Project 3: Cross Species Characterization of Gene Networks in Acute Responses

一个更完整的关于调节酒精反应的基因网络的图片将改善我们的研究。 对醉酒的理解，酒精耐受性的发展，最终成瘾。整体 这个项目的目标是使用模式生物，秀丽隐杆线虫，以扩大我们的理解， 基因网络在调节对乙醇的急性行为反应中起作用。的候选基因 已经通过小鼠、人类和果蝇的研究确定，将在一些已建立的 行为测定C.优雅一旦使用蠕虫系统确认了候选基因， 将确定其遗传途径的其他已知成员的作用。以补充我们 了解乙醇反应途径中的候选基因的工作，新的成员， 相互作用的基因网络，调节C.将通过遗传学方法 战略布局鉴于急性酒精反应和酗酒倾向之间的联系，人类基因 与本研究中描述的那些网络同源的网络可能是基因的强有力的候选者， 使一个人易于酗酒。 以下具体目标描述了识别这些基因网络的方法， 评估。 1.确认参与乙醇反应的候选基因或基因网络， 人类、老鼠和果蝇项目。将评估待验证基因的功能丧失， 表型效应对乙醇敏感性和急性耐受性的发展， 行为分析 2.候选网络的基因网络-行为关系的预测机制将是 使用双突变体组合的遗传分析证实。 3.使用正向遗传策略，我们将在基因网络的相互作用成员中分离突变， 一个经过验证的乙醇反应基因，具有未知或不确定的网络连接。新成员 发现调节乙醇反应的基因网络将代表小鼠相关研究的候选者， 苍蝇和人类的相关研究。

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.