The Genetics of Acute Tolerance to Ethanol

乙醇急性耐受的遗传学

• 批准号: 7806428
• 负责人: JILL C BETTINGER
• 金额: $ 25.55万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806428
• 关键词: Acute; Address; Alcohol abuse; Alcoholism; Alcohols; Animals; Behavioral; Blood; Brain; Caenorhabditis elegans; Cloning; Cognitive; Development; Dose; Economics; Ethanol; Etiology; Exposure to; Family; Genes; Genetic; Genetic Screening; Genetic Variation; Goals; Homologous Gene; Human; Individual; Locomotion; Mammals; Mediating; Molecular; Mus; Mutation; Nature; Nematoda; Nervous System Physiology; Nervous system structure; Neurons; Neurophysiology - biologic function; Neurotransmitters; Pathway interactions; Pharmaceutical Preparations; Principal Investigator; Process; Proteins; Recovery; Research; Research Personnel; Screening procedure; Signal Transduction; Study models; Testing; Variant; addiction; alcohol exposure; alcohol research; alcohol response; alcoholism therapy; cell type; design; gene cloning; gene discovery; gene function; molecular mechanics; mutant; neuropeptide Y-Y1 receptor; novel; programs; public health relevance; receptor; response; social

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.

描述（由申请人提供）：酗酒是当前药物治疗不足的主要社会和经济问题。开发酗酒的新治疗方法的主要困难是，神经系统与药物相互作用的分子性质是不完全理解的。酒精是一种易于扩散的小分子，可能与所有神经元中的许多蛋白质相互作用。研究人员的一个重大挑战是确定哪些相互作用对于改变神经系统功能以及最终对成瘾的发展很重要。神经系统对暴露于酒精的动态反应，该反应包括耐受性的几个层次。宽容的发展在成瘾的病因中很重要。发展耐受能力的变化是遗传多样性的重要组成部分，该遗传多样性预测了滥用酒精的倾向。我们研究了急性耐受性乙醇的分子力学，在单个乙醇暴露期间，在哺乳动物中，这在哺乳动物中被观察到比乙醇级别更高的乙醇级别的恢复，这是乙醇级别的恢复。 （秀丽隐杆线虫），我们观察到急性耐受性在单个剂量的乙醇中的恢复，秀丽隐杆线虫是对神经功能的出色模型轻松剖析神经系统功能的手段，并可以有效地解决药物对神经元影响的问题。该项目旨在确定急性公差发展的分子机制。我们将通过遗传筛查破坏急性耐受性乙醇的突变来采取一种前瞻性遗传学方法。该提案的具体目的是：1-遗传上筛选突变破坏急性耐受性乙醇的突变。 2-分子表征在遗传筛选中分离的几个突变。 3-表征在急性耐受性中特定目标2中鉴定的基因的功能。总之，该提案的具体目的旨在彻底检查船尾发展的分子机制。公共卫生相关性该项目旨在使用远期遗传屏幕来识别线虫秀丽隐杆线虫中急性耐受性乙醇所需的基因。如果发现的基因与人类基因有关，则这些基因的变异或调节其活性或表达的基因可能会影响个人对酒精的初始反应，因此可能使该人对酒精中毒感到倾向。