The Genetics of Acute Tolerance to Ethanol

描述（由申请人提供）：酒精滥用是一个主要的社会和经济问题，目前的药物治疗是不够的。开发酒精中毒新疗法的主要困难是神经系统与药物相互作用的分子本质尚未完全了解。酒精是一种小的、容易扩散的分子，可能与所有神经元中的许多蛋白质相互作用。研究人员面临的一个重大挑战是确定哪些相互作用对改变神经系统功能以及最终对成瘾的发展至关重要。神经系统对暴露于酒精的动态反应包括几个水平的耐受性发展。耐受性的发展在成瘾的病因学中是重要的。形成耐受性的能力的变异是遗传多样性的重要组成部分，它可以预测个体的酗酒倾向。我们研究了急性乙醇耐受的分子机制，它在单次乙醇暴露过程中发展。在哺乳动物中，这被观察为在血液乙醇水平高于最初使动物中毒的水平时协调和认知能力的恢复。在秀丽隐杆线虫（C. habditis elegans）中，elegans），我们观察到急性耐受性作为在单次暴露于恒定剂量的乙醇期间协调运动的恢复。C.秀丽线虫是研究神经功能的极好模型，因为其极其简单且特征明确的神经系统（302个神经元）包含至少118种不同的神经元细胞类型，并且使用许多与哺乳动物脑所使用的相同的神经递质。C.线虫遗传学提供了一种剖析神经系统功能的简便方法，并可有效地用于解决药物对神经元的作用问题。本项目旨在确定急性耐受发展的分子机制。我们将采取正向遗传学方法，通过遗传学筛选破坏乙醇急性耐受性发展的突变。这项建议的具体目标是：1-基因筛选突变，破坏急性乙醇耐受性的发展。2-从分子上表征遗传筛选中分离的几个突变。3-描述特定目标2中鉴定的基因在急性耐受性中的功能。总之，本提案的具体目标旨在彻底研究AFT发展的分子机制。公共卫生相关性该项目旨在使用正向遗传筛选来识别线虫C。这是对乙醇产生急性耐受所必需的。如果发现的基因与人类基因相关，那么这些基因或调节其活性或表达的基因的变异可能会影响个体对酒精的最初反应，因此可能使个体易于酗酒。

DESCRIPTION (provided by applicant): Alcohol abuse is a major social and economic problem for which current drug treatments are inadequate. A primary difficulty with the development of novel treatments for alcoholism is that the molecular nature of the interaction of the nervous system with the drug is incompletely understood. Alcohol is a small, easily diffusible molecule that probably interacts with many proteins in all neurons. A significant challenge for researchers is to determine which interactions are important for altering nervous system function and, ultimately, for the development of addiction. The nervous system mounts a dynamic response to exposure to alcohol that consists of several levels of the development of tolerance. The development of tolerance is important in the etiology of addiction. Variation in the ability to develop tolerance is an important component of the genetic diversity that predicts an individualb"s propensity to abuse alcohol. We study the molecular mechanics of acute tolerance to ethanol, which develops during a single ethanol exposure. In mammals, this is observed as a recovery of coordination and cognitive ability at a blood ethanol level that is higher than the level that intoxicated the animal initially. In Caenorhabditis elegans (C. elegans), we observe acute tolerance as a recovery of coordinated locomotion during a single exposure to a constant dose of ethanol. C. elegans is an excellent model for the study of neural function because its extremely simple and well-characterized nervous system (302 neurons) contains at least 118 different neuronal cell types and uses many of the same neurotransmitters as are used by the mammalian brain. C. elegans genetics provides a facile means of dissecting nervous system function, and can be used effectively to address questions of drug effects on neurons. This project is designed to determine the molecular mechanisms of the development of acute tolerance. We will take a forward genetics approach by genetically screening for mutations that disrupt the development of acute tolerance to ethanol. The specific aims of this proposal are: 1- Genetically screen for mutations that disrupt development of acute tolerance to ethanol. 2- Molecularly characterize several of the mutations isolated in the genetic screen. 3- Characterize the function of the genes identified in Specific Aim 2 in acute tolerance. Together, the specific aims of this proposal are designed to thoroughly examine the molecular mechanisms of development of AFT. PUBLIC HEALTH RELEVANCE The project aims to use a forward genetic screen to identify genes in the nematode C. elegans that are required for the development of acute tolerance to ethanol. If the discovered genes are related to human genes then variation in those genes or in genes that regulate their activity or expression is likely to impact on an individual's initial response to alcohol and therefore could predispose that individual to alcoholism.