Cross Species Characterization of Gene Networks in Acute Responses to Ethanol

描述（由申请人提供）：酒精依赖（AD）基因研究下一阶段的挑战和目标将是：1)确认候选基因；2)了解AD中单个基因的作用机制；3)利用分子和遗传信息确定AD新干预措施的潜在靶点。作为实现这些复杂目标的策略，我们制定了三个主要的组织假设，这些假设集成并指导了这个开发（P20）应用程序的各个组件。这些包括：1；关注基因网络而不是单个基因，这将提供影响酒精相关行为和AD风险的分子事件的机制信息、靶标鉴定和跨物种验证。2. 一个双向的跨物种基因发现和验证方案，可以提供候选基因的有力确认和机制信息。我们计划在小鼠（项目1），人类（项目2，试点2），秀丽隐杆线虫（项目3）和黑腹线虫（试点1）中的研究将相互加强。3. 对乙醇的初始敏感性和急性耐受性是具有广泛跨物种实验适用性的表型，并与AD相关。对于这个项目，我们要求四年的支持，我们概述了一系列三个发展项目和两个试点项目，这些项目形成了一个高度整合和新颖的方法来实施上述假设。行政核心和生物信息学核心将提供跨项目所需的支持。个别项目的具体目标将包括发展方面，以寻求扩大我们的科学基础，增加中心组件之间的整合，并扩展我们的实验模型，最终包括其他行为表型，如急性和慢性耐受和依赖。我们期望我们对急性乙醇效应的跨物种分析对酒精研究领域做出新的贡献。

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.