Genes Determining the Behavioral Responses to Ethanol

决定对乙醇行为反应的基因

• 批准号: 6784506
• 负责人: STEVEN LEE MCINTIRE
• 金额: $ 32.44万
• 依托单位: ERNEST GALLO CLINIC AND RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6784506
• 关键词: Caenorhabditis elegans; behavior test; behavioral /social science research tag; biotechnology; ethanol; functional /structural genomics; gene mutation; genetic mapping; genetic models; genetic screening; invertebrate locomotion; molecular cloning; neurophysiology; neurotoxicology; substance abuse related behavior

DESCRIPTION (provided by applicant): Ethanol is one of the most widely abused substances in the world, yet the molecular mechanisms of action of ethanol is poorly understood. Ethanol has been shown to disrupt ion channel functions in vitro through interactions with hydrophobic domains of channel subunit proteins. It is still unclear, however, how these effects of ethanol relate to the behavioral changes observed in humans and other organisms. Unlike other drugs of abuse, ethanol is likely to act through multiple molecular targets rather than upon a single major neurotransmitter receptor or transporter. We have initiated studies using C. elegans as a model system to understand the neurobiological effects of ethanol. We have shown that C. elegans exhibits similar behavioral responses to ethanol as mammalian systems including acute intoxication, adaptive neural responses or acute tolerance and state-dependency. We propose to isolate mutants that are hypersensitive to the intoxicating effects of ethanol on different behaviors. We have devised screens that provide for the isolation of mutants hypersensitive to the effects of ethanol on locomotory and egg laying behaviors. We will also identify mutants defective in acute tolerance to ethanol and mutants exhibiting enhanced tolerance. A final screen provides for an enrichment in mutants that are insensitive to the state-dependent effects of ethanol. Secondary behavioral characterizations and pharmacological assays will be carried out to determine whether the mutations affect neural activity and whether the phenotypes are likely to be ethanol specific. We will map the mutations to specific chromosomal regions and molecularly characterize many of the mutants. The genes identified are likely to encode relevant targets of ethanol, either as direct targets or as members of a pathway affected by ethanol. The studies should also lead to a greater understanding of the molecular mechanisms mediating the effects of ethanol invertebrate systems. The determination of the mechanisms of action of ethanol should provide the basis for a directed approach to the development of therapeutics to treat alcoholism and alcoholic neurological disorders.

描述（由申请人提供）：乙醇是世界上滥用最广泛的物质之一，但是乙醇作用的分子机制知之甚少。通过与通道亚基蛋白的疏水结构域相互作用，乙醇已显示出在体外破坏离子通道功能。但是，尚不清楚乙醇的这些作用与人类和其他生物体中观察到的行为变化有何关系。与其他滥用药物不同，乙醇可能通过多个分子靶标作用，而不是单个主要的神经递质受体或转运蛋白。我们已经开始使用秀丽隐杆线虫作为模型系统的研究，以了解乙醇的神经生物学作用。我们已经表明，秀丽隐杆线虫对乙醇的行为反应与哺乳动物系统相似，包括急性中毒，适应性神经反应或急性耐受性和状态依赖性。我们建议分离对乙醇对不同行为的醉人作用过敏的突变体。我们已经设计了筛选，该屏幕可以分离突变体对乙醇对运动和产卵行为的影响的过敏。我们还将确定突变体对乙醇和突变体的急性耐受性有缺陷，表现出增强的耐受性。最终屏幕可以使对乙醇状态依赖性作用不敏感的突变体富集。将进行次级行为特征和药理学测定，以确定突变是否影响神经活动以及表型是否可能是特定于乙醇的。我们将这些突变映射到特定的染色体区域，并分子表征许多突变体。所鉴定的基因可能是乙醇的相关靶标，无论是直接靶标还是受乙醇影响的途径成员。这些研究还应使人们对介导乙醇无脊椎动物系统的作用的分子机制有更深入的了解。确定乙醇作用机理的确定应为开发治疗酒精中毒和酒精神经系统疾病的疗法的方法提供基础。