The proposed Pathway to Independence Career Development Award is designed to build upon the previous experience of the candidate and facilitate new scientific training geared towards understanding the neurobiology of an alcohol use disorder. Alcoholism is a chronic relapsing condition that causes widespread changes in gene expression throughout different brain regions and cell-types. Next-generation sequencing of the transcriptome (RNA-seq) from postmortem brain tissue has shown dynamic changes in coordinately expressed gene networks, encapsulating several hundred genes, related to an alcohol use disorder. Many of the changes, witnessed in discrete areas of the human brain, are evolutionary conserved in the central nervous system (CNS) within animal models of alcohol drinking behavior. The molecular machinery of the CNS is comprised of interacting protein-coding and non-coding RNA; however, protein-coding genes represent less than 2% of the total genome. Non-coding RNAs, such as long non-coding RNA (lncRNA), are an abundant part of the mammalian transcriptome, having key functional and regulatory roles over vast transcriptional networks. Identifying and testing the biological role of lncRNAs in the context of the brain and alcohol drinking behavior will lead to an improved understanding of disease, and potentially may lead to new pharmacotherapies. During the K99 training phase of this proposal the candidate will acquire news skills, tailored to complement his existing experience, that will permit the investigation of an evolutionary conserved lncRNA involved in alcohol drinking behavior. Drs. R. Adron Harris and R. Dayne Mayfield, both of whom are experts in the field of alcoholism research, will directly mentor this project and provide assistance for interrogating the role of novel molecular candidates in the neuropathology of addiction. Collectively this project will (1) perform targeted in- depth sequencing of lncRNA, and discover affected molecular networks from (2) controlling lncRNA expression in a specific brain region and (3) cell-types to discern the molecular mechanism and behavioral phenotypes impacted by lncRNA. Integration of large-scale systems-based bioinformatics approaches with direct examination of prioritized candidate(s) in animal models will establish lncRNA(s) as important mediators of alcohol abuse and dependence. The training received under this career development award will provide the necessary training to become an independent investigator in the field of alcohol and addiction research.
Alcohol use disorder is a serious mental health disorder negatively impacting society. Chronic alcohol abuse causes long-term changes gene expression and brain chemistry. The proposed studies will use computational biology, state-of-the-arte sequencing, and focused gene-targeting approaches to study the neurobiology of chronic alcohol abuse, which may lead to improved gene-based diagnostics and treatment options for alcohol use disorders.
