Rat Animal Models and Gene Testing Core

描述（由申请人提供）：该U 01研究核心申请的总体目标是（a）提供选择性饲养的高乙醇（EtOH）消耗大鼠，其经历了黑暗中饮酒（DID）EtOH狂饮方案及其对照，或来自这些大鼠的全脑或脑亚区;和（B）使用shRNAi和其它药理学工具来帮助鉴定参与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”基因及其相关的分子网络内的扩展杏仁核和相关的大脑区域显着有助于发展和维护，和一个倾向，过量乙醇饮用。将通过（a）提供酒精偏好（P）和高酒精饮用（HAD）大鼠，（B）使用shRNAi减少延伸杏仁核和相关区域内“候选”基因的表达;以及（c）检测靶向“候选”基因产物的配体及其分子网络对暴饮暴食的影响。深入了解导致动物模型中过量饮酒行为的发展和维持的复杂分子和细胞事件具有非常重要的意义，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多个遗传易感“家庭”中“候选”基因的表达（即，P、HAD 1和HAD 2）以及参与调节饮酒的离散CNS区域。该U 01研究核心通过解决INIA的前两个具体目标，即，确认基因靶点，并为治疗酒精滥用和酒精中毒的药物确定药物靶点。

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.