Systems Genetic Analysis of Mechanisms Underlying Excessive Alcohol Consumption

项目摘要/摘要： 尽管遗传因素与酗酒和酗酒的关系早在以前就被假设 在现代遗传学时代，寻找治疗靶点的尝试收效甚微。这一事实反映了 酒精使用障碍背后的复杂遗传结构。由于全基因组表达的到来 例如微阵列和rna-seq技术，系统遗传学已经成为一条新的途径。 酒精研究方面的研究。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与酒精相关行为之间的关系。动物模型 寻求反映人类的行为模式，如过度饮酒和反复酗酒/戒断 循环。该项目将使用权重基因共表达网络分析(WGCNA)，这是一个基于 基于相关表达的距离度量构建表达网络的模型，用于研究 过量饮酒背后的大脑基因表达模式。这将通过两个动物模型来完成 长期酗酒。表达数量性状基因座定位和功能生物信息学将为 作为对WGCNA的补充分析，以便最好地识别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 与慢性间歇性酒精暴露相关的网络，以及使用BXD增加饮酒量 重组近交系小鼠小组；2)在多个大脑区域进行深入的基因组分析 蒸汽室慢性间歇性酒精暴露后C57BL/6J小鼠；3)提纯乙醇反应 小鼠的基因网络通过比较它们与酒精反应基因网络在小鼠中的差异 程序诱导多饮范式下恒河猴(Macaca Mulatta)额叶皮质的研究 用腺相关病毒载体靶向从乙醇反应网络中鉴定的候选基因 确定基因表达改变对酒精相关行为的影响。

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.