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: 7595246
• 负责人: Gregg W Roman
• 金额: $ 21.42万
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7595246
• 关键词: Affect; Alcohol abuse; Alcoholic Intoxication; Alcoholism; Alcohols; Animals; Arrestins; Behavioral; Biological; Complementary DNA; Data; Defect; Development; Dissection; Dopamine; 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; adenylyl cyclase 1; alcohol effect; alcohol sensitivity; desensitization; gain of function; insight; loss of function; mutant; non-visual arrestins; 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）：该提案的目的是为控制酒精镇静剂的过程开发一个遗传框架。该框架将通过对果蝇中几个定义的信号突变体的上学分析产生。该框架将集中在果蝇上的非视觉阻止蛋白库尔茨，并将定义调节行为对酒精敏感性的遗传相互作用。库尔茨的突变体对镇静作用酒精过敏。通过神经系统中库尔茨cDNA的靶向表达来挽救这种敏感性，这表明在对酒精的陶醉特性的正常耐药性中的神经要求。提出的实验将检查该需求是否是库尔茨的发育功能，还是缺乏抑制素活性使神经系统在生理上对酒精的镇静作用敏感。该实验还将通过功能良好的救援实验来绘制神经灶的功能，以调节酒精镇静剂的功能。随着对库尔兹在何处和何时起作用来调节酒精敏感性的何时和何时的理解，我们将定义与库尔茨相互作用的其他分子在酒精中毒的发展中相互作用。已经证明了一种这种相互作用，其中KRZ1突变可以抑制rutabaga typei adenylyl果层的酒精敏感性表型。从这些征收中获得的数据将提供对动物对酒精敏感性的分子过程的功能解剖。