Rat Animal Models and Gene Testing Core

描述（由申请人提供）：本U01研究核心申请的总体目标是(a)提供选择性培育的高乙醇（EtOH）消耗大鼠，这些大鼠经历了在黑暗中饮酒（DID） EtOH狂欢饮酒协议及其对照，或来自这些大鼠的整个大脑或大脑子区域；(b)使用shRNAi和其他药理学工具来帮助识别参与EtOH暴饮暴食的易感性、发展和维持的基因、基因系统和受体。总的假设是，特定的“候选”基因及其在扩展的杏仁核和相关的大脑区域内的相关分子网络显著地促进了过量EtOH饮酒的发展和维持，并具有易感性。整个假设将通过(a)将嗜酒(P)和高酒精（HAD）大鼠（或其整个大脑或大脑区域）提供给其他INIA U01研究人员进行测试；(b)使用shRNAi减少扩展杏仁核和相关区域内“候选”基因的表达；(c)检测针对“候选”基因产物的配体及其分子网络对酗酒的影响。深入了解动物模型中导致过度饮酒行为发展和维持的复杂分子和细胞事件是非常重要的，因为这些发现将为开发针对酒精滥用和酒精中毒的新治疗策略提供必要的基础。这是一个高度创新的项目，因为它将使用最先进的技术来选择性地减少大鼠的多个遗传易感“家族”（即P， HAD1和HAD2）和参与调节饮酒的离散中枢神经系统区域的“候选”基因的表达。这个U01研究核心通过解决INIA的前两个特定目标，即确认基因靶点和确定治疗酒精滥用和酒精中毒的药物的可药物靶点，与INIA- west的几个组成部分提供协同作用。

DESCRIPTION (provided by applicant): The overall objectives of this U01 research core application are to (a) provide selectively bred high ethanol (EtOH)-consuming rats that have experienced the drinking-in-dark (DID) EtOH binge-drinking protocol and their controls, or whole brains or brain sub-regions from these rats; and (b) use shRNAi's and other pharmacological tools to help identify genes, gene systems and receptors involved in the predisposition for, and development and maintenance of, EtOH binge-drinking. The overall hypothesis is that particular 'candidate' genes and their associated molecular networks within the extended amygdala and associated brain regions significantly contribute to the development and maintenance of, and a predisposition for, excessive EtOH drinking. The overall hypothesis will be tested by (a) providing alcohol-preferring (P) and high-alcohol-drinking (HAD) rats (or their whole brains or brain regions) that have been taken through the binge drinking protocol to other INIA U01 investigators; (b) using shRNAi's to reduce expression of 'candidate' genes within the extended amygdala and associated regions; and (c) examining the effects of ligands targeted for 'candidate' gene products and their molecular networks on, binge-drinking. Providing insight into the complex molecular and cellular events that lead to the development and maintenance of excessive alcohol drinking behavior in animal models is highly significant since these findings will provide the necessary foundation for developing novel treatment strategies targeting alcohol abuse and alcoholism. This is a highly innovative project since it will use state-of-the-art techniques to selectively reduce expression of 'candidate' genes in multiple genetically predisposed 'families' (i.e., the P, HAD1 and HAD2) of rats and in discrete CNS regions that are involved in regulating alcohol drinking. This U01 research core provides synergy with several INIA-West components by addressing the first two specific aims of INIA, i.e., confirm gene targets and identify drugable targets for medications focused on treating alcohol abuse and alcoholism.