During the current period of support we completed next generation sequencing (RNA-Seq) from cohorts of human brain samples obtained from the NSW Tissue Resource Center-University of Sydney. We also defined expression changes of microRNAs (miRNAs) in both human and mouse brain, proposing that miRNA act as master switches, responsible for many of the changes in gene expression changes and that a single miRNA can alter alcohol consumption. Our previous microarray studies identified potential splice variations in GABAB receptors in human alcoholics and we used RNA-Seq to discover novel, complex splicing of the GABAB1 gene in human brain and showed that chronic alcohol produces additional splicing complexity. We also used our RNA-Seq data to perform a systems network analysis on alcoholics and matched controls across brain regions (prefrontal cortex and basolateral and central amygdala) to define molecular networks based upon lifetime alcohol consumption. We then identified gene networks based on mRNA and microRNA transcriptome profiling that significantly overlap in human alcoholics and mouse models of excessive alcohol consumption. In our proposed studies, we will mine our extensive human RNA-Seq transcriptome profiles in novel and innovative ways to link gene expression changes with genetic differences found in the Collaborative Studies on Genetics of Alcoholism (COGA) studies. We will focus our efforts on identifying candidate FDA approved drugs that can be tested in mouse models of alcohol consumption.
Three Specific Aims are proposed: 1) bioinformatics analysis of next generation sequencing and genome-wide association studies will reveal human genes contributing to the risk of alcohol dependence, 2) convergent changes in gene expression between human alcoholics and mouse models of excessive alcohol consumption will be determined using network analysis of synaptoneurosome and microglia genes in the amygdala and prefrontal cortex of both species, and 3) novel therapeutics based on drugs that are in late-phase clinical trials or have existing FDA approval for other purposes will be selected and tested in alcohol drinking models in mice. Identification of effective target compounds in mice will facilitate testing in humans. The repurposing strategy has been used successfully to advance treatment for other diseases but has not been used for alcohol dependence, a disease lacking effective treatment options.
We propose that alcohol-induced changes in brain function are due to alterations in gene expression and we will explore these changes with several innovative approaches to alcohol research, including next generation sequencing and strategies to identify potential alcohol treatment options using repurposed FDA approved drugs. This work will provide new opportunities for gene-based diagnosis and treatment of alcohol dependence.
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