Gene Network Perturbations in Alcohol Dependence - A Systems Biology Approach

描述（由申请人提供）：强迫性酒精使用被假设为由多种强化来源驱动，这些强化来源随着个人从社交饮酒过渡到滥用和对酒精的物质依赖而变化。本项目背后的首要假设是，了解与酒精依赖相关的神经适应性变化背后的基因调节网络的失调，将有助于确定新的和更有效的酒精滥用治疗靶点。具体而言，本研究的目标是使用最先进的系统生物学策略，结合依赖诱导的升级饮酒和激光显微解剖的验证大鼠模型来重建中枢神经系统相互作用组（CNSi）。CNSi将整合多个水平的基因表达调控，包括转录（mRNA）、转录后（miRNA）和翻译后（蛋白质-蛋白质相互作用和转录因子活性调节剂）水平。CNSi将用于识别主调控基因（MRs），该基因激活与从中度到过量饮酒过渡相关的特定基因特征，这些过渡与大脑奖励和压力系统区域的依赖有关。目前的多首席研究员（MPI）项目将包括两个组成部分：1)斯克里普斯研究所（TSRI）组成部分将进行动物模型和与奖励和压力系统相关的大脑区域的激光显微解剖；2)哥伦比亚大学（CU）将执行系统生物学策略。预计过量饮酒的MRs及其活性调节剂的鉴定将为新的治疗策略和候选药物靶点提供信息。

DESCRIPTION (provided by applicant): Compulsive use of alcohol has been hypothesized to be driven by multiple sources of reinforcement that change with the individual's transition from social drinking to abuse and substance dependence on alcohol. The overarching hypothesis behind the present project is that understanding the dysregulations of the gene regulatory network that underlie the neuroadaptive changes associated with alcohol dependence will allow the identification of new and more effective therapeutic targets for alcohol abuse. Specifically, the goal of the present study is to use a state of the art systems biology strategy in conjunction with a validated rat model of dependence-induced escalated drinking and laser microdissection to reconstruct a Central Nervous System interactome (CNSi). The CNSi will integrate multiple levels of gene expression regulation including the transcriptional (mRNA), post-transcriptional (miRNA) and post-translational (protein-protein interactions and modulators of transcription factor activity) levels. The CNSi will be used to identify the master regulator genes (MRs) that activate specific gene signatures associated with the transition from moderate to excessive alcohol intake associated with dependence in brain regions of the reward and stress systems. The present multiple principal investigator (MPI) project will involve 2 components: 1) The Scripps Research Institute (TSRI) component will carry out the animal models and laser microdissections of brain regions relevant to the reward and stress systems; 2) the Columbia University (CU) component will execute the systems biology strategy. It is expected that the identification of MRs of excessive alcohol intake and modulators of their activity will inform new therapeutic strategies and candidate druggable targets.