Role of lncRNA Malat1 in Alcohol Use Disorder - Project Summary Alcohol use disorder (AUD) is a prevalent and debilitating disease; however, the underlying mechanisms for AUD remain largely unknown. Despite the predominant focus of protein coding genes in AUD, non-coding RNAs play a vital role in regulating multiple cellular functions including RNA transcription, RNA- protein interactions, and gene expression. The long non-coding RNA (lncRNA) Malat1 has been implicated in the transcriptional regulation of gene expression. Recent findings from our laboratory and others have linked Malat1 to neuroinflammatory pathways associated with AUD. Additional data from our laboratory suggests Malat1 regulates neuroinflammatory gene expression in astrocytes, a CNS cell type shown to mediate neuroimmune responses and behavior. In my research proposal, I will determine whether Malat1 in astrocytes regulates alcohol consumption and neuroinflammatory activation. I hypothesize Malat1 drives astrocyte- mediated neuroinflammatory response to alcohol, regulating alcohol action and pro-inflammatory gene expression. Aim 1 of my proposal will utilize behavioral pharmacology and single nucleus RNA sequencing to demonstrate the role of quercetin, a chemical known to inhibit Malat1, in the regulation of alcohol consumption and neuroinflammatory gene expression. Aim 2 of my proposal will use genetically engineered mice and immunofluorescence to assess the functional role of Malat1 in astrocytes underlying the pathogenesis of AUD. Overall, my research proposal introduces a novel approach for testing neuroinflammatory mechanisms underlying behavioral changes in AUD and will provide a crucial step in understanding how Malat1 perpetuates AUD physiological phenotypes. With limited treatments currently available for AUD the results obtained from these studies may identify a novel pharmacological approach to assist with AUD treatment.
