Systems Genetic Analysis of Mechanisms Underlying Excessive Alcohol Consumption

项目概要/摘要： 虽然从以前就有人假设酗酒和酒精依赖与遗传有关， 在现代遗传学时代，试图确定治疗靶点的努力取得了有限的成功。这一事实反映了 复杂的遗传结构导致酒精使用障碍。由于全基因组表达的出现， 随着微阵列和RNA-seq技术等平台的出现，系统遗传学已经成为一种新的遗传学途径， 研究酒精。系统遗传学使用网络分析和建模技术来绘制链接 酒精暴露的基因表达反应和酒精相关行为之间的关系。动物模型 试图反映人类的行为模式，如过度饮酒和反复狂欢/戒断 自行车.该项目将使用权重基因共表达网络分析（WGCNA），一个基于无尺度的 一种基于相关表达距离测度的表达网络构建模型， 大脑中的基因表达模式是过度饮酒的基础。这将用两个动物模型来完成 慢性酒精暴露表达数量性状基因座定位和功能生物信息学将服务于 作为WGCNA的补充分析，以最好地确定影响酒精的候选基因， 喝酒这一目标将通过以下具体目标来实现：1）识别表达 与慢性间歇性乙醇暴露相关的网络，以及使用BXD增加饮酒 重组近交系小鼠组; 2）跨重组近交系小鼠的多个脑区域进行深入的基因组分析。 C57 BL/6 J小鼠慢性间歇性乙醇暴露后的蒸汽室; 3）精炼乙醇响应 通过将小鼠中的基因网络与预处理中的乙醇响应基因网络进行比较， 恒河猴（Macaca mulatta）在程序诱导的多饮范式下的额叶皮层; 4） 用腺相关病毒载体靶向从乙醇响应网络中鉴定的候选基因， 确定基因表达改变对乙醇相关行为的影响。

Project Summary/Abstract: Although hereditary links to abusive and dependent alcohol use have been hypothesized since before the Modern Genetic Era, attempts to identify therapeutic targets have had limited success. This fact reflects the complex genetic architecture underlying alcohol use disorders. Due to the advent of genome-wide expression platforms such as microarrays and RNA-seq technologies, systems genetics has emerged as a new route of study in alcohol research. Systems genetics uses network analysis, and modeling techniques to draw links between the gene expression response to alcohol exposure, and alcohol related behaviors. Animal models seek to reflect behavioral patterns seen in humans such as excessive drinking and repeated binge/withdrawal cycles. This project will use Weight Gene Co-expression Network Analysis (WGCNA), a scale-free based model that builds expression networks based on distance measures of correlated expression, to investigate gene expression patterns in the brain underlying excessive drinking. This will be done with two animal models of chronic alcohol exposure. Expression quantitative trait loci mapping, and functional bioinformatics will serve as complimentary analyses to WGCNA in order to best identify a candidate gene that influences alcohol drinking. This objective will be accomplished though the following specific aims: 1) Identify expression networks associated with chronic intermittent ethanol exposure, and increased drinking using the BXD recombinant inbred mouse panel; 2) Perform an in-depth genomic analysis across multiple brain regions of C57BL/6J mice after chronic intermittent ethanol exposure by vapor chamber; 3) Refine ethanol responsive gene networks identified in the mouse by comparing them to ethanol responsive gene networks in the pre- frontal cortex of rhesus macaques (Macaca mulatta) under the schedule induced polydipsia paradigm; 4) Target a candidate gene identified from ethanol responsive networks with adeno-associated viral vectors to determine the effect of altered gene expression on ethanol related behaviors.