Pharmacogenomics of ethanol and myelin gene expression

Virginia Commonwealth University, Richmond VA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Alcoholism is associated with several neurological diseases accompanied by aberrant myelination. Functional genomics techniques, which can provide simultaneous, non-biased measurement of expression levels for thousands of genes, have been applied to problems of alcohol-related neurological disease. DNA microarray studies demonstrate coordinate decrease of myelin-related genes in frontal cortex of human alcoholics. We have observed a coordinate increase in expression of myelin-related genes in prefrontal cortex of adult DBN2J mice in response to acute ethanol. This effect was blocked by naltrexone. Together, these data suggest that acute and chronic ethanol differentially regulate myelin gene expression. We hypothesize that a crucial signaling pathway, which may involve opioid receptor and/or cAMP signaling, is responsible for regulation of myelin by ethanol. The goal of this application is to characterize this mechanism by fulfilling the following specific areas: 1) Characterize myelin gene expression with specific opioid receptor antagonists in control and ethanol-treated DBA mice. 2) Characterize myelin gene expression in control and ethanol-treated mature cultured mouse oligodendrocytes. 3) Confirm the role of transfected candidate genes in mature oligodendrocyte cell culture. These studies into myelin regulation by ethanol may give novel insight into signaling events evoked by acute ethanol and the mechanism(s) of certain of alcohol-associated neurological disorders. [unreadable] [unreadable]