The administrative core of the P50 application on Center for Alcohol Research in Epigenetics (CARE) will coordinate multiple research and pilot projects and the epigenetic core to evaluate ethanol-induced epigenetic changes (histone modifications and DNA methylation/demethylation mechanisms) in specific brain circuitries that lead to alcoholism. The overall hypothesis of CARE is to evaluate epigenetic changes that are operative in the regulation of neurocircuitry function during the pathogenesis of alcoholism. To test this hypothesis, we have selected four interrelated research projects and two pilot projects on epigenetics and one epigenetic core that will use rat, human post-mortem brains, and tissue culture models to examine facets of the heterogeneous nature of human alcoholics. Research project #1 will evaluate epigenetic changes in the ventral tegmental area (VTA) and its role in GABA sensitivity in the modulation of dopaminergic neuronal function related to the euphoric properties of ethanol. Research project #2 will investigate epigenetic changes and synaptic remodeling in the amygdaloid circuitry in relation to the dysphoric (negative emotional state) aspects of ethanol exposure. Negative (anxiety and depression) and positive effects of ethanol play a prominent role in the etiology of alcoholism. Research project #3 will evaluate epigenetic changes in astrocytes and their role in hippocampal plasticity during ethanol exposure. Research project #4 will investigate the DNA-methylation and DNA-demethylation networks in cortico-limbic structures of post-mortem brains of alcoholics (compared with age/sex-matched control subjects). Pilot project #1 will explore the mitochondrial epigenome in the brain, whereas work proposed in pilot project #2 will explore epigenetic changes in microglia to examine its role in neuroinflammatory processes during alcoholism. The administrative core will provide administrative leadership, overall management, and oversight in order to enhance the epigenetic work and will also manage outreach community and training programs within CARE. The work proposed will provide mechanistic information on how ethanol-induced epigenetic changes may be involved in adaptive changes in the brain during alcoholism.
The multidisciplinary approaches and involvement of experts in epigenetic, molecular and behavioral neuroscience, electrophysiology, biostatistics, and animal models will lead to the successful completion of the proposed epigenetic studies and the identification of novel therapeutic targets impacting chromatin structures that can be used to develop new drugs for the treatment and prevention of alcoholism.
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