Genes that Regulate Ethanol Responses in Drosophila

调节果蝇乙醇反应的基因

基本信息

批准号：
8117465
负责人：
ULRIKE A HEBERLEIN
金额：
$ 35.27万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-02-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8117465
关键词：
Acute Affect Alcohol consumption Alcoholic Intoxication Animal Model Behavior Behavioral Assay Behavioral Paradigm Biological Assay Biological Models Brain region Candidate Disease Gene Chronic Collection Complex Computer software Consumption Cues Data Development Drosophila genus Drug Exposure Environmental Risk Factor Ethanol Exhibits FDA approved Food Genes Genetic Genetic Screening Goals Human Human Genetics Intoxication Laboratories Libraries Liquid substance Locomotion Mammals Measures Mediating Medical Medicine Modeling Molecular Musculoskeletal Equilibrium Nervous system structure Neuromodulator Neuropeptides Pathway interactions Pattern Pharmaceutical Preparations Pharmacotherapy Phase III Clinical Trials Relapse Resolution Rewards Risk Rodent Model Role Screening procedure Sedation procedure Self Administration Sensory Social Interaction Social Problems Societies System Testing Time Translating Translations alcohol behavior alcohol effect alcohol relapse alcohol response alcohol sensitivity alcohol use disorder base behavior influence deprivation experience feeding fly insight meetings mutant neural circuit neurochemistry neuromechanism novel pre-clinical preference psychosocial public health relevance social software development success tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Alcohol use disorders (AUDs) are a major problem in medicine and society, and the few available treatment strategies have so far met with limited success. It is well established that genetic, psychosocial, and environmental factors contribute to an increased risk for AUDs. Our laboratory has pioneered the development of Drosophila as a model system for the identification of genes and molecular pathways that regulate simple ethanol-induced behaviors, such as intoxication and the development of tolerance, and many of the underlying molecular mechanisms have been found to be conserved between flies and mammals. Here, we propose to investigate the mechanisms underlying more complex behaviors - ethanol consumption, preference, relapse, and reward - in Drosophila. The Specific aims of this proposal are: 1) to characterize in detail, using newly developed software, the behavior of flies during ethanol self-administration and relapse, and study the influences of experience as well as social and environmental context; 2) to define the neuromodulators and neural circuits engaged during these behaviors; 3) to establish whether genes that regulate acute ethanol intoxication also mediate ethanol consumption, relapse and reward, and identify novel genes that regulate these behaviors; and 4) to identify potential pharmacotherapies for AUDs by screening a large collection of FDA-approved drugs for their efficacy in curbing ethanol consumption and relapse. The ease, potential for high throughput, and relatively low expense of Drosophila studies make the fly a powerful system to investigate the molecular and neural mechanisms underlying ethanol preference, relapse and reward. These mechanisms will provide novel insights into these complex behaviors, which can be translated to rodent models, provide candidate genes for the genetics of AUDs in humans, and ultimately, suggest potential targets for pharmacotherapy. PUBLIC HEALTH RELEVANCE: We will identify novel mechanisms underlying ethanol self-administration, relapse, and reward in flies, mechanisms which can be then be translated rapidly to preclinical rodent models, provide candidate genes for the human genetics of alcohol use disorders, and suggest new pharmacotherapies for this immense medical and social problem.

描述（由申请人提供）：酒精使用障碍（AUD）是医学和社会中的主要问题，到目前为止，很少有可用的治疗策略取得了有限的成功。众所周知，遗传，社会心理和环境因素有助于增加AUD的风险。我们的实验室率先开发了果蝇作为模型系统的发展，用于鉴定调节简单乙醇引起的行为的基因和分子途径，例如中毒和耐受性的发展，并且在苍蝇和哺乳动物之间已经存在许多基本的分子机制。在这里，我们建议研究果蝇中更复杂行为的机制 - 乙醇消耗，偏好，复发和奖励。该提案的具体目的是：1）使用新开发的软件，乙醇自我管理和复发期间的果蝇行为进行详细表征，并研究经验以及社会和环境环境的影响； 2）定义在这些行为过程中参与的神经调节剂和神经回路； 3）确定调节急性乙醇中毒的基因是否还可以介导乙醇消耗，复发和奖励，并确定调节这些行为的新型基因； 4）通过筛选大量FDA批准的药物来确定AUD的潜在药物治疗，以在抑制乙醇消耗和复发方面有效。果蝇研究的轻松，高吞吐量和相对较低的费用使苍蝇成为研究乙醇偏好，复发和奖励的分子和神经机制的强大系统。这些机制将提供对这些复杂行为的新见解，这些行为可以翻译成啮齿动物模型，为人类AUDS的遗传学提供候选基因，并最终提出了药物治疗的潜在靶标。公共卫生相关性：我们将确定乙醇自我给药，复发和奖励的新型机制，然后可以将其迅速转化为临床前啮齿动物模型，为酒精使用障碍的人类遗传学提供候选基因，并为这种巨大的医学和社会问题提供新的药物治疗。