Translational Genomics Research Institute

CONSORTIUM TO STUDY THE GENETICS OF LONGEVITY

THE SOUTHWEST COMPREHENSIVE CENTER FOR DRUG DISCOVERY AND DEVELOPMENT

COMBINING GENOME, FUNCTION, AND PHENOTYPE TO DEFINE THE CELL TYPE SPECIFIC GENE REGULATORY ARCHITECTURE OF IDIOPATHIC PULMONARY FIBROSIS

TARGETS TO THERAPEUTICS IN PANCREATIC CANCER

MOLECULAR ANTIBIOTIC RESISTANCE ARRAYS FOR CLINICAL MICROBIOLOGY LABORATORIES

SYSTEMATIC DEVELOPMENT OF NOVEL, DRUGGABLE CANCER TARGETS

EXTRACELLULAR VESICLE CARGO AND RISK OF NAFLD AND NASH IN LATINO YOUTH - PROJECT SUMMARY/ABSTRACT THE PREVALENCE OF PEDIATRIC NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ESCALATING IN US YOUTH, PARTICULARLY IN THOSE OF LATINO ANCESTRY. NAFLD IN CHILDREN IS ASSOCIATED WITH POOR LONG-TERM OUTCOMES, INCLUDING DIABETES, CARDIOVASCULAR DISEASE, AND HIGHER LIVER-RELATED MORBIDITY AND MORTALITY IN ADULTHOOD. DESPITE THE CLINICAL SIGNIFICANCE OF PEDIATRIC NAFLD, THE MECHANISMS UNDERLYING ITS PATHOGENESIS ARE POORLY UNDERSTOOD. THIS LACK OF KNOWLEDGE IS A MAJOR OBSTACLE TO THE DEVELOPMENT OF EFFECTIVE TREATMENT AND PREVENTION STRATEGIES. EMERGING STUDIES SUPPORT A ROLE FOR EXTRACELLULAR VESICLES (EVS) IN NAFLD. CIRCULATING EVS CAN INFLUENCE INTRACELLULAR SIGNALING, TISSUE INJURY AND REPAIR, AND MATRIX REMODELING IN LIVER CELLS. PLASMA EV LEVELS DISCRIMINATE BETWEEN ADULT PATIENTS WITH NAFLD AND NONALCOHOLIC STEATOHEPATITIS (NASH), AND ARE POSITIVELY CORRELATED WITH HISTOLOGICAL GRADE. WE CONDUCTED A SERIES OF PROOF-OF-PRINCIPLE STUDIES THAT DEMONSTRATE: 1) DISTINCTIVE PROTEIN SIGNATURES IN PLASMA EVS ISOLATED FROM LATINO CHILDREN WITH NAFLD, 2) NAFLD-SPECIFIC SIGNATURES APPROXIMATE NON-NAFLD SIGNATURES FOLLOWING LIFESTYLE INTERVENTION THAT REDUCED LIVER FAT, AND 3) ISOLATION OF HEPATOCYTE- SPECIFIC EVS SHOWED ENRICHMENT OF LIVER-SPECIFIC PROTEINS IN NAFLD. TO DATE, HOWEVER, INVESTIGATIONS OF EVS IN PEDIATRIC NAFLD ARE SCARCE, AND THE ROLE OF EV-DERIVED CARGO IN NAFLD PATHOGENESIS IN YOUTH REMAINS UNKNOWN. HERE WE PROPOSE A STRATEGY TO CHARACTERIZE THE BIOLOGICAL ROLE OF EVS IN PEDIATRIC NAFLD. IN AIM 1, WE WILL APPLY UNBIASED METHODS TO STUDY PROTEINS AND RNAS CARRIED IN CIRCULATING AND HEPATOCYTE-ENRICHED EVS TO DERIVE CHARACTERISTIC SIGNATURES ASSOCIATED WITH NAFLD AND NASH IN LATINO YOUTH. IN AIM 2, WE WILL MEASURE EV CONCENTRATION AND CONTENT IN YOUTH WITH NAFLD WHO EXPERIENCED CHANGES IN HEPATIC FAT FRACTION FOLLOWING TWO DISTINCT INTERVENTION MODALITIES (I.E., INTENSIVE LIFESTYLE AND BARIATRIC SURGERY). IMPORTANTLY IN AIM 3, WE PROPOSE A SERIES OF MOLECULAR EXPERIMENTS TO OBTAIN MECHANISTIC INSIGHT INTO THE FUNCTIONAL ASPECTS OF EV CARGO. THE COMBINATION OF THESE APPROACHES IS INNOVATIVE; AND THE STRATEGY COMPRISES A NOVEL AND SEQUENTIALLY APPROPRIATE SET OF AIMS THAT HAS NOT PREVIOUSLY BEEN USED TO ADDRESS POTENTIAL MECHANISMS OF PATHOGENESIS IN PEDIATRIC NAFLD. THE FOCUS ON CHILDREN IS ESPECIALLY IMPACTFUL DUE TO THE GROWING PREVALENCE OF NAFLD IN THIS POPULATION, THE ASSOCIATION OF PEDIATRIC NAFLD WITH POOR HEALTH OUTCOMES IN ADULTHOOD, AND THE EXPECTED FUTURE ECONOMIC BURDEN TO CARE FOR THESE INDIVIDUALS. THE FOCUS ON LATINO CHILDREN AS AN UNDERREPRESENTED YET GROWING POPULATION DEMOGRAPHIC IS CRITICAL, BECAUSE AT EVERY STAGE OF LIFE AND ALONG THE ENTIRE NAFLD SPECTRUM, LATINOS EXPERIENCE A DISPROPORTIONATE BURDEN OF DISEASE. THE IDENTIFICATION OF EV-DERIVED CARGO ASSOCIATED WITH PEDIATRIC NAFLD WILL ENHANCE OUR UNDERSTANDING OF THE BIOLOGICAL MECHANISMS CONTRIBUTING TO DISEASE PATHOGENESIS, PROVIDE A MEANS TO IMPROVE DIAGNOSTIC AND THERAPEUTIC STRATEGIES, AND IDENTIFY NEW TARGETS FOR POTENTIAL DRUG DEVELOPMENT.

PROFILING EXTRACELLULAR VESICLE CARGO IN OBESITY AND TYPE 2 DIABETES

BURKHOLDERIA: INTERNATIONAL COLLABORATIVE DEVELOPMENT OF NOVEL DIAGNOSTICS

INTEGRATIVE OMICS TO ENHANCE THERAPEUTICS DEVELOPMENT FOR HEALTHY AGING - ABSTRACT/SUMMARY A NUMBER OF DRUGS AND INTERVENTIONS HAVE BEEN IDENTIFIED THAT CURB MORBIDITIES ASSOCIATED WITH INDIVIDUAL AGE- RELATED DISEASES, AND A FEW COMPOUNDS HAVE BEEN IDENTIFIED THAT INCREASE LONGEVITY IN MICE AND OTHER NON- HUMAN SPECIES. HOWEVER, FEW, IF ANY, HAVE BEEN DEFINITIVELY SHOWN TO WORK BY SLOWING THE AGING PROCESS AND THEREBY SIMULTANEOUSLY DELAYING THE ONSET OF MULTIPLE DISEASES AND ULTIMATELY EXTENDING HUMAN LONGEVITY. THUS, CURRENT SEARCHES FOR DRUG AND INTERVENTION TARGETS THAT CAN LEAD TO THE DEVELOPMENT OF LONGEVITY- ENHANCING `GEROPROTECTORS,' I.E., INTERVENTIONS WHICH STAVE OFF MULTIPLE AGE-RELATED DISEASES AND INCREASE LONGEVITY BY SLOWING OR DISRUPTING ASPECTS OF THE AGING PROCESS, NEED TO BE IMPROVED. ONLY VERY INTEGRATED APPROACHES ARE LIKELY TO LEAD TO SUCCESSFUL SEARCHES GIVEN THE NEED TO RECONCILE COMPLEXITIES SURROUNDING THE PATHOGENESIS OF AGE-RELATED DISEASES WITH PROCESSES CONTRIBUTING TO THE SYNCHRONIZED DECAY OF MULTIPLE SYSTEMS THAT DEFINES AGING. WE BELIEVE THAT SUCH INTEGRATION CAN BE ACHIEVED PRACTICALLY BY: 1. PURSUING MULTIPLE HUMAN LONGITUDINAL STUDIES FOCUSING ON THE DISCOVERY OF METABOLITES AND PROTEINS ASSOCIATED WITH A BIOLOGICALLY-COMPELLING DEFINITION OF SLOW AND HEALTHY HUMAN AGING IN DIFFERENT TISSUES; 2. EXPLOITING NOVEL CROSS- SPECIES LONGEVITY STUDIES INVOLVING MULTIPLE TISSUES TO OBTAIN INSIGHTS INTO CONSERVED PATHWAYS IMPACTING LONGEVITY WHOSE ELEMENTS MAY BE CONSISTENT WITH FACTORS DISCOVERED IN HUMAN STUDIES AND HENCE VALIDATE THEM AS TRULY RELATED TO LONGEVITY AND NOT JUST DISEASE; AND 3. AGGREGATING DATA ARISING FROM ITEMS 1-2 ALONG WITH RELEVANT AVAILABLE PUBLIC DOMAIN DATA TO GENERATE/VALIDATE HYPOTHESES, IN ADDITION TO PURSUING A GWAS TO IDENTIFY PROTECTIVE FACTORS FOR DISEASE AND USING NOVEL STATISTICAL AND INFERENTIAL METHODS. OUR PROPOSED STUDIES ARE SOME OF THE FIRST TO CHAMPION THE NOTION THAT THE `TRIANGULATION' OF DISPARATE SCIENTIFIC STUDIES AND DISCOVERIES, I.E., THE ATTEMPT TO UNIFY RESULTS FROM DIFFERENT STUDY DESIGNS BASED ON THEIR BIOLOGICAL COHERENCE, IS THE OPTIMAL WAY TO ADVANCE IDENTIFICATION OF HUMAN TARGETS FOR LONGEVITY-ENHANCING GEROPROTECTIVE DRUGS AND INTERVENTIONS. IMPORTANTLY, ALTHOUGH WE BELIEVE THAT EACH OF THE INDIVIDUAL STUDIES WE ARE PROPOSING IS ITSELF POWERFUL ENOUGH TO IDENTIFY POTENTIAL GEROPROTECTOR TARGETS, THEIR COLLECTIVE AND INTEGRATED USE WITH NOVEL ANALYTIC METHODS WILL HAVE UNPRECEDENTED POWER AND PROVIDE A PARADIGM FOR ANTI-AGING DRUG DISCOVERY RESEARCH WITHIN THE ACADEMIC COMMUNITY. FOR EXAMPLE, WE ARE PROPOSING THE FIRST HUMAN LONGITUDINAL STUDY TO SEARCH FOR DRUGGABLE FACTORS ASSOCIATED WITH THE EPIGENETIC CLOCK AND OTHER VALIDATED MEASURES OF THE AGING RATE/HEALTHY AGING IN THOUSANDS OF INDIVIDUALS; THE LARGEST METABOLOMICS AND PROTEOMIC CROSS-SPECIES MULTI- TISSUE STUDY (N=60 SPECIES) OF FACTORS ASSOCIATED WITH LIFESPAN; THE LARGEST HUMAN LONGITUDINAL COMPARATIVE TISSUE STUDY OF AGING EXPLORING BLOOD, MUSCLE, FAT AND SKIN SAMPLES; AND THE LARGEST STUDY OF AGGREGATED DATA FROM PUBLIC DOMAIN SOURCES FOR ASSOCIATION ANALYSES INCLUDING STANDARD GWAS AND A UNIQUE POLYGENIC RISK SCORE-BASED HEALTHY GENOME GWAS.

HIGH-RESOLUTION, VIROME-WIDE INFECTION ANALYSIS IN TYPE 1 DIABETES BIRTH COHORTS - PROJECT ABSTRACT/SUMMARY TYPE 1 DIABETES (T1D) AFFECTS >20 MILLION PEOPLE GLOBALLY, CAUSING LIFE-LONG DEPENDENCY ON EXOGENOUS INSULIN AND REDUCED LIFE EXPECTANCY. ALTHOUGH THE DISEASE HAS A STRONG GENETIC BASIS, A SUBSTANTIAL FRACTION OF RISK IS NOT EXPLAINED BY GENETIC FACTORS ALONE, AND NEITHER IS THE MARKED INCREASE IN T1D INCIDENCE OVER RECENT DECADES. THE IDENTIFICATION OF ENVIRONMENTAL DETERMINANTS OF T1D IS IMPORTANT BECAUSE IT CAN REVEAL UNDERLYING MECHANISMS OF PATHOGENESIS AND HIGHLIGHT INTERVENTION STRATEGIES THAT MAY BE DEVELOPED AND/OR DEPLOYED FOR HIGH-RISK SUBJECTS. WHILE INFECTION BY PARTICULAR VIRUSES HAS LONG BEEN POSTULATED AS A RISK FACTOR FOR T1D, PRIOR STUDIES IN THIS AREA HAVE BEEN LIMITED IN THEIR POWER AND/OR BREADTH, WITH MANY INVESTIGATING RELATIVELY SMALL CROSS-SECTIONAL COHORTS. LARGE, PROSPECTIVE, LONGITUDINAL STUDIES – INCLUDING TEDDY (IN THE US / EUROPE) AND ENDIA (IN AUSTRALIA) – OFFER OPPORTUNITIES TO OVERCOME THESE LIMITATIONS, HOWEVER EXISTING VIRAL ANALYSES OF THESE COHORTS HAVE SO FAR BEEN LIMITED IN THEIR RESOLUTION (FOCUSED ON INFECTIONS DEFINED SYMPTOMATICALLY) AND/OR SENSITIVITY (RELYING ON THE DIRECT DETECTION OF VIRUSES AT THE TIME/SITE OF INFECTION). IN THIS PROJECT, WE WILL OVERCOME THESE LIMITATIONS BY USING AN INNOVATIVE TECHNOLOGY (“PEPSEQ”) TO PERFORM A FIRST-IN-CLASS, LONGITUDINAL, VIROME- WIDE SEROLOGY-BASED ANALYSIS OF THE TEDDY AND ENDIA COHORTS. PEPSEQ USES PROGRAMMABLE, HIGHLY- MULTIPLEXED LIBRARIES OF DNA-BARCODED PEPTIDES TO ENABLE VIROME-WIDE SEROLOGY AT EPITOPE-LEVEL RESOLUTION. WE RECENTLY SHOWED THAT PEPSEQ CAN BE COMBINED WITH LONGITUDINAL SAMPLING AND AN INNOVATIVE ANALYSIS ALGORITHM (PSEA) TO ENABLE THE DETECTION OF TEMPORALLY-RESOLVED, VIROME-WIDE INFECTION EVENTS AT SUBSPECIES RESOLUTION. BUILDING DIRECTLY ON THIS WORK, WE WILL USE PEPSEQ+PSEA TO STUDY ~14,000 LONGITUDINAL PLASMA SAMPLES FROM TEDDY+ENDIA CASE/CONTROL SUBJECTS AND COMPREHENSIVELY CATALOG THE TIMING AND IDENTITY OF VIRAL INFECTION EVENTS. WE WILL BEGIN BY EXTENDING OUR EXISTING PEPSEQ HUMAN VIROME LIBRARY (WHICH IS ALREADY CAPABLE OF SUBSPECIES RESOLUTION) TO ENABLE HIGHLY-CONTROLLED COMPARISONS ACROSS ~600-700 VIRUS SUBTYPES (AIM 1). NEXT, WE WILL TEST WHETHER AND WHEN THESE VIRUSES ARE ASSOCIATED WITH AUTOIMMUNITY IN CASES VS. MATCHED CONTROLS, USING SELECTED LONGITUDINAL SAMPLES FROM (I) THE FIRST YEAR OF LIFE, (II) THE YEAR PRECEDING THE ONSET OF T1D/IA, AND (III) MOTHERS DURING PREGNANCY. OVERALL, OUR APPROACH COMBINES THE POWER OF LONGITUDINAL SAMPLING (TO ESTABLISH A TEMPORAL LINK WITH AUTOIMMUNITY), THE SENSITIVITY OF SEROLOGY (TO DETECT INFECTIONS ACROSS ALL BODY SITES) AND THE BREADTH AND RESOLUTION OF PEPSEQ (USING 10,000S OF PEPTIDES TO ADDRESS THE VIROME COMPREHENSIVELY AND AT SUBSPECIES RESOLUTION). TOGETHER, THESE INNOVATIONS HAVE THE POTENTIAL TO REVEAL VIRAL ASSOCIATIONS WITH AUTOIMMUNITY THAT COULD NOT HAVE BEEN DETECTED WITH PREVIOUS, LESS POWERED APPROACHES. MOREOVER, BY GENERATING THE LARGEST KNOWN LONGITUDINAL DATASET OF VIROME-WIDE, SUBTYPE-RESOLVED INFECTION EVENTS IN TWO HIGHLY-CHARACTERIZED BIRTH COHORTS, THIS PROJECT WILL ENABLE FUTURE STUDIES FOCUSED ON THE NATURAL HISTORY AND CONSEQUENCES OF VIRAL INFECTIONS DURING ONTOGENY.

RON KINASE AS A MULTIFACETED THERAPEUTIC TARGET FOR METASTATIC BREAST CANCER

A SCALABLE PLATFORM FOR HIGHLY-MULTIPLEXED ANALYSIS OF ANTIBODY REACTIVITY FROM <1UL OF BLOOD

EPIGENETIC MARKERS OF SEVERITY IN NONALCOHOLIC FATTY LIVER DISEASE

EXRNA SIGNATURES PREDICT OUTCOMES AFTER BRAIN INJURY

INTEGRATED ANALYSIS OF MULTI-OMIC QTLS AT SINGLE CELL RESOLUTION - PROJECT SUMMARY NOVEL STATISTICAL AND COMPUTATIONAL TOOLS HAVE ENABLED THE BROAD ADOPTION OF GENOMICS TECHNOLOGIES AND SERVED AS THE FOUNDATION FOR THE MODERN AGE OF HUMAN GENOMICS. INDEED, THE RECENT ADVENT AND POPULARITY OF SINGLE CELL GENOMICS PLATFORMS – MOST NOTABLY SINGLE CELL RNA SEQUENCING (SCRNA-SEQ) – HAS LED TO A PROLIFERATION OF SINGLE- CELL DATA PROCESSING, QC, AND ANALYSIS FRAMEWORKS. HOWEVER, TO FULLY REALIZE THE PROMISE OF SINGLE CELL GENOMICS APPROACHES WE NEED TO CONNECT CELL-TYPE LEVEL REGULATORY PHENOTYPES WITH COMPLEX DISEASE. THE MOST PROMISING APPROACH TO THIS CHALLENGE IS TO IDENTIFY FUNCTIONALLY RELEVANT GENETIC VARIATION BY MAPPING QUANTITATIVE TRAIT LOCI (QTLS). INDEED, STUDIES IDENTIFYING REGULATORY VARIATION ASSOCIATED WITH A NUMBER OF REGULATORY PHENOTYPES, INCLUDING BUT NOT LIMITED TO GENE EXPRESSION (EQTLS), DNA METHYLATION (MEQTLS), CHROMATIN ACCESSIBILITY (CAQTLS), AND PROTEIN (PQTLS), HAVE BEEN CARRIED OUT EXTENSIVELY IN BULK SAMPLES. THESE STUDIES HAVE ADVANCED OUR UNDERSTANDING OF THE MOLECULAR UNDERPINNINGS OF COMPLEX DISEASE, BUT THE LACK OF GRANULARITY PROVIDED BY BULK ANALYSES CONTINUES TO HINDER PROGRESS. AS WE MOVE THESE APPROACHES TOWARDS THE CELL-TYPE LEVEL ANALYSES ENABLED BY SINGLE CELL GENOMICS IT HAS BECOME CLEAR THAT THE METHODS DEVELOPED FOR BULK SAMPLES ARE NOT WELL SUITED TO HANDLE THE COMPLEXITY AND SPECIFIC CHARACTERISTICS OF SINGLE CELL DATA; OR INDEED TO TAKE FULL ADVANTAGE OF THE RESOLUTION AND RICHNESS OF SINGLE CELL DATA. HERE WE PROPOSE DEVELOPING, VALIDATING, AND DEPLOYING METHODS FOR MAPPING QTLS USING DATA FROM SINGLE CELL `OMICS TECHNOLOGIES. WE BELIEVE IT IS CRITICALLY IMPORTANT TO BUILD THESE METHODS USING RELEVANT DATA OBTAINED FROM PRIMARY HUMAN TISSUE IN A DISEASE STATE. THUS, WE WILL JOINTLY COLLECT SCRNA-SEQ, SCATAC-SEQ AND SINGLE CELL PROTEIN LEVELS FROM TWO TISSUE TYPES: LUNG AND PERIPHERAL BLOOD COLLECTED FROM PATIENTS WITH PULMONARY FIBROSIS (PF) OR HEALTHY CONTROLS. THIS DATA COLLECTION WILL BE FACILITATED BY OUR EXISTING BIOREPOSITORY AND BUILD UPON OUR EXPERTISE BUILDING TOOLS FOR ANALYZING GENOMIC DATA, MAPPING QTLS FOR REGULATORY PHENOTYPES, AND ANALYZING SCRNA-SEQ COLLECTED FROM LUNG TISSUE FROM PATIENTS WITH PF. USING THESE DATA WE WILL BUILD METHODS FOR UNIVARIATE SCQTL MAPPING, MULTI-OMIC SCQTL MAPPING, THE IDENTIFICATION OF CONTEXT SPECIFIC SCQTLS, AND INTEGRATION OF SCQTL RESULTS WITH THE RESULTS FROM GWAS STUDIES. THESE METHODS WILL BE RELEASED AS OPEN-SOURCE SOFTWARE PACKAGES ENABLING BROAD ADOPTION BY THE FIELD. OUR TEAM BRINGS TOGETHER UNIQUE EXPERTISE IN STATISTICAL GENOMICS, COMPUTATIONAL BIOLOGY, FUNCTIONAL GENOMICS, SINGLE CELL GENOMICS, AND DISEASE SPECIFIC EXPERTISE IN PF MAKING US PARTICULARLY WELL SUITED TO CARRY OUT THIS WORK.

GENETIC DETERMINANTS OF NAFLD SEVERITY AND PROGRESSION

MICROARRAY CENTER FOR RESEARCH ON THE NERVOUS SYSTEM

GENETIC DETERMINANTS OF TOTAL CHOLESTEROL LEVELS IN AMERICAN INDIANS

A LARGE-SCALE EXTRACELLULAR VESICLE RNA-SEQ RESOURCE FOR PARKINSONS DISEASE - PROJECT SUMMARY/ABSTRACT PARKINSON'S DISEASE (PD) IS A DEVASTATING AND PROGRESSIVE NEUROLOGICAL DISEASE THAT IMPACTS 6 MILLION PEOPLE WORLDWIDE. THE LACK OF VALIDATED BIOMARKERS OF PD HAS HAMPERED IMPROVEMENTS IN PREDICTING DISEASE PROGRESSION, IDENTIFYING NEW PATHWAYS FOR THERAPEUTIC DEVELOPMENT, AND PATIENT STRATIFICATION TOWARD RATIONAL CLINICAL TRIAL DESIGN. RECENT ADVANCEMENTS IN THE CAPTURE AND CHARACTERIZATION OF EXTRACELLULAR, CIRCULATING RNAS (EXRNAS) HAVE SPURRED THE IDENTIFICATION OF DISEASE MECHANISMS, THERAPEUTIC TARGET ENGAGEMENT, AND BIOMARKER DISCOVERY IN NEUROLOGICAL DISEASES. EXTRACELLULAR VESICLES (EVS), WHICH CAN TAKE PIECES OF CELLULAR CARGO AND MAKE THEIR WAY INTO CIRCULATION, OFFER A UNIQUE OPPORTUNITY TO MONITOR RNA CHANGES IN PATIENTS LIVING WITH PD. OUR TEAM HAS HELPED TO MATURE THE CAPTURE AND CHARACTERIZATION OF EVS TOWARDS DEPLOYMENT FOR MONITORING DISEASE – USING STRATEGIES THAT CAN LOOK AT THE CARGO FROM THE TOTAL EV POPULATION AS WELL AS EVS DERIVED FROM SPECIFIC BRAIN CELL TYPES AFFECTED BY DISEASES LIKE PD. THE LONGITUDINAL COLLECTION OF THOUSANDS OF SAMPLES, WITH EXTENSIVE PHENOTYPING FROM HUNDREDS OF PATIENTS IN THE AMP-PD COHORTS, OFFERS AN UNPRECEDENTED OPPORTUNITY TO DEVELOP A COMPREHENSIVE RESOURCE, THAT CAN EASILY BE ACCESSED AND UTILIZED BY THE PD RESEARCH COMMUNITY. WE HYPOTHESIZE THAT DIRECTLY ISOLATING DISEASE-RELEVANT CHANGES IN RNA FROM PLASMA WILL PROVIDE IMPORTANT BIOMARKER CANDIDATES FOR PD. THE PURPOSE OF THIS PROPOSAL IS TO DEVELOP A COMPREHENSIVE, PLASMA-BASED, EXRNA RESOURCE THAT CAN EASILY BE ACCESSED AND UTILIZED BY THE PD RESEARCH COMMUNITY. THE RESULTING DATA WILL BE DEPOSITED IN THE ACCELERATED MEDICAL PARTNERSHIPS FOR PARKINSON'S DISEASE (AMP-PD) KNOWLEDGE PORTAL. OUR SPECIFIC AIMS ARE TO 1) ISOLATE AND CHARACTERIZE RNA ALTERATIONS FROM BRAIN-DERIVED EVS FROM PD PATIENT PLASMA AND AGE-MATCHED NON-PD CONTROLS; 2) MEASURE EXRNAS ISOLATED FROM THE TOTAL EV POPULATION IN PLASMA FROM PD PATIENTS AND AGE-MATCHED, NON-PD CONTROLS; AND 3) UNIFORMLY AND COMPREHENSIVELY SEQUENCE THE LONG RNA FROM CAPTURED EVS FOR DATA ANALYSIS AND DEPOSITION IN AMP-PD KNOWLEDGE PORTAL. THE APPROACH PROPOSED IN THIS STUDY IS AT THE LEADING EDGE OF THE EV FIELD, EXRNA DETECTION, AND ANALYSIS. SUCCESSFUL COMPLETION OF THE WORK WILL HAVE EMPLOYED INNOVATIVE APPROACHES IN EV CAPTURE, SEQUENCING, AND ANALYSES TO DEVELOP A COMPREHENSIVE RESOURCE THAT ENABLES FUTURE SCIENTIFIC INQUIRIES WITH BROAD APPLICABILITY IN BIOMARKER DISCOVERY AND VALIDATION IN PD.

CANINE HEREDITARY CANCER CONSORTIUM: FROM BARK TO BEDSIDE

CANINE HEREDITARY CANCER CONSORTIUM: FROM BARK TO BEDSIDE

HIGHLY PARALLEL SUPERCOMPUTING FOR TRANSLATIONAL RESEARCH

TARGETING STROMAL COLLAGEN IN PANCREATIC CANCER

GENOMIC ANALYSIS OF COMPLEX MICROBIAL COMMUNITIES IN WOUNDS

DANGEROUS PATHOGENS DNA FORENSICS AND MOLECULAR EPIDEMIOLOGY

RAPID EMERGENCE OF LIVESTOCK-ASSOCIATED MRSA ST398: HOST-ADAPTATION & VIRULENCE

GENOMIC DISSECTION OF STRUCTURAL MUTATIONS FOLLOWING TELOMERE DYSFUNCTION IN GLIOBLASTOMA CELLS AND PATIENTS

TARGETING THE FN14-RAC1 SIGNALING PATHWAY IN INVASIVE GLIOMAS

GENETIC DETERMINANTS OF LIPID TRAITS IN TYPE 2 DIABETES MELLITUS

INTEGRATED MOLECULAR PATHOGENESIS OF PULMONARY FIBROSIS

DATA PROCESSING AND VISUALIZATION FOR 1000 GENOMES

GENETIC VARIATION IN KIBRA AND ITS ROLE IN HUMAN EPISODIC MEMORY

CATT: DEVELOPMENT AND APPLICATION OF A NEURONAL CELL ACTIVITY-TAGGING TOOLBOX

REAL-TIME PCR ASSAYS /DIRECT DETECTION OF SEPSIS /CAP PA

THE PURPOSE OF THIS AWARD IS TO ADDRESS GAPS IN SURVEILLANCE AND INVESTIGATION ACTIVITIES FOR SARS-COV-2 IN ANIMALS, INCLUDING FARMED ANIMALS, CAPTIVE WILDLIFE, FREE-RANGING WILDLIFE, AND COMPANION ANIMALS.THIS WORK AIMS TO ENHANCE SURVEILLANCE FOR SARS-COV-2 IN DOGS TO CHARACTERIZE THESE RISK FACTORS AND UNDERSTAND POTENTIAL IMPLICATIONS OF VIRAL SPREAD AT HUMAN-DOG AND DOG-ANIMAL INTERFACES. THIS PROJECT WILL ALSO FURTHER INVESTIGATE THE IMPACT OF SARS-COV-2 ON THE PERFORMANCE AND SCENT DETECTION CAPABILITIES OF WORKING DOGS TO INFORM VETERINARY AND MANAGEMENT PRACTICES THAT MAY BE UNIQUE TO THIS DOG POPULATION. IN COLLABORATION WITH VETERINARY PARTNERS, WE WILL ENROLL SEVEN UNIQUE POPULATIONS OF DOGS IN ARIZONA: A) DOGS LIVING IN TRADITIONAL HOUSEHOLD SETTINGS, B) DOGS CARED FOR BY INDIVIDUALS EXPERIENCING HOMELESSNESS, C) FARM/RANCH DOGS, D) THERAPY DOGS, E) WORKING DOGS (E.G., POLICE, SEARCH AND RESCUE, DETECTION), F) FREE-ROAMING DOGS FROM TRIBAL COMMUNITIES, AND G) DOGS LIVING IN SHELTER OR RESCUE SETTINGS. THE PROJECT WILL INCLUDE THE COLLECTION OF NASAL SWABS AND BLOOD SAMPLES FROM DOGS TO TEST FOR THE PRESENCE OF THE SARS-COV-2 VIRUS AND FOR ANTIBODIES. OU TCOMES FROM THIS PROJECT WILL BE TRANSLATED INTO TARGETED RECOMMENDATIONS (E.G., SURVEILLANCE, PREVENTION, AND MANAGEMENT STRATEGIES OF SARS-COV-2 IN DOGS) FOR PUBLIC HEALTH, VETERINARY PROFESSIONALS, AND PEOPLE INTERACTING WITH DOGS IN VARIOUS OTHER SETTINGS. THIS WORK WILL FURTHER INFORM OUR UNDERSTANDING OF HOW SARS-COV-2 IMPACTS DIFFERENT GROUPS OF DOGS AND THE RISKS SURROUNDING POTENTIAL EXPOSURES. ADDITIONALLY, WE WILL ENGAGE TRIBAL COMMUNITIES, ANIMAL SHELTER/RESCUE GROUPS, AND OTHER UNDERSERVED AUDIENCES IN THIS A ND FUTURE COLLABORATIVE MULTI-DISCIPLINARY ONE HEALTH STUDIES. RESULTS FROM THIS PROJECT WILL BE VALUABLE TO SEVERAL STAKEHOLDERS, INCLUDING PUBLIC HEALTH OFFICIALS, WILDLIFE MANAGERS, AND MEMBERS OF THE PUBLIC THAT WILL LIKELY CONTACT WILD ANIMALS. THE DATA THE PROJECT GENERATES WILL ALSO BE OF VALUE TO SCIENTIFIC RESEARCHERS IN THE FIELDS OF VIROLOGY AND VETERINARY MEDICINE. THE RECIPIENT MUST MEET THE OBJECTIVES AND DELIVERABLES STATED IN THEIR WORK PLAN AND MUST COMPLETE QUARTERLY FINANCIAL AND PERFORMANCE REPORTS AND A FINAL ACCOMPLISHMENT REPORT. DIVERSE AUDIENCES WILL BENEFIT FROM THIS WORK. THESE INCLUDE VETERINARIANS AND ANIMAL HEALTH PROFESSIONALS CARING FOR DOMESTIC CANINE POPULATIONS, PUBLIC AND TRIBAL HEALTH ENTITIES, OWNERS AND HANDLERS OF THERAPY AND RANCH/FARM DOGS, AGENCIES THAT EMPLOY WORKING DOGS, AND ANIMAL SHELTER/RESCUE STAFF. INDIVIDUALS OWNING, CARING FOR, AND INTERACTING WITH DOGS IN VARIOUS ENVIRONMENTS (E.G., HOUSEHOLDS, DUTY, TRIBAL AND CONGREGATE AND COMMUNITY SETTINGS) WILL ALSO GAIN VALUABLE INSIGHT FROM PROJECT OUTCOMES. THIS PROJECT HAS SUBAWARDS FOR TEXAS A <(>&<)>M UNIVERSITY (DR. SARAH HAMER WILL SERVE AS A CO-PI ASSISTING WITH THE EXECUTION OF OBJECTIVE 1, 2, AND 3 ACTIVITIES. DR. HAMER AND HER TEAM WILL SPECIFICALLY ASSIST WITH THE ENROLLMENT OF WORKING DOGS, AS WELL AS DATA COLLECTION, SAMPLE PROCESSING, AND ANALYSIS OF QUESTIONNAIRE DATA FROM THIS SUB-POPULATION.); MIDWESTERN UNIVERSITY COLLEGE OF VETERINARY MEDICINE (DR. RACHAEL KRIESLER WILL SERVE AS A CO-PI ASSISTING WITH THE EXECUTION OF OBJECTIVE 1 AND 2 ACTIVITIES. DR. KRIESLER LEADS THE OPERATION OF THE MOBILE UNIT; HER TEAM WILL ASSIST IN THE ENROLLMENT OF AND SAMPLE COLLECTION FROM SEVERAL SUB POPULATIONS OF DOGS INCLUDED IN THIS STUDY. ) AND FOR A VETERINARY CONSULTANT (CONTRACT VETERINARIAN TO CONSULT/ASSIST WITH SAMPLE COLLECTIONS AND DATA ANALYSIS (OBJECTIVES 1-3); 150HRS @ $150/HR )

TWEAK-FN14 HTS COMPOUND SCREENING

GENOMIC ANALYSIS OF TUMOR CONTEXT VULNERABILITIES IN HUMAN METASTATIC MELANOMA

GENOTYPIC AND PHENOTYPIC EXAMINATION OF DISEASE PATHOGENESIS IN C9ORF72 FTD

OPTIMIZATION AND NORMALIZATION STUDIES FOR CSF AS A BIOMARKER

CROSS-SPECIES ANALYSIS TO IDENTIFY CONSERVE LONGEVITY-RELATED PATHWAYS AND PUTATIVE DRUG TARGETS

"COLONIZATION AND EXTRAINTESTINAL INFECTION WITH MULTIDRUG RESISTANT E. COLI; IDENTIFYING OMMUNITY RESERVOIRS"1049

COLONIZATION AND EXTRAINTESTINAL INFECTION WITH MULTIDRUG RESISTANT E. COLI: IDENTIFYING COMMUNITY RESERVOIRS

PROSPECTIVE MOLECULAR CHARACTERIZATION OF BURN WOUND COLONIZATION: NOVEL TOOLS AND ANALYSIS

AURORA KINASES AS THERAPEUTIC TARGETS IN PANCREATIC CANCER

HEALTH CARE AND OTHER FACILITIES

PHENOTYPIC VARIABILITY IN TUBEROUS SCLEROSIS COMPLEX (TSC)

HIGH DEFINITION CLONAL ANALYSES OF ARCHIVAL PANCREATIC ADENOCARCINOMA SAMPLES

GENETIC AND EPIGENETIC STRATEGIES FOR THE ACQUISITION OF TELOMERE MAINTENANCE IN HUMAN CANCER CELLS - PROJECT SUMMARY/ABSTRACT TELOMERASE REACTIVATION IS A FUNDAMENTAL EVENT IN THE GENESIS OF NEARLY EVERY HUMAN CANCER. ALTHOUGH TRANSCRIPTIONALLY SILENT IN DIFFERENTIATED ADULT CELLS, ITS CATALYTIC COMPONENT TELOMERASE REVERSE TRANSCRIPTASE (TERT) IS EXPRESSED IN OVER 80% OF HUMAN CANCERS. DESPITE THE RECENT DISCOVERY OF REACTIVATING TERT PROMOTER MUTATIONS, VERY LITTLE IS KNOWN ABOUT MECHANISMS LEADING TO THE REACTIVATION OF TELOMERASE IN HUMAN CANCER. THIS PROPOSAL AIMS TO DETERMINE THE UNDERLYING MOLECULAR MECHANISMS REGULATING TERT EXPRESSION IN CANCER. DR. BARTHEL HAS PREVIOUSLY SHOWN THAT METHYLATION OF A REGION IN THE TERT PROMOTER WAS ASSOCIATED WITH INCREASED TRANSCRIPTION. HERE, HE WILL FUNCTIONALLY RESOLVE THAT DNA METHYLATION IS RESPONSIBLE FOR REACTIVATING TELOMERASE IN CANCER DEVELOPMENT (AIM 1). THIS AIM USES EPIGENETIC EDITING TO MEASURE THE IMPACT OF MANIPULATING DNA METHYLATION ON TELOMERASE ACTIVITY. FURTHERMORE, HE WILL ASSESS MOLECULAR MECHANISMS THAT ARE AFFECTED BY METHYLATION AT THE TERT PROMOTER (AIM 2). HE WILL DETERMINE WHETHER CHROMATIN CONFORMATION AND TRANSCRIPTION FACTOR (TF) BINDING ARE REGULATED VIA METHYLATION. FINALLY, HE WILL IDENTIFY WHAT CHANGES IN DNA METHYLATION, TF BINDING AND CHROMATIN CONFORMATION ARE ASSOCIATED WITH TELOMERASE REACTIVATION IN CANCER DEVELOPMENT (AIM 3). COLLECTIVELY, THE PROPOSED STUDIES WILL ESTABLISH THE ROLE OF METHYLATION IN REACTIVATING TELOMERASE IN CANCER AND PROVIDE INSIGHTS INTO THE NATURE OF ITS SPONTANEOUS REACTIVATION. THE LONG-TERM GOAL OF DR. BARTHEL IS TO IDENTIFY VULNERABILITIES OF TELOMERASE REACTIVATION DURING CANCER DEVELOPMENT. OVER THE COURSE OF THIS AWARD DR. BARTHEL WILL BE SUPPORTED BY HIS PRIMARY MENTOR, DR. ROEL VERHAAK, A RENOWNED COMPUTATIONAL BIOLOGIST WITH A REMARKABLE TRACK RECORD STUDYING THE MOLECULAR BIOLOGY OF CANCER. HIS CO-MENTOR, DR. ALBERT CHENG HAS PIONEERED INNOVATIVE GENETIC ENGINEERING TECHNOLOGIES. IN ADDITION, DR. BARTHEL HAS ASSEMBLED AN ADVISORY COMMITTEE THAT INCLUDES: DR. JERRY SHAY, A LEADER ON TELOMERES AND TELOMERASE IN CANCER; DR. YIJUN RUAN, AN EXPERT ON THREE-DIMENSIONAL CHROMATIN CONFORMATION; AND DR. SUNEET AGARWAL, WHO USES INDUCED PLURIPOTENT STEM CELLS TO STUDY TELOMERE DISEASE. TOGETHER, THIS MULTIDISCIPLINARY TEAM WILL ENABLE DR. BARTHEL TO SUCCESSFULLY EXECUTE THE PROPOSED EXPERIMENTS AND ADVANCE HIS PROFESSIONAL DEVELOPMENT PLAN TO FACILITATE HIS TRANSITION TO AN INDEPENDENT ACADEMIC POSITION. PILLARS OF THE PROPOSED RESEARCH SKILLS TRAINING PROGRAM INCLUDE ADVANCED TRAINING IN GENETIC ENGINEERING, CHROMATIN CONFORMATION ANALYSIS AND INDUCED PLURIPOTENCY. PROFESSIONAL DEVELOPMENT WILL FEATURE KEY ELEMENTS INCLUDING MENTORSHIP, GRANT WRITING AND LABORATORY MANAGEMENT. WORK TOWARDS THE PROPOSED PROJECT WILL PRIMARILY BE CONDUCTED AT THE JACKSON LABORATORY FOR GENOMIC MEDICINE, WHICH OFFERS ALL THE STATE-OF-THE ART FACILITIES REQUIRED FOR THE SUCCESSFUL COMPLETION OF THE AIMS IN ADDITION TO A COLLEGIAL SCIENTIFIC ENVIRONMENT. GIVEN HIS DETAILED RESEARCH PLAN, EXCELLENT ADVISORY COMMITTEE AND COMPREHENSIVE TRAINING PLAN IT IS EXPECTED THAT DR. BARTHEL WILL QUICKLY TRANSITION TO AN INDEPENDENT FACULTY POSITION THROUGH THIS AWARD.

IDENTIFICATION OF PATHOGENIC MECHANISMS IMPORTANT IN MULTIPLE SYSTEM ATROPHY

A NOVEL APPROACH FOR DEEP PHENOTYPING THE CD4 T CELL RESPONSE TO MYCOBACTERIUM TUBERCULOSIS

UNDERSTANDING THE NATURAL COCCIDIOIDES BIOAEROSOL IN TIME AND SPACE AND ITS RELATIONSHIP TO DISEASE

EPHB2 AS A PROSTATE CANCER TUMOR SUPPRESSOR AND RISK FACTOR IN AFRICAN AMERICANS

PROTEOME-WIDE DISCOVERY OF DIAGNOSTIC TARGETS FOR COCCIDIOIDOMYCOSIS - PROJECT SUMMARY ANTIBODY MEDIATED IMMUNITY HAS LONG BEEN CONSIDERED IRRELEVANT TO THE DISEASE COCCIDIOIDOMYCOSIS (CM) – AN ENDEMIC FUNGAL INFECTION IN THE SOUTHWESTERN UNITED STATES THAT CAN CAUSE SEVERE MORBIDITY AND MORTALITY. HOWEVER, NEW EVIDENCE HAS REVEALED AN IMPORTANT AND PREVIOUSLY UNAPPRECIATED ROLE FOR ANTIBODIES IN OTHER FUNGAL INFECTIONS, SUGGESTING THAT THE PREVAILING PARADIGM IS INCOMPLETE. SINCE ANTIBODIES ARE AN ATTRACTIVE TARGET FOR DIAGNOSTICS, AN IMPROVED UNDERSTANDING OF THEIR POTENTIAL IN THE SETTING OF CM IS CRUCIAL; BUT THIS REMAINS A SIGNIFICANTLY UNDER-DEVELOPED AREA OF INVESTIGATION. WE HYPOTHESIZE THAT ANTIBODIES PLAY A ROLE IN CM DISEASE COURSE AND CAN INFORM THE DEVELOPMENT OF IMPROVED AND RAPID DIAGNOSTIC ASSAYS. IN THIS PROPOSAL, WE WILL TEST THE FOLLOWING SUBSIDIARY HYPOTHESES: 1), THAT THERE ARE UNDISCOVERED IMMUNOGENIC PROTEIN TARGETS WITHIN THE COCCIDIOIDES PROTEOME; 2), THAT THESE ANTIGENIC TARGETS WILL GROUP INTO CONSERVED ANTIGEN RECOGNITION PATTERNS ACROSS PATIENTS; AND 3), THAT GENOMIC ANALYSIS OF B CELLS ISOLATED FROM CM PATIENTS WILL IDENTIFY NOVEL MONOCLONAL ANTIBODIES WHICH TARGET KNOWN AND PREVIOUSLY UNKNOWN COCCIDIOIDES PROTEINS. TO TEST THESE HYPOTHESES, WE PROPOSE TO APPLY TWO INNOVATIVE TECHNOLOGIES; FIRST WE WILL IDENTIFY NOVEL CM ANTIGENS AT PROTEOME-WIDE SCALE USING PEPSEQ, A HIGHLY-MULTIPLEXED, EPITOPE-RESOLVED SEROLOGICAL ASSAY. SECONDLY, WE WILL COMBINE NEWLY-IDENTIFIED ANTIGENS WITH KNOWN ANTIGENS TO BUILD PROBESETS FOR THE MULTIPLEXED ANALYSIS OF 100,000S OF SINGLE B CELLS FROM CM PATIENTS. THIS WILL ALLOW US TO IDENTIFY ANTIGEN/EPITOPE-SPECIFIC IGH/L CHAIN SEQUENCES AND GENERATE AND VALIDATE A DIVERSE PANEL OF NOVEL MONOCLONAL ANTIBODIES. SUCH ANTIBODIES WILL HAVE POTENTIAL AS THERAPEUTIC AND/OR DIAGNOSTIC TOOLS, TO BE DEVELOPED IN FUTURE STUDIES.

FUNCTIONAL GENOMIC ANALYSES OF EMERGING CRYPTOCOCCUS SUBTYPES IN NORTH AMERICA

DIMENSIONS: COLLABORATIVE RESEARCH: THE TAXONOMIC, GENOMIC, AND FUNCTIONAL DIVERSITY OF SOIL CARBON DYNAMICS

TARGETING CELLULAR SENESCENSE IN PANCREATIC CANCER - PROJECT SUMMARY CELLULAR SENESCENCE IS A STRESS RESPONSE THAT IMPOSES A GROWTH ARREST ON CANCER AND NONMALIGNANT CELLS DURING CANCER PROGRESSION AND/OR THERAPY. ALTHOUGH SENESCENCE IS KNOWN TO PLAY A TUMOR SUPPRESSIVE ROLE, STUDIES HAVE ALSO DEMONSTRATED THE TUMOR-PROMPTING FUNCTIONS OF SENESCENT CELLS IN THE TUMOR MICROENVIRONMENT (TME). RECENT EVIDENCE SUGGESTS THAT THE MALIGNANT BEHAVIOR OF PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) IS INFLUENCED BY A SENESCENT CELL-ASSOCIATED, STRONGLY IMMUNOSUPPRESSIVE TME. CANCER ASSOCIATED FIBROBLASTS ARE RESPONSIBLE FOR A DESMOPLASTIC REACTION SURROUNDING TUMOR GLANDS IN PDAC. PRO-FIBROTIC SENESCENT FIBROBLASTS THICKEN AND STIFFEN THE EXTRACELLULAR MATRIX; SUCH DESMOPLASTIC STIFFENING IMPEDES IMMUNE INFILTRATION AND DRUG DELIVERY. BY SECRETING A PLETHORA OF PROINFLAMMATORY GROWTH FACTORS COLLECTIVELY TERMED THE SENESCENCE- ASSOCIATED SECRETORY PHENOTYPE (“SASP”), SENESCENT CELLS CAN PROMOTE CANCER PROGRESSION AND METASTASIS. MOREOVER, THE SASP MOLECULES ARE SHOWN TO DRIVE THERAPY RESISTANCE AND MEDIATE THE ADVERSE EFFECTS OF CANCER THERAPIES. HENCE, WE HYPOTHESIZE THAT DEPLETION OF SENESCENT AND PRO-FIBROTIC CELLS IN PDAC COULD LEAD TO THE REMODELING OF TUMOR MICROENVIRONMENT AND ANTITUMOR ACTIVITY. IN THIS PROJECT WE PROPOSE TO DETERMINE THE BIOLOGICAL EFFECTS OF A SENESCENT CELL TARGETD ANTIBODY, SIWA318, AND DETERMINE ITS ACTIVITY IN IMPROVING THE EFFICACY OF STANDARD OF CARE CHEMOTHERAPY OR IMMUNE CHECKPOINT INHIBITORS (ICIS) IN PRECLINICAL MODELS FOR PDAC. TO ACHIEVE THIS GOAL, WE WILL CONDUCT STUDIES WITH THE FOLLOWING SPECIFIC AIMS: 1) TO DETERMINE THE BIOLOGICAL EFFECTS OF SIWA318 TREATMENT ON TME IN MOUSE MODELS FOR PDAC AND 2) TO DETERMINE THE ANTITUMOR ACTIVITY AND BIOLOGICAL EFFECTS OF SIWA318 IN COMBINATION WITH STANDARD OF CARE AGENTS OR AN ICI IN MOUSE MODELS FOR PDAC. THE OVERALL GOAL OF THIS PROJECT IS TO DEVELOP A SENESCENT CELL TARGETED NEW THERAPEUTIC THAT IMPROVES THE EFFICACY OF CURRENT STANDARD CARE AGENTS OR ICIS IN PDAC. IF SUCCESSFUL, IT WILL LEAD TO NOVEL THERAPIES FOR PATIENTS WITH PDAC AND VALIDATE THE APPROACH OF TARGETING SENESCENCE CELLS FOR CANCER TREATMENT, OPENING THE DOOR FOR MORE EFFECTIVE THERAPIES FOR OTHER CANCER TYPES.

GENOMIC-BASED DIAGNOSTICS FOR COCCIDIOIDES THE CAUSATIVE AGENT OF VALLEY FEVER

THE OVERARCHING LONG-TERM GOAL OF THIS PROJECT IS TO IMPROVE FOOD-BORNE DISEASE (FBD) SURVEILLANCE AND DETECTION TECHNOLOGY THAT WILL ALLOW FOR THE EVENTUAL REDUCTION AND PREVENTION OF MICROBIAL CONTAMINATION ACROSS THE COMPLETE NETWORK OF FOOD PRODUCTION, REDUCTION OF THE RECALL RATE DUE TO FOOD CONTAMINATION, AND THE ULTIMATE REDUCTION OF THE FBD BURDEN (INCLUDING THE ACCOMPANYING ANTIMICROBIAL RESISTANCE IMPACT). WE PROPOSE TO ADVANCE THE CAPACITY FOR NEXT GENERATION SURVEILLANCE OF FBD PATHOGENS ACROSS THE FOOD PRODUCTION NETWORK THROUGH THE DEVELOPMENT OF FOOD-PATH, AN ADVANCED, BUT ACCESSIBLE, AMPLICON SEQUENCING-BASED FBD SURVEILLANCE TOOL. TO ACCOMPLISH THIS WE WILL ACHIEVE THE FOLLOWING OBJECTIVES: 1) DEVELOP A HIGH-THROUGHPUT AMPLICON SEQUENCING ASSAY SYSTEM (INCLUDING AUTOMATED DATA ANALYSIS) TO DETECT FBD ORGANISMS THAT ARE RELEVANT TO BOTH FOOD SAFETY AND PUBLIC HEALTH; 2) EVALUATE THE FOOD-PATH TOOL&#39;S ABILITY TO DETECT AND CHARACTERIZE CRITICAL FBD PATHOGENS IN UPSTREAM AND DOWNSTREAM FOOD PROCESSING SAMPLES (I.E., COMPLEX MIXED GENOME SAMPLES); AND 3) EVALUATE THE ABILITY OF FOOD-PATH TO DISCERN STRAIN TYPES, SEROTYPES AND OTHER GENOTYPES WITH COMPARATIVE WHOLE GENOME SEQUENCING.

TARGETING PHD2 IN PANCREATIC CANCER

GENOMIC ANALYSIS OF TUMOR CONTEXT VULNERABILITIES IN HUMAN METASTATIC MELANOMA

MOLECULAR MECHANISMS OF PERINEURAL INVASION IN PANCREATIC CANCER

SINGLE: SIGNATURE ENABLING GLIOMA ENROLLMENT

NEUROFIBRILLARY TANGLE-INDUCED DEMENTIA IN AD

MOLECULAR CARTOGRAPHY OF INITIATING AND INFILTRATING GLIOMA CELLS USING MULTISECTOR SAMPLING AND SPATIAL TRANSCRIPTOMICS - SUMMARY DIFFUSE DISSEMINATION OF TUMOR CELLS INTO THE BRAIN IS ONE OF THE KEY PROBLEMS IMPACTING OPTIMAL TREATMENT OF GLIOMAS. WE HYPOTHESIZE THAT DISTINCT TYPES OF TUMOR CELLS HARBOR CHARACTERISTIC DIFFUSION PATTERNS. SPECIFICALLY, WE SUSPECT THAT NPC-LIKE CELLS PREDOMINATE IN THE CORTICAL LAYERS AND INTERACT WITH THE LAMINAR EXTENSION OF NEURONAL CELLS IN THE CORTEX, WHILE OPC-LIKE CELLS DOMINATE SUBCORTICALLY AND ASSOCIATE WITH AXONS AND APC-LIKE CELLS ASSOCIATE WITH VASCULAR AND IMMUNE CELLS. IN ORDER TO PROVIDE FOUR-DIMENSIONAL RECONSTRUCTIONS OF TUMOR DEVELOPMENT AND TEST OUR HYPOTHESES, WE WILL PERFORM SPATIAL TRANSCRIPTOMICS ON N = 254 IMAGE-MAPPED SAMPLES FROM N = 22 DISTINCT TUMORS (AIM 1). TUMOR-MICROENVIRONMENT INTERACTIONS WILL BE EVALUATED SEPARATELY FOR EACH PATIENT AND BY COMPARING DISTINCT LOCATIONS ACROSS PATIENTS. FINALLY, WE WILL DEVELOP AN AGENT-BASED MODEL USING N = 179 SAMPLES FROM N = 20 INDIVIDUAL WITH INTEGRATED IMAGING, DNA METHYLATION AND DNA SEQUENCING INFORMATION TO RECONSTRUCT HISTORICAL AND FORECAST FUTURE TUMOR DEVELOPMENT IN SPACE AND TIME (AIM 2). THE FINDINGS OF THESE STUDIES WILL ALLOW FOR A HIGH-RESOLUTION DISSECTION OF THE IDENTITY AND LOCATION OF ANCESTRAL STEM- LIKE TUMOR CELL POPULATIONS, AS WELL AS THE IDENTIFICATION OF SITES OF DIFFUSE INFILTRATION. A FOUR-DIMENSIONAL MODEL OF TUMOR CELL DISSEMINATION WILL ENABLE INDIVIDUALIZED LOCAL TREATMENT PLANNING AND PROGNOSTICATION.

HEALTH CARE AND OTHER FACILITIES

HEALTH CARE AND OTHER FACILITIES

FUNCTIONAL ANALYSIS OF REGIONS OF INTROGRESSION BETWEEN SPECIES OF COCCIDIOIDES

MOLECULAR PROFILES OF COLORECTAL ADENOMAS BY ARRAY CGH

DISSECTING SPATIOTEMPORAL HETEROGENEITY OF GLIOBLASTOMA EVOLUTION UNDER THERAPY - PROJECT SUMMARY: GLIOBLASTOMA (GBM) IS AN UNCURABLE FORM OF PRIMARY BRAIN TUMOR WITH EXTREMELY POOR PROGNOSIS. DESPITE MULTI- MODAL THERAPY INCLUDING SURGERY, IRRADIATION AND CHEMOTHERAPY, ALL PATIENTS EXPERIENCE TUMOR PROGRESSION. NO STANDARD OF CARE IS ESTABLISHED IN RECURRENT OR PROGRESSIVE GBM. THE IDENTIFICATION OF A NEURONAL CELLULAR STATE OF GBM AS A MORE DIFFERENTIATED STATE ENRICHED AT RECURRENCE AND PERIPHERY OF THE TUMOR PROVIDES NEW INSIGHTS INTO HOW NEURONAL ACTIVITY REGULATES TUMOR INVASION. DECONVOLUTION OF NORMAL CELL TYPES FROM SINGLE-CELL RNASEQ AND BULK TUMORS REVEALED THAT NEURONAL STATE OF GBM IS ASSOCIATED WITH HIGH INFILTRATION OF NON-MALIGNANT CELLS. THE INTRICATE SYNAPTIC COMMUNICATIONS BETWEEN NEURONS AND BRAIN TUMOR CELLS ARE CRUCIAL FOR GLIOMA PROGRESSION AND RESISTANCE TO STANDARD THERAPIES, WHICH IS SUPPORTED BY AMPLE DATA FROM THE RAPIDLY EMERGING FIELD OF “CANCER NEUROSCIENCE”. HOWEVER, THE MOLECULAR MECHANISMS DRIVING ENHANCED NEURONAL ACTIVITY AT RECURRENCE REMAINS TO BE UNDERSTOOD. DISSECTING THE SPATIOTEMPORAL DYNAMICS OF GLIOMA ECO-SYSTEM DURING EVOLUTION WILL BE NECESSARY TO IDENTIFY THERAPEUTIC VULNERABILITY OF RECURRENT GBM. HERE, PROTEOGENOMICS AND SINGLE-NUCLEI RNASEQ PROFILING OF MATCHED PRIMARY AND RECURRENT GBM IDH WILD-TYPE SUGGEST THAT THE EVOLUTIONARY TRANSITION FROM A MORE PROLIFERATIVE-PROGENITOR TOWARDS THE NEURONAL STATE IN GBM IS REGULATED BY BOTH GENETIC AND POST- GENETIC MOLECULAR EVENTS AND POTENTIAL FUNCTIONAL INTERACTIONS BETWEEN MALIGNANT AND NON-MALIGNANT CELLS. IN AIM 1, THE DEVELOPMENT OF A MULTIOMICS-BASED NETWORK DIFFUSION APPROACH WILL ENLIGHTEN SUBNETWORKS OF PROTEINS/PHOSPHO-PROTEINS SIGNIFICANTLY AFFECTED BY UPSTREAM GENETIC EVENTS DRIVING ACTIVATION OF NEURONAL PROGRAMS DURING PROGRESSION. GENERATION OF IN SILICO KNOCK-OUT NETWORKS SCREEN AND INTEGRATIVE ANALYSIS OF PROTEOMICS AND PHARMACOLOGICAL DATA OF CANCER CELL LINES WILL PRIORITIZE LETHAL AND ESSENTIAL PROTEINS IN THE SUBNETWORKS TO IDENTIFY POTENTIAL THERAPEUTIC VULNERABILITIES IN NEURONAL-RECURRENT GBM. IN AIM 2, SINGLE-NUCLEI AND SPATIAL TRANSCRIPTOMICS PROFILING OF MATCHED PRIMARY AND RECURRENT GBM IDH WILD-TYPE WILL IDENTIFY THE FUNCTIONAL CONNECTIONS BETWEEN NEURODEVELOPMENTAL TUMOR CELLULAR STATES AND CELL TYPES IN TUMOR MICROENVIRONMENT. THE DEVELOPMENT OF A SPATIAL INFORMED CELL–CELL COMMUNICATIONS ALGORITHM AND THE RECONSTRUCTION OF INTERCELLULAR SIGNALING NETWORKS WILL INFER THE KEY FUNCTIONAL INTERACTIONS BETWEEN NEURODEVELOPMENTAL TUMOR CELLULAR STATES AND CELL TYPES IN TUMOR MICROENVIRONMENT ALONG WITH THE POTENTIAL EFFECT OF THESE INTERACTIONS ON DOWNSTREAM REGULATORY MOLECULAR PATHWAYS. THESE STUDIES LAY THE FOUNDATION FOR MY FUTURE RESEARCH PROGRAM AND WILL ADVANCE THE UNDERSTANDING OF THE MOLECULAR MECHANISMS MEDIATING GLIOMA CONNECTOMES AND DRIVING GLIOMA INVASION. THESE STUDIES WILL ADVANCE THE NEUROSCIENCE FIELD THROUGH DISCOVERY OF TARGETABLE PATHWAYS AND PROTEINS PROVIDING THERAPEUTIC OPPORTUNITIES FOR RECURRENT GBM.

CHARACTERIZATION OF THE ROLE OF SUPER-ENHANCERS IN OVARIAN CANCER TREATMENT RESPONSE

CHARACTERIZING THE EFFECTS OF CIS-REGULATORY VARIATION ON PATIENT OUTCOMES AND TREATMENT RESPONSE IN MULTIPLE MYELOMA - ABSTRACT MULTIPLE MYELOMA (MM) IS A MALIGNANCY OF PLASMA CELLS AND THE SECOND MOST COMMON HEMATOLOGICAL CANCER ACCOUNTING FOR 2% OF CANCER DEATHS. MM IS ASSOCIATED WITH A POOR PROGNOSIS, AND WHILE NEW THERAPIES HAVE IMPROVED SURVIVAL RATES, MOST PATIENTS STILL EXPERIENCE RELAPSES. MM SHOWS A STRONG HEREDITARY GENETIC COMPONENT AS RELATIVES OF MM PATIENTS HAVE A TWO- TO FOUR-FOLD HIGHER RISK OF DISEASE DEVELOPMENT. MOREOVER, MM DISPLAYS A DISPARITY IN OCCURRENCE AND MORTALITY AMONG SEXES WITH MALES HAVING A HIGHER RISK THAN FEMALES. MANY RISK LOCI ASSOCIATED WITH MM SUSCEPTIBILITY IDENTIFIED BY GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND META-ANALYSIS ARE LOCATED WITHIN OR ADJACENT TO THE REGULATORY REGIONS, INDICATING A ROLE IN TRANSCRIPTIONAL REGULATION. HOWEVER, HOW THESE RISK LOCI CONTRIBUTE TO TUMOR ETIOLOGY, PROGRESSION AND OUTCOME ARE POORLY UNDERSTOOD. TO ACCELERATE THE DISCOVERY OF NOVEL TREATMENTS FOR MM PATIENTS, THE MULTIPLE MYELOMA RESEARCH FOUNDATION’S (MMRF) DEVELOPED THE LONGITUDINAL COMMPASS STUDY. THIS WORK, LED BY DR. JONATHAN KEATS AT TGEN, HAS IDENTIFIED NOVEL MM SUBTYPES USING SOMATIC MUTATION AND TRANSCRIPTION PROFILE. NEVERTHELESS, THE GENETIC ARCHITECTURE UNDERLYING GENE REGULATION CONTRIBUTING TO PATIENT OUTCOMES HAS NOT BEEN EXAMINED. USING THE COMMPASS DATA, WE IDENTIFIED 7,737 VARIANTS ASSOCIATED WITH CHANGES IN GENE EXPRESSION (EXPRESSION QUANTITATIVE TRAIT LOCUS; EQTL); AMONG THESE 1,764 ARE MALE-SPECIFIC AND 847 ARE FEMALE-SPECIFIC EQTLS. FURTHERMORE, 1,034 OF THE IDENTIFIED EQTLS ARE ASSOCIATED WITH SURVIVAL IN THE COMMPASS COHORT. HOWEVER, FUNCTIONAL VALIDATION IS NECESSARY TO CONFIRM THE REGULATORY EFFECTS AND BETTER ASSESS THE FUNCTIONAL CONSEQUENCES OF THIS VARIATION. TO THIS END, I PROPOSE USING A MULTIPLEX HIGH THROUGHPUT CRISPR ACTIVATOR/INTERFERENCE (CRISPRA/I) SCREEN FOLLOWED BY SINGLE-CELL RNA SEQUENCING TO VALIDATE THE ROLE OF PUTATIVE CIS-REGULATORY LOCI ON GENE EXPRESSION LEVELS. TO DETERMINE HOW THESE LOCI MODULATE TUMOR ETIOLOGY, I WILL PERFORM ASSAYS INVESTIGATING THE EFFECTS OF THESE PERTURBATIONS ON TUMOR FITNESS AND RESPONSE TO TREATMENT. THE PROPOSED STUDY WILL PROVIDE VALUABLE INSIGHTS INTO THE REGULATORY LANDSCAPE UNDERLYING MM OCCURRENCE, PROGRESSION, AND RESPONSE TO TREATMENT, AND POTENTIAL CANDIDATES FOR DEVELOPING MORE TARGETED TREATMENTS FOR MM PATIENTS. FURTHERMORE, THE TRAINING I WILL RECEIVE IN THIS STUDY ON CANCER GENETICS AND CANCER GENOMICS WILL OPEN UP NEW OPPORTUNITIES FOR MY FUTURE RESEARCH DIRECTIONS AS AN INDEPENDENT INVESTIGATOR.

RAPID: COMPREHENSIVE INTERACTION AND ANNOTATION (CIA) ANALYSIS OF THE SARS-COV-2 GENOME AND RELATED GENOMES

IDENTIFICATION OF NOVEL BLOOD-BASED BIOMARKERS OF ALZHEIMER'S DISEASE BY PSEUDOTIME ANALYSIS - PROJECT SUMMARY ALZHEIMER'S DISEASE (AD) IS THE MOST PREVALENT NEURODEGENERATIVE DISEASE IN UNITED STATES. CURRENT MEDICATIONS ARE ONLY EFFECTIVE AT IMPROVING THE SYMPTOMS FOR A SHORT PERIOD OF TIME AND BLOOD-BASED BIOMARKERS FOR THE DISEASE ARE ONLY RECENTLY BEGINNING TO EMERGE IN RESEARCH AND CLINICAL PRACTICE. IN THIS PROPOSAL WE AIM TO APPLY PSEUDOTIME ANALYSIS ON PUBLICLY AVAILABLE RNA PROFILING DATA TO DETECT BOTH NOVEL MOLECULAR PROCESSES IN BRAIN TISSUE AND BLOOD-BASED RNA BIOMARKERS ASSOCIATED WITH AD PROGRESSION. PSEUDOTIME ALGORITHMS ARE MACHINE LEARNING APPROACHES CAPABLE OF EXTRACTING LATENT TEMPORAL INFORMATION TO ORDER SAMPLES ALONG A PSEUDOTEMPORAL PROGRESSION. THESE APPROACHES UTILIZE CROSS-SECTIONAL DATA WITHOUT THE NEED OF DISEASE STAGE INFORMATION OR LONGITUDINAL SPECIMEN SAMPLING MAKING THEM UNIQUELY WELL SUITED TO THE LARGE COLLECTION OF CROSS-SECTIONAL GENE EXPRESSION DATA CURRENTLY AVAILABLE FOR AD. IN AIM 1 WE WILL FOCUS ON POST-MORTEM BRAIN GENE EXPRESSION ANALYSIS, USING RNA SEQUENCING DATA FROM BULK SAMPLED BRAIN TISSUE AS WELL AS SINGLE CELL SEQUENCING STUDIES (E.G., MOUNT SINAI, ROSMAP) THAT INCLUDE CLINICAL AND NEUROPATHOLOGICAL VARIABLES RELATED TO AD STAGING. AFTER EXTRACTING THE PSEUDOTIME TRAJECTORIES WITH THE PHENOPATH METHOD, WE WILL PRIORITIZE GENES ACCORDING TO THEIR STATISTICAL CORRELATION WITH PSEUDOTIME. MOLECULAR PROCESSES ASSOCIATED WITH DISEASE ONSET AND PROGRESSION WILL BE INFERRED BY WEIGHTED GENE COEXPRESSION NETWORK ANALYSIS (WGCNA). IN AIM 2 WE WILL FOCUS ON RNA EXPRESSION PROFILING DATA FROM WHOLE BLOOD. PSEUDOTIME TRAJECTORIES WILL BE DETERMINED FROM EXISTING AD PATIENT BLOOD-BASED GENE EXPRESSION DATA AS IN AIM 1, AND GENES WILL BE PRIORITIZED ACCORDING TO THEIR CORRELATION WITH PSEUDOTIME. THEN, WE WILL RETAIN GENES HIGHLY CORRELATED WITH PSEUDOTIME THAT SIMULTANEOUSLY EXHIBIT SIGNIFICANT DIFFERENTIAL EXPRESSION WHEN COMPARED TO CONTROL SAMPLES, WITH THE GOAL OF FINDING GENES THAT DEMONSTRATE A GRADIENT OF EXPRESSION CHANGE FROM A NON-PATHOLOGICAL TO A PATHOLOGICAL STAGE THAT ARE ALSO CORRELATED WITH DISEASE PROGRESSION. FINALLY, WE WILL VALIDATE THE FINDINGS OBTAINED FROM WHOLE BLOOD IN POST-MORTEM BRAIN DATA FROM AIM 1, TO ASSESS THE CORRELATION WITH THE GOLD- STANDARD NEUROPATHOLOGICAL-BASED STAGING. THE FINDINGS FROM THIS PROPOSAL WILL ALLOW US TO IDENTIFY TARGETS FOR NEW AD TREATMENTS AND IDENTIFY POTENTIAL CANDIDATE BLOOD-BASED BIOMARKERS OF AD PROGRESSION.

GENOMIC DETERMINANTS OF SLEEP TRAITS AS RISK AND PROTECTIVE FACTORS FOR ALZHEIMER'S DISEASE - PROJECT SUMMARY ALZHEIMER'S DISEASE (AD) IS THE MOST PREVALENT NEURODEGENERATIVE DISEASE IN THE UNITED STATES AND THERE ARE NO EFFECTIVE TREATMENTS OR CURE. THE DETECTION OF MODIFIABLE PROTECTIVE OR RISK FACTORS CAN IMPROVE THE POSSIBILITY OF INTERVENTION THROUGH LIFE-STYLE HABITS FOCUSED TO REDUCE THE DISEASE RISK OR ELEVATE DISEASE PROTECTION. SLEEP DISORDERS AND DISTURBANCES HAVE RECENTLY BEEN RECOGNIZED AS RISK FACTORS FOR AD ACCORDING TO EVIDENCE FROM EPIDEMIOLOGICAL STUDIES AS WELL AS ASSOCIATIONS WITH SPECIFIC AD NEUROPATHOLOGICAL HALLMARKS SUCH AS PLAQUES AND TANGLES IN THE BRAIN. HOWEVER, THE CAUSAL RELATIONSHIP BETWEEN SLEEP DISORDERS AND DISTURBANCES AND AD HAS NOT BEEN WELL ESTABLISHED. IN THIS SECONDARY DATA ANALYSIS PROPOSAL, WE AIM TO STUDY THE CAUSAL EFFECTS OF SLEEP TRAITS ON AD USING LARGE PUBLICLY AVAILABLE GENOMICS DATASETS INCLUDING THE UK BIOBANK (UKB), THE AD GENETIC CONSORTIUM (ADGC), AND OTHERS. WE WILL USE A BIOINFORMATICS WORKFLOW CONSISTING OF INNOVATIVE ANALYTICAL METHODS DESIGNED TO SHED LIGHT ON THE CAUSAL RELATIONSHIP AND IDENTIFY SPECIFIC GENOMICS FACTORS INVOLVED. THE PROJECT WILL BE CARRIED OUT AS FOLLOWS: 1) WE WILL LEVERAGE LARGE-SCALE GENOME-WIDE ASSOCIATION STUDIES (GWAS) CONDUCTED ON SLEEP TRAITS TO PRIORITIZE GENES USING A METHOD (TRANSCRIPTOME-WIDE ASSOCIATION STUDY - TWAS) CAPABLE OF DETECTING PHENOTYPE-ASSOCIATED GENES UNDER GENETIC CONTROL AND SIMULTANEOUSLY RELATED TO CHANGES IN GENE EXPRESSION. THEN, AD RNA PROFILING STUDIES WILL BE ANALYZED USING PSEUDOTIME ALGORITHMS, EXTRACTING LATENT TEMPORAL INFORMATION AND ORDERING THE SAMPLES ACCORDING TO DISEASE PROGRESSION. GENES IDENTIFIED IN THIS STEP (SHOWING A HIGH CORRELATION WITH THE DISEASE PROGRESSION AND PREVIOUSLY DETECTED IN THE TWAS) WILL BE FURTHER INVESTIGATED BY MENDELIAN RANDOMIZATION TO ASSESS THE CAUSAL RELATIONSHIP BETWEEN SLEEP TRAITS (EXPOSURE) AND AD (OUTCOME). 2) A SECOND INDEPENDENT ANALYSIS WILL BE CONDUCTED BY MENDELIAN RANDOMIZATION, PRIORITIZING VARIANTS BY STATISTICAL SIGNIFICANCE FROM THE LARGE SCALE GWAS CONDUCTED ON SLEEP TRAITS AND ASSESSING THE CAUSAL RELATIONSHIP WITH AD. ADDITIONALLY, A RECENTLY DEVELOPED ALGORITHM (LATENT CAUSAL VARIABLE METHOD) WILL BE APPLIED AS WELL TO DETECT CAUSAL RELATIONSHIPS BETWEEN SLEEP TRAITS AND AD. THIS ANALYTICAL WORKFLOW AND THE LARGE SIZE OF THE COHORTS INCLUDED WILL PROVIDE US WITH THE STATISTICAL POWER TO IDENTIFY MODIFIABLE RISK AND PROTECTIVE FACTORS TO DEMONSTRATE A CAUSAL RELATIONSHIP WITH AD.

SINGLE: SIGNATURE ENABLING GLIOMA ENROLLMENT

HOST DNA METHYLATION AS A MECHANISM OF MICROBIOME INFLUENCE ON INTERNALIZING BEHAVIOR

COLLABORATIVE RESEARCH: A NEW PARADIGM FOR UNDERSTANDING HOW LEAF LITTER QUALITY AFFECTS STREAM ECOSYSTEMS

IDENTIFYING KEY MOLECULAR DIFFERENCES BETWEEN LEWY BODY AND ALZHEIMER'S DISEASE VIA MULTI-OMICS ANALYSIS - PROJECT SUMMARY: DEMENTIA AFFECTS NEARLY 7 MILLION AMERICANS AND INCLUDES MULTIPLE UNDERLYING PATHOLOGIES THAT ARE FREQUENTLY MISDIAGNOSED DUE TO OVERLAPPING CLINICAL SYMPTOMS.1,2 WHILE ALZHEIMER’S DISEASE (AD) IS THE MOST COMMON FORM OF NEURODEGENERATIVE DEMENTIA, DEMENTIA WITH LEWY BODIES (DLB) AND PARKINSON’S DISEASE DEMENTIA (PDD) ARE ALSO PREVALENT IN INDIVIDUALS OVER THE AGE OF 65.3,4 LEWY BODY DISEASE (LBD) ENCOMPASSES BOTH DLB AND PDD AND IS CHARACTERIZED BY ABNORMAL Α-SYNUCLEIN AGGREGATES, OFTEN CO-OCCURRING WITH AD PATHOLOGY - AMYLOID-Β (AΒ) PLAQUES AND NEUROFIBRILLARY TANGLES (NFTS).5 AD AND LBD CAN AFFECT OVERLAPPING CORTICAL REGIONS AND PRESENT WITH SIMILAR SYMPTOMS, COMPLICATING DIAGNOSIS AND TREATMENT.5 A KEY KNOWLEDGE GAP LIES IN UNDERSTANDING THE MOLECULAR ALTERATIONS THAT DIFFERENTIATE LBD AND AD. ADDITIONALLY, GENETIC SEX STRONGLY INFLUENCES DISEASE RISK, PROGRESSION, AND THERAPEUTIC RESPONSE IN NEURODEGENERATIVE DISORDERS.6,7 ADDRESSING THIS REQUIRES INCORPORATING SEX AS A BIOLOGICAL VARIABLE TO INFORM TARGETED TREATMENT STRATEGIES. THIS PROJECT AIMS TO CLOSE THESE GAPS BY CHARACTERIZING TRANSCRIPTOMIC AND GENOMIC ALTERATIONS IN POSTMORTEM ANTERIOR CINGULATE CORTEX TISSUE FROM 607 NEUROPATHOLOGICALLY DEFINED CASES, INCLUDING LBD, AD, AMYLOID-ONLY PATHOLOGY, AND CONTROLS.8 THE PROPOSED RESEARCH WILL PURSUE FOUR AIMS: AIM 1 (K99 Y1): INVESTIGATE ISOFORM DYSREGULATION ACROSS PATHOLOGIES USING BULK SHORT-READ AND LONG-READ RNA SEQUENCING, IDENTIFYING ALTERNATIVE SPLICING AND CRYPTIC EXON INCLUSION. AIM 2 (K99 Y2): CHARACTERIZE CELL-TYPE-SPECIFIC TRANSCRIPTIONAL CHANGES USING SINGLE-NUCLEUS RNA SEQUENCING, REVEALING CELL-TYPE HETEROGENEITY AND MOLECULAR COMPLEXITY IN MIXED PATHOLOGIES. AIM 3 (R00 Y3): IDENTIFY EQTLS AND SQTLS BY INTEGRATING SNP ARRAY AND BULK RNASEQ DATA TO LINK GENOMIC VARIANTS WITH DYSREGULATED GENE AND ISOFORM EXPRESSION. AIM 4 (R00 Y4–Y5): DEVELOP AND EVALUATE PREDICTIVE DEEP LEARNING MODELS THAT INTEGRATE MULTI-OMICS DATA FROM AIMS 1–3 AND EXTERNAL DATASETS TO IDENTIFY EARLY MOLECULAR MARKERS OF PATHOLOGY. COLLECTIVELY, THIS RESEARCH PROPOSAL LEVERAGES A LARGE, UNIQUE DATASET AND ADVANCED ‘OMICS TECHNOLOGIES TO INVESTIGATE ISOFORM DYSREGULATION, CELL-TYPE-SPECIFIC TRANSCRIPTIONAL CHANGES, AND QTLS UNIQUE TO OR SHARED BY LBD AND AD. IT ALSO EVALUATES SEX DIFFERENCES BY MEASURING THE EFFECT SIZE OF SEX IN MOLECULAR ANALYSES, OFFERING INSIGHTS INTO SEX-BIASED DISEASE MECHANISMS. CAREER DEVELOPMENT: THIS AWARD WILL SIGNIFICANTLY ENHANCE MY CAREER DEVELOPMENT, ENABLING ME TO EXPAND MY EXPERTISE IN TRANSCRIPTOMIC AND GENOMIC ANALYSIS THROUGH MULTI-OMICS APPROACHES. DURING THE K99 PHASE AT TGEN, I WILL RECEIVE MENTORED TRAINING IN LONG-READ AND SINGLE-NUCLEUS RNA SEQUENCING, AS WELL AS WET LAB TECHNIQUES FOR VALIDATING FINDINGS. I WILL ALSO ENGAGE IN COLLABORATION WORKSHOPS, SEMINARS ON EMERGING ‘OMIC TECHNOLOGIES, AND THE COLUMBIA UNIVERSITY CAREER MODE PROGRAM TO SUPPORT MY TRANSITION TO INDEPENDENCE. IN THE R00 PHASE, I WILL ESTABLISH MY OWN LAB TO INVESTIGATE MOLECULAR ALTERATIONS IN NEURODEGENERATION BY INTEGRATING ‘OMICS DATA GENERATED IN THIS RESEARCH PROPOSAL WITH PUBLIC DATASETS. GUIDED BY A MULTIDISCIPLINARY TEAM OF MENTORS, THIS STRUCTURED TRAINING PLAN WILL SUPPORT MY GOAL OF LAUNCHING AN INDEPENDENT RESEARCH PROGRAM FOCUSED ON THE MOLECULAR MECHANISMS OF NEURODEGENERATION, PARTICULARLY THE SIGNIFICANT ROLE OF PATHOLOGY AND SEX DIFFERENCES.

ACTIVATED FGFR2 AS A VIABLE THERAPEUTIC TARGET IN A SUBSET OF OVARIAN CANCERS