Control of Alcohol Responses by Actin-Regulating Genes

肌动蛋白调节基因控制酒精反应

基本信息

批准号：
8242783
负责人：
Adrian Rothenfluh
金额：
$ 36.25万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8242783
关键词：
Actins Acute Address Affect Alcohol abuse Alcoholism Alcohols Animal Model Behavior Behavior Control Behavioral Binding Biochemical Biological Assay Cell Culture Techniques Cell membrane Complex Cytoskeleton Data Dendritic Spines Development Disease Dose Drosophila genus Drosophila melanogaster Environmental Risk Factor Equilibrium Ethanol F-Actin Family G Actin Gene Proteins Genes Genetic Genetic Predisposition to Disease Genetic Screening Goals Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Health Health Care Costs Healthcare Hyperactive behavior In Vitro Individual Invertebrates Knock-out Learning Link Mammalian Cell Mammals Measures Mediating Membrane Protein Traffic Memory Molecular Molecular Genetics Monomeric GTP-Binding Proteins Morphology Mus Mutation Nervous system structure Neuronal Plasticity Neurons Neurophysiology - biologic function Pathway interactions Play Protein Biochemistry Protein Isoforms Proteins Public Health RNA Interference Regulation Regulator Genes Regulatory Pathway Research Risk Factors Role Sedation procedure Signal Pathway Signal Transduction Societies Susceptibility Gene Synapses Technology Testing Transgenic Organisms United States Vertebrates alcohol abuse therapy alcohol behavior alcohol exposure alcohol response alcohol use disorder base cofilin defined contribution density disability drinking fly genetic regulatory protein in vivo insight member mortality mutant novel novel therapeutics public health relevance research study response rho rho GTP-Binding Proteins therapeutic target vinegar fly

项目摘要

DESCRIPTION (provided by applicant): Alcohol abuse disorders are a major health care concern that affect millions of people every year in the United States. Alcoholism has a significant genetic etiology, but few genes are known that significantly contribute to the development of the disease. The goal of this proposal is to study genes regulating the actin cytoskeleton, and the molecular mechanisms by which they do so, to regulate ethanol-induced behaviors in Drosophila. This idea emerged in parallel in two model organisms. First, previous genetic screens for Drosophila mutants with altered behavioral responses to alcohol identified mutations in multiple genes regulating the actin cytoskeleton. Second, mice with a knock-out of an actin regulatory protein also showed altered responses to alcohol, including increased voluntary drinking. We therefore postulate that the dynamic regulation of the actin cytoskeleton is a major determinant of behavioral responses to ethanol. We propose genetic, molecular, biochemical, and cell culture approaches to define the roles of two small GTPase pathways, the Arf6, and Rho-family of GTPases in regulating alcohol-induced behaviors. First, we will study how two distinct isoforms of a regulatory protein of Rho-GTPases, RhoGAP18B, are differentially involved in the regulation of both ethanol-induced hyperactivity, and sedation. Second, we will test mutations in members of the Arf6 signaling pathway for their responses to alcohol. Arf6 regulates membrane traffic and actin dynamics at the plasma membrane. We will use genetic, and biochemical approaches to define what the molecular links are between the Rho and Arf6 signaling pathways. Third, we will test the contribution of other actin regulatory genes to ethanol-induced behaviors, notably the role of cofilin, an actin-severing protein that controls the balance between free globular and filamentous actin protein. The members of these small GTPase signaling pathways are highly conserved from Drosophila to mammals, and some are known to participate in complex behaviors such as learning and memory, in vertebrates and invertebrates. We predict that these pathways are also functionally conserved in their regulation of ethanol-induced behaviors. Alcoholism is a devastating disease that severely impacts personal, and public health. The proposed research will advance our understanding of the genetic basis for the development of alcoholism. This in turn, will result in the identification of new risk factors and potential therapeutic targets for the treatment of alcohol abuse disorders. PUBLIC HEALTH RELEVANCE: Alcoholism is a devastating disorder that significantly contributes to mortality, disability, and to healthcare costs. The goal of this research is to understand the genes that determine, and mediate the behavioral responses to alcohol. In conducting this research, we hope to identify risk factors for the development of alcoholism, as well as provide leads for the development of new therapeutic strategies aiding in the treatment of alcohol use disorders.

描述（由申请人提供）：酒精滥用障碍是一个主要的医疗保健问题，每年影响数百万人。酗酒具有重要的遗传病因，但已知很少有基因对这种疾病的发展有显着贡献。该提案的目标是研究调节肌动蛋白细胞骨架的基因及其分子机制，以调节果蝇乙醇诱导的行为。这个想法同时出现在两种模式生物中。首先，之前对酒精行为反应改变的果蝇突变体的基因筛选发现了调节肌动蛋白细胞骨架的多个基因的突变。其次，肌动蛋白调节蛋白被敲除的小鼠也表现出对酒精的反应改变，包括自愿饮酒的增加。因此，我们假设肌动蛋白细胞骨架的动态调节是对乙醇行为反应的主要决定因素。我们提出了遗传、分子、生化和细胞培养方法来定义两个小 GTP 酶途径（Arf6 和 GTP 酶的 Rho 家族）在调节酒精诱导行为中的作用。首先，我们将研究 Rho-GTP 酶调节蛋白 RhoGAP18B 的两种不同亚型如何不同地参与乙醇诱导的多动症和镇静的调节。其次，我们将测试 Arf6 信号通路成员的突变，以了解它们对酒精的反应。 Arf6 调节质膜上的膜交通和肌动蛋白动力学。我们将使用遗传和生化方法来定义 Rho 和 Arf6 信号通路之间的分子联系。第三，我们将测试其他肌动蛋白调节基因对乙醇诱导行为的贡献，特别是肌动蛋白丝切蛋白（一种控制游离球状肌动蛋白和丝状肌动蛋白之间平衡的肌动蛋白切断蛋白）的作用。这些小 GTP 酶信号通路的成员从果蝇到哺乳动物都高度保守，其中一些已知参与脊椎动物和无脊椎动物的复杂行为，例如学习和记忆。我们预测这些途径在调节乙醇诱导的行为方面也具有功能保守性。酗酒是一种毁灭性的疾病，严重影响个人和公共健康。拟议的研究将增进我们对酗酒发展的遗传基础的理解。反过来，这将导致确定新的危险因素和治疗酒精滥用疾病的潜在治疗靶点。公共卫生相关性：酗酒是一种毁灭性的疾病，会显着增加死亡率、残疾和医疗费用。这项研究的目的是了解决定和介导酒精行为反应的基因。在进行这项研究时，我们希望确定酒精中毒发展的危险因素，并为开发有助于治疗酒精使用障碍的新治疗策略提供线索。