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

对调控酒精反应的基因网络的更完整的了解将改善我们的 对醉酒的理解，酒精耐受性的发展，最终成瘾。整体而言 本项目的目标是利用模式生物秀丽线虫，扩大我们对 基因网络在调节对酒精的急性行为反应中起作用。候选基因 已经被老鼠、人类和果蝇鉴定出来的研究将在一些已建立的 线虫的行为分析。一旦使用蠕虫系统确认了候选基因， 他们的遗传途径中其他已知成员的作用将被确定。为了补充我们的 对候选基因工作的乙醇反应途径的理解，新成员 调控线虫乙醇反应的相互作用的基因网络将被识别为使用基因 战略。鉴于急性酒精反应和酒精中毒易感性之间的联系，人类基因 与这项研究中描述的那些同源的网络可能是基因的有力候选者 使一个人容易酗酒。 以下具体目标描述了这些基因网络将被识别和 评估过了。 1.确认参与酒精反应的候选基因或基因网络 人类、老鼠和果蝇的项目。将对待验证基因的功能丧失进行评估 标准化的酒精敏感性表型效应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为 用双突变组合的遗传分析证实了这一点。 3.使用正向遗传策略，我们将分离基因网络中相互作用的成员中的突变 具有未知或不确定网络连接的有效乙醇反应基因。一个新的成员 被发现调节酒精反应的基因网络将代表相关研究的候选小鼠或 苍蝇和对人类的关联研究。

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.