Project Grant F31AA032437

INTEGRATIVE MULTI-OMICS APPROACH TO IDENTIFY CELL-TYPE AND BRAIN-REGION SPECIFIC GENETIC DRIVERS OF ALCOHOL USE DISORDER - ALCOHOL USE DISORDER (AUD) IS A COMPLEX CONDITION INFLUENCED BY BOTH GENETIC AND ENVIRONMENTAL FACTORS, SIGNIFICANTLY AFFECTING MILLIONS WORLDWIDE. THIS PROJECT AIMS TO ELUCIDATE THE GENETIC AND REGULATORY MECHANISMS UNDERLYING AUD IN SEVERAL BRAIN REGIONS PREVIOUSLY IMPLICATED IN ALCOHOL CONSUMPTION AND ADDICTION, NAMELY, THE CAUDATE NUCLEUS, EXTENDED AMYGDALA, ANTERIO-LATERAL HYPOTHALAMUS, AND MIDDLE TEMPORAL GYRUS. UTILIZING ADVANCED SINGLE-CELL MULTI-OMICS TECHNIQUES, WE WILL IDENTIFY CELL-TYPE-SPECIFIC GENE EXPRESSION AND CHROMATIN ACCESSIBILITY DIFFERENCES IN THESE BRAIN REGIONS BETWEEN INDIVIDUALS WITH AND WITHOUT AUD. SPECIFIC AIM 1 WILL INVOLVE PERFORMING DIFFERENTIAL EXPRESSION AND CHROMATIN ACCESSIBILITY ANALYSES USING SINGLE-NUCLEUS RNA-SEQ AND ATAC-SEQ DATA. WE WILL IDENTIFY CIS-REGULATORY MECHANISMS DRIVING THESE DIFFERENCES BY INTEGRATING EXPRESSION QUANTITATIVE TRAIT LOCI (EQTL) AND GENOME-WIDE ASSOCIATION STUDIES (GWAS) DATA. ADDITIONALLY, WE WILL INFER TRANS-REGULATORY MECHANISMS USING ADVANCED BIOINFORMATICS TOOLS TO IDENTIFY TRANSCRIPTION FACTORS AND REGULATORY PROTEINS INVOLVED IN AUD. SPECIFIC AIM 2 WILL FOCUS ON IDENTIFYING GENES LIKELY TO SIGNIFICANTLY CONTRIBUTE TO DEVELOPMENT OF AUD, USING MENDELIAN RANDOMIZATION AND ELUCIDATING THEIR FUNCTIONS THROUGH HIGH-THROUGHPUT PERTURBATION EXPERIMENTS AND REAL-WORLD VALIDATION. WE WILL PERFORM EQTL ANALYSIS TO IDENTIFY VARIANTS ASSOCIATED WITH GENE EXPRESSION IN SPECIFIC CELL TYPES, FOLLOWED BY TWO-SAMPLE MENDELIAN RANDOMIZATION TO DETERMINE CAUSAL RELATIONSHIPS. HIGH-THROUGHPUT PERTURB-SEQ WILL BE USED TO ELUCIDATE THE DOWNSTREAM FUNCTIONS OF THESE CAUSAL GENES, AND WE WILL LEVERAGE DRUG-TARGET PERTURBATION DATABASES TO IDENTIFY POTENTIAL THERAPEUTIC TARGETS FOR AUD. THE FELLOWSHIP TRAINING PLAN INCLUDES DEVELOPING EXPERTISE IN CUTTING-EDGE GENOMICS AND BIOINFORMATICS TECHNIQUES, GAINING HANDS-ON EXPERIENCE WITH EXPERIMENTAL METHODS SUCH AS PERTURB-SEQ, AND ENHANCING SCIENTIFIC COMMUNICATION SKILLS. TRAINING WILL TAKE PLACE IN DR. YUNLONG LIU'S LAB AT INDIANA UNIVERSITY SCHOOL OF MEDICINE, PROVIDING ACCESS TO STATE-OF-THE-ART FACILITIES AND A COLLABORATIVE RESEARCH ENVIRONMENT. THIS COMPREHENSIVE TRAINING WILL PREPARE ME FOR A SUCCESSFUL CAREER AS AN INDEPENDENT RESEARCHER IN GENOMICS AND NEUROBIOLOGY, CONTRIBUTING TO THE DEVELOPMENT OF TARGETED TREATMENTS FOR AUD AND ADVANCING PUBLIC HEALTH.