MOUSE AND HUMAN ATHEROMA. ISR IS AN ELABORATE, HOMEOSTATIC SIGNALING ACTIVATED BY A RANGE OF CONDITIONS SUCH AS HYPOXIA, HYPERLIPIDEMIA AND ENDOPLASMIC RETICULUM (ER) AND MITOCHONDRIAL STRESS, WHICH ARE KNOWN TO PROMOTE ATHEROSCLEROSIS. SMALL MOLECULES AND GENETIC MODELS THAT PREVENT HYPERCHOLESTEROLEMIA-INDUCED ISR SIGNALING WERE SHOWN TO PREVENT ATHEROSCLEROSIS PROGRESSION, DEMONSTRATING ISR’S CAUSALITY IN ATHEROSCLEROSIS DEVELOPMENT. DESPITE REGULATING LIPID-INDUCED STERILE INFLAMMATION, THEREBY REPRESENTING A NOVEL THERAPEUTIC OPPORTUNITY IN CARDIOVASCULAR DISEASE (CVD), THERAPEUTIC TARGETING OF A HOMEOSTATIC PATHWAY SUCH AS ISR IN A CHRONIC DISEASE IS NOT WITHOUT ITS CHALLENGES. DECIPHERING THE DETAILED MECHANISMS BY WHICH ISR GOVERNS MACROPHAGE IMMUNOMETABOLISM AND ATHEROGENESIS CAN PAVE THE WAY TO EFFECTIVE AND SPECIFIC THERAPEUTIC STRATEGIES IN CVD WHILE ESCAPING TOXICITY THAT MAY BE ASSOCIATED WITH TARGETING HOMEOSTATIC SIGNALING. WE MADE THE STRIKING DISCOVERY THAT ISR INHIBITION IN HYPERCHOLESTEROLEMIC MICE LEADS TO INCREASED 5- HYDROXYMETHYLCYTOSINE (5-HMC) TO 5-METHYLCYTOSINE (5-MC) RATIO IN MACROPHAGES AND PLAQUES WHILE REDUCING IL-1B AND ATHEROSCLEROSIS PROGRESSION. THE OXIDATION OF 5-MC TO 5-HMC IS CATALYZED BY TEN ELEVEN TRANSLOCATION (TET) FAMILY OF METHYLCYTOSINE DIOXYGENASES, SOMATIC MUTATIONS IN WHICH ARE ASSOCIATED WITH CORONARY HEART DISEASE AND EARLY-ONSET MYOCARDIAL INFARCTION (MI). THE INACTIVATION OF TET-2 IN MICE PROMOTES ATHEROSCLEROSIS PROGRESSION AND CARDIAC DYSFUNCTION. OUR ROBUST PRELIMINARY DATA SHOWS THAT HYPERCHOLESTEROLEMIA INDUCES 2- HYDROXYGLUTARATE (2HG), A POTENT TET INHIBITORY METABOLITE, IN AN ISR-DEPENDENT MANNER. FURTHERMORE, SUPPLEMENTATION WITH A-KETOGLUTARATE (AKG), A COFACTOR FOR TET, STIMULATES TET ACTIVITY WHILE INHIBITING IL-1B SECRETION IN MOUSE AND HUMAN MACROPHAGES. AKG SUPPLEMENTATION IN A SMALL GROUP OF HYPERCHOLESTEROLEMIC MICE PREVENTED INFLAMMATION WHILE REVERSING TET INHIBITION. BUILDING ON THE INSIGHT GAINED THROUGH OUR ROBUST PRELIMINARY STUDIES AND INCORPORATING ADDITIONAL EVIDENCE FROM LITERATURE, WE HYPOTHESIZE THAT HYPERLIPIDEMIA- INDUCED ISR SIGNALING GENERATES AN IMMUNOMETABOLITE THAT CAN PROMOTE MACROPHAGE INFLAMMATORY RESPONSE AND ATHEROSCLEROSIS. WE PROPOSE TO INVESTIGATE ATF4’S ROLE IN REGULATING MACROPHAGE IMMUNOMETABOLISM AND PROMOTING ATHEROSCLEROSIS IN VIVO. WE WILL ALSO INVESTIGATE THE CONSEQUENCES OF MODULATING 2HG LEVELS IN MYELOID CELLS ON INFLAMMATION AND ATHEROSCLEROSIS IN HYPERCHOLESTEROLEMIC MICE. THE COMPLETION OF THE PROPOSED STUDIES WILL ILLUMINATE THE METABOLIC AND EPIGENETIC CONSEQUENCES FOR ISR SIGNALING IN MACROPHAGES ON STERILE INFLAMMATION AND ATHEROSCLEROSIS DEVELOPMENT. THE NEW KNOWLEDGE GAINED THROUGH THESE STUDIES COULD PAVE THE WAY FOR THE DEVELOPMENT OF EFFECTIVE AND SPECIFIC THERAPEUTIC STRATEGIES TO ANTAGONIZE ISR SIGNALING COMPONENTS THAT PROMOTE STERILE INFLAMMATION AND DRIVE ATHEROSCLEROSIS PROGRESSION.

BASAL CELLS IN AIRWAY AND ALVEOLAR REMODELING - ABSTRACT ACUTE RESPIRATORY VIRAL INFECTIONS REPRESENT AN ENORMOUS SOCIETAL AND ECONOMIC BURDEN WITH THE POTENTIAL FOR PERSISTENT DECLINES IN LUNG FUNCTION AMONG RECOVERING PATIENTS. SEVERE INFECTIONS TRIGGER ABNORMAL REPAIR PROCESSES AND INFLAMMATION LEADING TO REMODELING OF SMALL AIRWAYS AND ALVEOLI, IMPAIRED PULMONARY FUNCTION AND DEATH IN PARTICULARLY SUSCEPTIBLE INDIVIDUALS. THESE FEATURES OF LUNG INJURY, REPAIR AND REMODELING OF SMALL AIRWAYS AND ALVEOLI, ARE RECAPITULATED IN MOUSE MODELS OF H1N1 INFLUENZA (PR8) VIRUS INFECTION, WHEREIN ALVEOLAR INJURY LEADS TO EXPANSION OF BASAL CELLS (BC) IN AIRWAYS AND REPLACEMENT OF DAMAGED ALVEOLAR EPITHELIUM. IN PRELIMINARY STUDIES WE PROVIDE EVIDENCE THAT NASCENT BC ARE DERIVED FROM A SEROUS-LIKE SUBSET OF AIRWAY SECRETORY CELLS (INTRALOBAR SEROUS OR IS). WE HAVE IDENTIFIED AN UNEXPECTED ROLE FOR TAP63 IN THE SPECIFICATION OF NASCENT BC AND THAT LCN2 EXPRESSION BY “ACTIVATED” AT2 CELLS OF THE PR8-INFECTED LUNG CONTRIBUTES TO BC RECRUITMENT TO INJURED ALVEOLI. FINALLY, WE SHOW THAT RECRUITMENT OF NASCENT BC TO DAMAGED ALVEOLAR REGIONS IMPACTS THE PROLIFERATIVE ACTIVITY AND CLONAL BEHAVIOR OF SURVIVING ALVEOLAR TYPE 2 (AT2) CELLS. AIMS OF THIS PROPOSAL SEEK TO TEST THE OVERARCHING HYPOTHESIS THAT PR8-ELICITED NASCENT BC THAT ULTIMATELY COLONIZE DAMAGED ALVEOLAR REGIONS ARE DERIVED FROM IS CELLS THROUGH A FATE TRANSITION THAT IS REGULATED BY TAP63. FURTHERMORE, WE HYPOTHESIZE THAT AT2-DERIVED LCN2 MEDIATES BC RECRUITMENT TO INJURED ALVEOLI WHERE THEY REGULATE LOCAL WNT SIGNALING AND INHIBIT AT2 CELL PROLIFERATION. AIM 1 WILL EXAMINE THE ROLE OF TAP63 AND ITS DOWNSTREAM TARGETS IN IS>BC SPECIFICATION FOLLOWING PR8-INDUCED LUNG INJURY. AIM 2 WILL INVESTIGATE ROLES FOR AT2-DERIVED LCN2 IN RECRUITMENT OF PR8-ELICITED BC TO INJURED ALVEOLI. AIM 3 WILL TEST THE HYPOTHESIS THAT NASCENT BC RECRUITED TO SITES OF PARENCHYMAL INJURY SUPPRESS THE REGENERATIVE CAPACITY OF SURVIVING AT2 CELLS AND WILL EXPLORE ROLES FOR BC- DERIVED WNT LIGANDS IN THIS PROCESS. COMPLETION OF THESE AIMS WILL PROVIDE NEW INSIGHTS INTO CELLULAR AND MOLECULAR MECHANISMS OF REPAIR IN ACUTE LUNG INJURY AND HOW PERSISTENT ACTIVATION OF THESE REPAIR PATHWAYS MIGHT CONTRIBUTE TO TISSUE REMODELING IN LUNG DISEASE.

A MICROPHYSIOLOGIC MULTICELLULAR ORGAN-ON-CHIP TO INFORM CLINICAL TRIALS IN FTD/ALS - PROJECT SUMMARY/ABSTRACT FRONTOTEMPORAL DEMENTIA (FTD) IS A COMMON DEMENTIA SYNDROME IN PATIENTS UNDER AGE 65, WHILE AMYOTROPHIC LATERAL SCLEROSIS (ALS) IS A PROGRESSIVE DEGENERATION OF MOTOR NEURONS CAUSING DEATH FROM RESPIRATORY FAILURE WITHIN 3-5 YEARS. FTD AND ALS REPRESENT A SPECTRUM OF NEURODEGENERATION, WITH SIGNIFICANT OVERLAP CLINICALLY, PATHOLOGICALLY, AND GENETICALLY. AGGREGATES OF TDP-43 ARE THE DEFINING PATHOLOGY OF FTD (FTLD-TDP VARIANT) AND ALS, AND THE MOST COMMON GENETIC CAUSE OF BOTH FTD AND ALS ARE REPEAT EXPANSIONS IN THE C9ORF72 GENE. C9ORF72 IS EXPRESSED IN MULTIPLE CELL TYPES IN THE BRAIN INCLUDING IN MICROGLIA AND NEURONS, AND THERE IS STRONG EVIDENCE THAT INTERACTION BETWEEN DIFFERENT CELL TYPES ARE NECESSARY FOR PATHOGENESIS OF FTD/ALS. WE WILL DEVELOP A MICROPHYSIOLOGIC SYSTEM (MPS) USING HUMAN INDUCED PLURIPOTENT STEM CELL (IPSC) DERIVED CORTICAL NEURONS, ASTROCYTES AND MICROGLIA ON A 3D PLATFORM THAT INCLUDES A BLOOD BRAIN BARRIER (BBB) COMPONENT TO MODEL C9-FTD/ALS FOREBRAIN ON A CHIP. OUR GOAL IN THIS PROJECT IS TO DEVELOP A HIGHLY REPRODUCIBLE AND TRANSLATABLE IN VITRO HUMAN CELL-BASED MODEL OF FTD/ALS TO DISCOVER AND VALIDATE TRANSLATABLE BIOMARKERS FOR PRECLINICAL EFFICACY TESTING, AND TO ASSIST IN PATIENT STRATIFICATION FOR CLINICAL TRIAL DESIGN. WE PROPOSE TO I) DEVELOP AND VALIDATE ROBUSTNESS OF A 3D FOREBRAIN MPS INCORPORATING CORTICAL NEURONS AND ASTROCYTES, MICROGLIA AND BRAIN MICROVASCULAR ENDOTHELIAL CELLS (BMECS) DERIVED FROM HUMAN IPSCS; II) UTILIZE FTD AND ALS PATIENT DERIVED FOREBRAIN MPS'S TO IDENTIFY DISEASE BIOMARKERS IN C9ORF72 RELATED FTD/ALS; III) CROSS VALIDATE BIOMARKERS IDENTIFIED USING CLINICAL DATA AND PATHOLOGY FROM C9-FTD/ALS PATIENTS USED TO SEED THE CHIPS, AND IV) ASSESS AND STRATIFY RESPONSES OF C9-FTD/ALS FMPS MODELS TO FIVE DIFFERENT THERAPEUTICS ENTERING EARLY PHASE CLINICAL TRIALS RANGING FROM ANTISENSE OLIGONUCLEOTIDES TO SMALL MOLECULE MODULATORS OF MITOCHONDRIAL FUNCTION, ENDOCYTIC TRAFFICKING AND CELL DEATH PATHWAYS.

A TEAM SCIENCE APPROACH TO THE CO DEVELOPMENT OF ORAL MUCOSA FOR THERAPEUTIC PURPOSES - PROJECT SUMMARY THE ORAL CAVITY SOFT TISSUES PROTECT AGAINST PATHOGENS, TOXINS, AND TRAUMA. OVER 100,000 SOFT TISSUE GRAFTS ARE PERFORMED ANNUALLY IN THE U.S. AFTER TRAUMA OR BIOPSY. CURRENT APPROACHES, INCLUDING AUTOLOGOUS GRAFTS, ALLOGRAFTS, AND XENOGRAFTS, HAVE SIGNIFICANT LIMITATIONS. AUTOLOGOUS MUCOSAL EQUIVALENTS DERIVED FROM INDUCED PLURIPOTENT STEM CELLS (IPSCS) COULD OVERCOME THESE OBSTACLES. IN THIS APPLICATION, WE PROPOSE TO BIOENGINEER VASCULARIZED, FUNCTIONAL GRAFTS THAT CAN BE TAILORED TO DIVERSE CLINICAL NEEDS. WE HAVE ASSEMBLED A TEAM WHOSE MEMBERS HAVE DEFINED THE FUNDAMENTAL PRINCIPLES OF RENEWAL IN THE ORAL MUCOSA, IDENTIFIED KEY PROGENITOR POPULATIONS IN BOTH MOUSE AND HUMAN, AND ESTABLISHED PIONEERING ADVANCES IN BIOENGINEERING TO ENABLE TRANSLATION TO PATIENTS. WE PROPOSE A GUIDED APPROACH THAT INTEGRATES SINGLE CELL/SPATIAL MULTIOMICS, DEVELOPMENTAL BIOLOGY, STEM CELL BIOLOGY, AND BIOENGINEERING TO ADDRESS THREE SPECIFIC AIMS. FIRST, WE WILL BUILD ON OUR MOLECULAR ATLAS OF ORAL TISSUES TO IDENTIFY ADDITIONAL PATHWAYS THAT REGULATE ORAL EPITHELIAL LINEAGE DECISIONS THROUGH INTERACTION WITH PERI-EPITHELIAL FIBROBLASTS. SECOND, WE WILL DEVELOP AND OPTIMIZE PROTOCOLS TO PRODUCE IPSC-DERIVED ORAL EPITHELIAL AND MESENCHYMAL POPULATIONS FOR TISSUE ENGINEERING. THIRD, WE WILL ENGINEER VASCULARIZED, AUTOLOGOUS ORAL TISSUE RUDIMENTS READY FOR SOFT TISSUE GRAFTING. AT THE END OF THE PROJECT, WE WILL HAVE GENERATED SCALABLE, VASCULARIZED, AUTOLOGOUS GRAFTS THAT MIMIC KERATINIZED AND NON-KERATINIZED MUCOSA THAT WE EXPECT TO REDUCE REJECTION AND IMPROVE OUTCOMES, POSITIONING US TO MOVE TOWARDS APPLICATIONS IN THE CLINIC.

CONTROL OF MACROPHAGE ACTIVATION IN LUNG DISEASE

MECHANISMS OF CYTOKINE DRIVEN TUMOR ELICITED INFLAMMATION IN COLORECTAL CANCER

AI-ENABLED CHARACTERIZATION OF FIBROCALCIFIC AORTIC VALVE DISEASE AND INFLAMMATION FROM CT ANGIOGRAPHY: PATIENT-SPECIFIC OUTCOME PREDICTION - PROJECT SUMMARY AORTIC STENOSIS (AS)—NARROWING OF THE AORTIC VALVE—IS THE MOST COMMON HEART VALVE DISEASE. DEGENERATION OF LEAFLETS IN AS LEADS TO VALVULAR OBSTRUCTION, THICKENING OF THE HEART MUSCLE, HEART FAILURE, AND DEATH. DUE TO AN AGING POPULATION, THE HEALTHCARE BURDEN OF AS CONTINUES TO RISE, YET IT REMAINS ONE OF THE MAJOR CARDIOVASCULAR DISEASES FOR WHICH THERE ARE NO PREVENTIVE OR DISEASE-MODIFYING TREATMENTS. CURRENTLY, THE CLINICAL STRATEGY IS WATCHFUL WAITING, UNTIL SEVERE SYMPTOMS APPEAR. AT THIS LATE STAGE, THE RISK OF DEATH RISES SIGNIFICANTLY, AND VALVE REPLACEMENT IS THE ONLY OPTION. CURRENTLY, WE LACK TOOLS TO PREDICT WHICH PATIENTS WILL EXPERIENCE A RAPID WORSENING OF THEIR CONDITION. COMPUTED TOMOGRAPHY ANGIOGRAPHY (CTA) IS INCREASINGLY USED FOR NONINVASIVE ASSESSMENT OF AS. GUIDED BY OUR PRELIMINARY STUDIES, WE PROPOSE TO DEVELOP AND VALIDATE ARTIFICIAL INTELLIGENCE (AI)-ENABLED FULLY AUTOMATED QUANTIFICATION OF FIBROTIC AND CALCIFIC AORTIC VALVE TISSUE CHARACTERISTICS FROM CTA. WE AIM TO DERIVE RADIOMIC FEATURES OF PERI-AORTIC ADIPOSE TISSUE (WHICH SERVE AS INDICATORS OF VASCULAR INFLAMMATION). WE PROPOSE TO PREDICT RAPID AORTIC VALVE DISEASE PROGRESSION, IN MEN AND WOMEN. WE WILL COMBINE CTA-MEASURED AORTIC VALVE TISSUE CHARACTERISTICS AND INFLAMMATION ALONG WITH PATIENT CLINICAL DATA, INTO A NEW INTEGRATED RISK SCORE FOR THE PREDICTION OF MORTALITY AND STROKE FOLLOWING VALVE REPLACEMENT. FOR THIS PROJECT, WE HAVE ASSEMBLED “REAL-WORLD” CLINICAL, IMAGING, AND FOLLOW-UP DATA IN 7442 PATIENTS FROM ALL STAGES OF AS—FROM PROSPECTIVE CLINICAL TRIALS AS WELL AS LARGE MULTICENTER, MULTIETHNIC PATIENT REGISTRIES. WE PROPOSE THREE SPECIFIC AIMS: (1) TO DEVELOP AND VALIDATE A FULLY AUTOMATED DEEP LEARNING ALGORITHM FOR THE CHARACTERIZATION OF FIBROTIC AND CALCIFIC AORTIC VALVE TISSUE FROM STANDARD CTA, IN COMPARISON WITH EXPERT READERS AND HISTOPATHOLOGICAL TISSUE ANALYSIS. (2) TO ASSESS THE CONCORDANCE BETWEEN FIBROCALCIFIC AORTIC VALVE TISSUE CHARACTERISTICS AND FUNCTIONAL VALVE HEMODYNAMICS BY ECHOCARDIOGRAPHY AND FURTHER, TO PREDICT RAPID AORTIC VALVE DISEASE PROGRESSION, IN MEN AND WOMEN, IN PROSPECTIVE AS CLINICAL TRIALS. (3) TO CREATE AND EXTERNALLY VALIDATE AN AI-POWERED RISK SCORE—INTEGRATING PATIENT CLINICAL DATA, FIBROTIC AND CALCIFIC AORTIC VALVE TISSUE CHARACTERISTICS, AND PERI-AORTIC VASCULAR INFLAMMATION—TO PREDICT DEATH AND STROKE WITHIN 1-YEAR POST-VALVE REPLACEMENT. THE PROPOSED WORK WILL PROVIDE, FOR THE FIRST TIME, AUTOMATED, MULTI-PARAMETRIC ASSESSMENT OF AORTIC VALVE TISSUE AND VASCULAR INFLAMMATION CHARACTERISTICS FROM STANDARD CTA. BY PREDICTING THE LIKELIHOOD OF ADVERSE OUTCOMES, THE TOOL COULD ENABLE THE CREATION OF PERSONALIZED TREATMENT AND MANAGEMENT PLANS, AND GUIDE POST- OPERATIVE MANAGEMENT, INCLUDING THE NEED FOR INTENSIVE MONITORING, MEDICATION ADJUSTMENTS, AND FOLLOW-UP APPOINTMENTS. THIS RESEARCH WILL ALLOW COMPREHENSIVE PHENOTYPING OF AS, PAVING THE WAY TO IMAGE-INFORMED CLINICAL TRIALS OF NEW THERAPIES.