RESEARCH ABSTRACT Alcohol use disorder (AUD) is a highly prevalent debilitating disorder and the third leading cause of preventable death worldwide, generating massive social and economic burden. The mesocorticolimbic dopaminergic system (MCL) has been consistently implicated in the development of AUD based on the functional specialization of connecting brain regions. Among others, the MCL includes the prefrontal cortex (PFC) and nucleus accumbens (NAc), important neuroanatomical structures responsible for executive function, motivation, and reward response. Chronic alcohol use leads to long-term neuroadaptations of the MCL with postmortem brain studies offering a unique opportunity to investigate the lasting impact of alcohol abuse in etiologically relevant tissue. Thus, the broad goals of this training and research strategy are to acquire important technical and methodological skills which will be used to identify differentially expressed genes (DEG) under epigenetic control in postmortem PFC and NAc of individuals diagnosed with alcohol dependence (AD).
Specific aims are: (1) Identify DEG and co-expressed gene networks associated with AD in PFC and NAc, and (2) test the impact of methylation on the expression of hub genes identified from gene networks associated with AD. The approach for Aim 1 will utilize weighted gene co-expression analysis (WGCNA) and gene-set enrichment analysis to identify biologically relevant hub genes associated with AD.
Aim 2 will apply hydroxymethylation-sensitive high resolution melting (hMS-HRM) for targeted DNA methylation analysis of AD associated hub gene regulatory elements. In addition to the strong research component, this proposal offers a robust training program to: (1) enhance statistical and bioinformatic skills of the applicant for the study of AUD, (2) improve technical expertise to expand upon existing targeted methylation approaches, (3) develop greater understanding of addiction as a psychiatric phenotype, and (4) foster the ability to disseminate experimental findings to scientific communities. These training aims will be completed with guided mentorship from faculty at the Virginia Institute of Psychiatric and Behavioral Genetics and Virginia Commonwealth University. Training activities will include directed coursework, technical workshops, and professional development opportunities. With the combination of applied training and a strong research strategy, this fellowship will foster the development of a future alcohol researcher beyond what is available through graduate training.
Alcohol use disorder is a widespread public health concern and debilitating psychiatric disorder. Our goal is to utilize a network-based approach to identify differentially expressed genes and epigenetic modifications within the postmortem prefrontal cortex and nucleus accumbens of individuals diagnosed with alcohol dependence. We hope the results will implicate potential neurobiological mechanisms that can serve as therapeutic targets for decreasing alcohol addiction.
