Cross Species Characterization of Gene Networks in Acute Responses to Ethanol

描述（由申请人提供）：酒精依赖（AD）遗传学研究下一阶段的挑战和目标将是i）确认候选基因，ii）了解AD中单个基因的作用机制，iii）使用分子和遗传信息识别AD新干预措施的潜在靶点。作为接近这些复杂目标的策略，我们制定了三个主要的组织假设，整合和指导这个发展（P20）应用程序的各个组成部分。这些措施包括：1.关注基因网络而不是单个基因，这将提供机制信息，目标识别和跨物种验证影响酒精相关行为和AD风险的分子事件。2.一个双向的跨物种基因发现和验证方案，可以提供候选基因和机制信息的强有力的确认。我们计划在小鼠（项目1），人类（项目2，试点2），C。elegans（Project 3）和D. melanogaster（Pilot 1）将相互加强。3.对乙醇的初始敏感性和急性耐受性是具有广泛的跨物种实验适用性和经验证的与AD相关的表型。对于这个项目，我们要求四年的支持，我们概述了一系列的三个发展和两个试点项目，形成了一个高度综合和新颖的方法，实现上述假设。一个行政核心和生物信息学核心将提供跨项目所需的支持。各个项目的具体目标将包括发展方面，旨在扩大我们的科学基础，增加中心组成部分之间的整合，并扩展我们的实验模型，最终包括其他行为表型，例如急性和慢性耐受性和依赖性。我们期待新的贡献，从我们的跨物种分析急性乙醇的影响，酒精研究领域。

DESCRIPTION (provided by applicant): The challenges and goals for the next phase of genetic research on alcohol dependence (AD) will be to i) confirm candidate genes, ii) to understand the mechanism(s) of action for individual genes in AD and iii) to use the molecular and genetic information to identify potential targets for novel interventions in AD. As a strategy to approach these complex goals, we have formulated three major organizing hypotheses that integrate and direct the individual components of this Developmental (P20) application. These include: 1. A focus on gene networks rather than individual genes which will provide mechanistic information, target identification and cross-species validation of molecular events affecting alcohol-related behaviors and risk for AD. 2. A bi-directional cross-species gene discovery and validation scheme that can provide both powerful confirmation of candidate genes and mechanistic information. Our planned studies in mice (Project 1), humans (Project 2, Pilot 2), C. elegans (Project 3), and D. melanogaster (Pilot 1) will be mutually reinforcing. 3. Initial sensitivity and acute tolerance to ethanol are phenotypes with broad cross-species experimental applicability and validated relevance to AD. For this project, for which we request four years of support, we outline a series of three developmental and two pilot projects which form a highly integrated and novel approach that implement the hypotheses outlined above. An Administrative Core and Bioinformatics Core will provide needed support across projects. The Specific Aims of individual projects will include developmental aspects that seek to broaden our scientific base, increase integration between Center components and extend our experimental models to eventually include additional behavioral phenotypes such as acute and chronic tolerance and dependence. We expect novel contributions to the field of alcohol research from our cross-species analysis of acute ethanol effects.