Genetics of Alcohol Sensitivity in Rats

描述(由申请人提供)：发生酒精中毒的一个重要的遗传风险因素是对急性剂量的酒精的不同敏感性。利用来自选择性繁殖的大鼠品系的分离群体，我们在大鼠染色体1和2上定位了对酒精的急性反应的数量性状基因座(QTL)，即翻正反射丧失(LORR)的持续时间。我们随后创造了同源基因和重组同源基因系，它们在确认QTL的同时减少了它们的基因组大小。我们假设在QTL区间内有一个或多个基因通过对基因表达和/或基因产物结构的多态相关影响而导致LOR的遗传变异。第二个重要的假设是，这些相同的基因将影响与酒精奖励相关的行为的遗传差异。为了解决这些假设，该项目将实现四个具体目标：1)使用重组同源基因策略对1号和2号染色体的QTL进行精细定位；2)在1号和2号染色体的精细定位区域中寻找候选基因；3)确定受QTL影响的丰富的功能通路和基因网络；以及4)确定1和2号染色体的QTL是否具有与酒精奖励相关的多效性。将使用当代遗传和基因组方法以及分析方法，包括高通量DNA和RNA测序，以实现这些目标。我们认为，这些实验的结果将为了解急性酒精敏感性的遗传变异的性质提供洞察力。这反过来将有助于更深入地了解人类酗酒的遗传风险。 公共卫生相关性：酒精中毒的发生和维持既受环境因素的影响，也受遗传因素的影响。该项目旨在识别影响急性酒精敏感性变异的基因，这一特征被认为是导致酒精中毒的遗传风险。这些知识对于全面了解酒精中毒的分子基础以及开发新的或改进的治疗策略是必不可少的。

DESCRIPTION (provided by applicant): An important genetic risk factor for the development of alcoholism is differential sensitivity to an acute dose of alcohol. Using segregating populations derived from selectively bred rat lines, we have mapped quantitative trait loci (QTLs) on rat chromosomes 1 and 2 for an acute response to alcohol, the duration of the loss of righting reflex (LORR). We have subsequently generated congenic and recombinant congenic lines that have confirmed the QTLs while simultaneously reducing their genomic size. We hypothesize that there are one or more genes within the QTL intervals that contribute to genetic variance for LORR through polymorphism- related effects on gene expression and/or on the structure of the genes' products. A second important hypothesis is that these same genes will influence genetic variance in alcohol reward-related behaviors. To address these hypotheses, the project will carry out four Specific Aims: 1) Fine-map the chromosome 1 and 2 QTLs using the recombinant congenic strategy; 2) Identify candidate genes in the fine-mapped areas of the chromosome 1 and 2 QTLs; 3) Identify enriched functional pathways and gene networks that are affected by the QTLs; and 4) Determine if the chromosome 1 and 2 QTLs are pleiotropic with alcohol reward-related behaviors. Contemporary genetic and genomic methods and analytical approaches, including high-throughput DNA and RNA sequencing, will be used to accomplish the goals of the Aims. We propose that the results of these experiments will offer insight into the nature of genetic variance for acute alcohol sensitivity. This in turn will contribute to a deeper understanding of genetic risk for human alcoholism. PUBLIC HEALTH RELEVANCE: The initiation and maintenance of alcoholism is influenced by both environmental and genetic factors. This project aims to identify genes that influence variation in acute alcohol sensitivity, a trait that is thought to contribute to genetic risk for alcoholism. Such knowledge is essential for a complete understanding of the molecular basis of alcoholism and for the development of new or improved strategies for its treatment.