Mapping the Foci of Arrestin's Role in Ethanol Sedation

绘制 Arrestin 在乙醇镇静作用中的作用点

• 批准号: 7305905
• 负责人: Gregg W Roman
• 金额: $ 13.97万
• 依托单位: UNIVERSITY OF HOUSTON
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7305905
• 关键词: Affect; Alcohol abuse; Alcoholic Intoxication; Alcoholism; Alcohols; Animals; Arrestin; Arrestins; Behavioral; Biological; Complementary DNA; Data; Defect; Depth; Development; Dissection; Dopamine; Drosophila arrestin; Drosophila genome; Drosophila genus; Ensure; Ethanol; G-Protein Signaling Pathway; GTP-Binding Proteins; Genetic; Genetic Epistasis; Goals; Heat-Shock Response; Intervention; Lead; Left; Maps; Modification; Molecular; Mutation; Nervous system structure; Neurons; Neuropil; Pathology; Pathway interactions; Phenotype; Process; Property; Resistance; Role; Rutabaga; Sedation procedure; Severities; Signal Pathway; Signal Transduction; Signaling Molecule; Testing; Time; Transgenes; Visual; adenylyl cyclase 1; alcohol effect; alcohol sensitivity; desensitization; gain of function; insight; loss of function; mutant; receptor; recidivism; relating to nervous system; research study; sedative

DESCRIPTION (provided by applicant): The objective of this proposal is to develop a genetic framework for the processes controlling alcohol sedation. The framework will be produced through epistasis analysis on several defined signaling mutants in Drosophila. This framework will center on the Drosophila non-visual arrestin kurtz, and will define genetic interactions that modulate behavioral sensitivity to alcohol. Mutants in kurtz are hypersensitive to the sedative effects alcohol. This sensitivity is rescued by the targeted expression of a kurtz cDNA within the nervous system, demonstrating a neural requirement for arrestin activity in the normal resistance to alcohol's intoxicating properties. The proposed experiments will examine whether this requirement is a developmental function of kurtz, or whether the absence of arrestin activity leaves the nervous system physiologically sensitized to the sedative effects of alcohol. The experiments will also map the neural foci for the function of kurtz in regulating alcohol sedation through gain-of-function rescue experiments. With this deeper understanding of where and when kurtz functions to modulate alcohol sensitivity, we will define additional molecules that interact with kurtz in the development of alcohol intoxication. One such interaction, in which the krz1 mutation can repress the alcohol sensitivity phenotype of the rutabaga typeI adenylyl cylase, has already been demonstrated. The data gained from these expriements will provide a functional dissection of the molecular processes that modify an animal's sensitivity to alcohol.

描述（由申请人提供）：本提案的目的是为控制酒精镇静的过程开发一个遗传框架。该框架将通过对果蝇中几个确定的信号突变体的上位性分析产生。这个框架将集中在果蝇的非视觉arrestin库尔茨，并将定义调节行为的酒精敏感性的遗传相互作用。库尔兹突变体对酒精的镇静作用过敏。这种敏感性被神经系统内的kurtz cDNA的靶向表达所拯救，证明了在对酒精的致醉特性的正常抵抗中对抑制蛋白活性的神经需求。拟议中的实验将检验这种要求是否是库尔茨的一种发育功能，或者是否缺乏抑制蛋白活性使神经系统对酒精的镇静作用在生理上敏感。实验还将通过功能获得性挽救实验绘制库尔茨在调节酒精镇静中的功能的神经灶。随着对库尔茨何时何地调节酒精敏感性的更深入了解，我们将定义在酒精中毒发展过程中与库尔茨相互作用的其他分子。一个这样的相互作用，其中krz1突变可以抑制酒精敏感性表型的芜菁I型腺苷酸环化酶，已经被证明。从这些实验中获得的数据将提供改变动物对酒精敏感性的分子过程的功能解剖。