Rat Animal Models and Gene Testing Core

描述(申请人提供)：本U01研究核心申请的总体目标是：(A)提供选择性培育的经历过黑暗中饮酒(DID)酒精狂饮协议的高乙醇(Etoh)消费大鼠及其对照，或这些大鼠的全脑或脑内亚区；(B)利用shRNAi及其他药理学工具帮助确定参与酒精暴饮症易感、发展和维持的基因、基因系统和受体。总体假设是，杏仁核和相关脑区中特定的候选基因及其相关的分子网络对酒精过量饮酒的发育和维持以及酒精过量的易感性有重要作用。这一总体假设将通过以下方式进行检验：(A)向其他INIA U01研究人员提供通过酗酒方案获得的偏爱酒精(P)和酗酒(HAD)大鼠(或其整个大脑或大脑区域)；(B)使用shRNAi来减少扩展的杏仁核及其相关区域内的“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。在动物模型中洞察导致过度饮酒行为发生和维持的复杂分子和细胞事件具有重要意义，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。这是一个极具创新性的项目，因为它将使用最先进的技术来选择性地减少多个遗传易感‘家族’(即P、HAD1和HAD2)中的‘候选’基因的表达，以及在参与调节饮酒的离散中枢神经系统区域中。这一U01研究核心通过解决INIA的前两个具体目标，即确认基因靶点和确定专注于治疗酒精滥用和酒精中毒的药物的可药物靶点，与INIA-WEST的几个成分协同作用。

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.