Dysregulated cell-type specific gene regulatory networks underlying alcohol dependence

Alcohol use disorders is a complex polygenic disease. Cell-type specific data from medial prefrontal cortex (mPFC) from alcohol-dependent mice shows dysregulated gene co-expression networks and transcription factors. This proposal tests the hypothesis that genetic rescuing of dependence-dysregulated gene regulatory networks and co-expression modules will result in reversing escalated alcohol use. The proposal tests this hypothesis in three specific aims: Aim 1 (K99): To test the effect of genetic rescuing an astrocytic dependence-upregulated gene co-expression module on escalated alcohol drinking through performing parallel perturbations of the top connected hub genes of the module. This aim will assess the contribution of gene co-expression modules to alcohol drinking phenotype; Aim 2 (K99): To identify cell-type specific dependence-dysregulated chromatin accessibility and gene regulatory networks. This aim will allow for the (a) construction of cell type-specific gene regulatory networks through connecting cell type-specific chromatin accessibility to gene expression data in alcohol-dependent and control samples, allowing for the identification of alcohol-dysregulated gene regulatory networks, Aim3 (R00): To reverse alcohol escalation through rescuing alcohol-dysregulated gene regulatory networks. This aim performs global non cell-type specific perturbation of a set of transcription factors in alcohol-dependent mice followed by characterization of the resulting changes in alcohol-drinking phenotypes. Dr. Nihal Salem’s goal is to be an independent researcher in the field of alcohol research and to develop a research program that spans genomics, bioinformatics, and functional studies linking transcriptomics to alcohol drinking phenotypes. This proposal outlines a research and training plan to provide Dr. Salem with two years of mentored postdoctoral training and three years of support to start her independent research direction.