Identification of Genetic Variants that Influence Compulsive Alcohol Intake in Outbred Rats

摘要 对药物滥用和成瘾的脆弱性具有遗传性。特别是家庭和双胞胎研究 研究表明，大约45-65%的酒精使用障碍的脆弱性是由遗传决定的。 因素在过去的十年里，遗传学的进步为寻找分子生物学提供了重要线索。 酒精使用和滥用的基础。人类全基因组关联研究（GWAS）已经扩展 在大小和复杂程度上都有很大的变化，这导致了数百个位点与一系列酒精有关， 相关特征。酒精使用障碍研究的一个主要障碍是表型的复杂性， 缺乏对环境变量的控制。我们提出一种互补的多学科方法 它将下一代测序与最先进的行为筛查相结合， 多样的非人类动物模型。这项提案的主要目标是确定基因变异， 与强迫性饮酒的脆弱性增加、耐受性和对FDA批准的 通过在N/NIH异质性储备大鼠中进行GWAS来给药。我们将使用最相关的动物 酒精使用障碍模型（即，慢性间歇性接触酒精蒸汽后的升级）和高度 强迫性酒精自我管理的标准化措施结合纵向评估， 撤退的迹象。增加这些发现的影响，促进转化和基础研究 为了研究强迫性饮酒的机制，我们还将建立一个数据/组织库， 从行为和遗传特征的动物，将使研究人员能够进一步调查 强迫性饮酒的细胞和分子机制，并确定生物学变化 与特定基因变体的表达相关。这个项目很可能会有一个持续的和强大的 对该领域的影响，因为它将（1）描述从控制到强迫性饮酒的过渡， 雄性和雌性远系繁殖大鼠，（2）确定与强迫性饮酒相关的基因， 目前FDA批准的药物，（3）创建酒精生物银行，将提供免费访问， 脑、肾、肝、脾、卵巢、睾丸、肾上腺及血液标本用各种组织保存 将允许产生诱导多能干细胞以及神经解剖学，分子， 生物化学和药理学研究的行为/遗传特征的动物。

Abstract Vulnerability to substance abuse and addiction has a heritable component. In particular, family and twin studies demonstrate that about 45-65% of the vulnerability to develop alcohol use disorder is determined by genetic factors. In the past decade, advances in genetics have provided critical clues in the search for the molecular basis of alcohol use and abuse. Human genome-wide association studies (GWAS) have expanded dramatically in size and sophistication, which has led to hundreds of loci being implicated in a range of alcohol- related traits. One major impediment to studies of alcohol use disorder is the complexity of the phenotype and the lack of control of environmental variables. We propose a complementary and multidisciplinary approach that combines next-generation sequencing with state-of-the-art behavioral screening in a unique, genetically diverse, nonhuman animal model. The primary goal of this proposal is to identify gene variants that are associated with increased vulnerability to compulsive alcohol use, tolerance and response to FDA approved medications by performing a GWAS in N/NIH heterogeneous stock rats. We will use the most relevant animal model of alcohol use disorder (i.e., escalation after chronic intermittent access to alcohol vapor) and highly standardized measures of compulsive alcohol self-administration combined with longitudinal assessment of withdrawal signs. To increase the impact of these findings and facilitate translational and basic research studies on the mechanisms underlying compulsive alcohol use, we will also establish a data/tissue repository from behaviorally and genetically characterized animals that will allow researchers to further investigate the cellular and molecular mechanisms underlying compulsive alcohol use and identify the biological changes associated with the expression of specific gene variants. This project is likely to have a sustained and powerful impact on the field because it will (1) characterize the transition from controlled to compulsive alcohol use in male and female outbred rats, (2) identify genes associated with compulsive alcohol use and the the response to the currently FDA approved medications , (3) create the Alcohol BioBank which will provide free access to brain, kidney, liver, spleen, ovary, testis, adrenal, and blood samples with a variety of tissue preservation protocols that will allow the generation of induced pluripotent stem cells as well as neuroanatomical, molecular, biochemical, and pharmacological studies on behaviorally/genetically characterized animals.