A more complete picture of the gene networks that regulate alcohol responses will improve our understanding of intoxication, the development of alcohol tolerance and, ultimately, addiction. The overall goal of this project is to use the model organism, Caenorhabditis elegans, to expand our understanding of gene networks that have roles in regulating acute behavioral responses to ethanol. Candidate genes that have been identified by mouse, human and Drosophila studies will be validated in a number of established behavioral assays in C. elegans. Once candidate genes have been confirmed using the worm system, the roles of other, known members of their genetic pathways will be determined. To complement our understanding of the ethanol response pathways in which candidate genes work, novel members of interacting gene networks that regulate ethanol responses in C. elegans will be identified using genetic strategies. Given the link between acute alcohol response and predisposition to alcoholism, the human gene networks homologous to those characterized in this study are likely to be strong candidates for genes that predispose an individual to alcoholism. The following specific aims describe the means by which these gene networks will be identified and assessed. 1. Confirm the involvement in ethanol responses of the candidate genes or gene networks identified by the human, mouse and Drosophila projects. Loss of function of the genes to be validated will be assessed for phenotypic effects on ethanol sensitivity and the development of acute tolerance using standardized behavioral assays. 2. The predicted mechanisms of the gene network-behavior relationships for candidate networks will be confirmed using genetic analysis of double-mutant combinations. 3. Using forward genetic strategies, we will isolate mutations in interacting members of the gene networks for a validated ethanol response gene that has unknown or uncertain network connections. Novel members of a gene network found to regulate ethanol responses will represent candidates for related studies in mice or flies and association studies in humans.
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