Genetic Models of Alcoholism

描述(由申请人提供)： 酗酒和酒精依赖是美国退伍军人面临的健康问题的重要原因。酒精中毒是一种多基因和多基因的疾病：也就是说，许多基因对增加风险或保护作用的影响不大。总的来说，遗传因素似乎占个人总风险的大约一半，另一半来自“环境”因素，如社会经济、家庭和同龄人的属性。我们现在只能根据一个人与酗酒者的遗传关系来预测他或她可能面临更高的统计风险。一个重要的目标是能够基于对特定基因的了解来预测实际的个体风险差异。目前还没有一种动物模型可以捕捉到酒精戒断的全部症状。在34年的持续资助中，这个功绩审查计划建立和研究了许多酒精(乙醇)依赖方面的遗传动物模型，并帮助识别了第一个影响药物依赖相关行为特征Mpdz的基因，该基因影响酒精戒断发作。由于小鼠/人类的遗传同源性很高(约85%)，在老鼠身上定位的基因能够预测人类基因的位置。然而，到目前为止，几乎所有关于酒精依赖的基因图谱工作都集中在戒断发作或偏爱饮酒上。从1999年开始，我们开始在几个行为领域(运动障碍、焦虑、活动、戒酒后饮酒增加)进行研究，以开始更广泛地描绘戒断的图景。一个重要的目标是确定导致酒精依赖额外症状风险增加和预防的基因。为了填补这一空白，该项目将(1)开发更全面的评估方法来描述酒精戒断对多种行为的影响，包括疼痛敏感性、快感缺失/抑郁、学习和记忆/认知障碍、热干扰和强化；(2)阐明每种戒酒效应的时间进程；(3)使用脑显微注射来测试特定的神经回路是否支持一种戒酒行为，即加剧饮酒；(4)对酒精依赖综合征最广泛使用的遗传动物模型，即戒断发作倾向(WSP)和戒断发作抵抗(WSR)小鼠系及其对照(WSC)的外显子组测序，以确定潜在的信息序列变体(SNV)；(5)利用世代策略，包括WSP×WSR的F2杂交，识别分离出不同戒断症状的SNV；以及(6)继续支持WSP、WSR、WSC以及近交系IWSP和IWSR小鼠品系。这些研究通过确定受酒精依赖和戒断症状影响的基因靶点，最终将直接提出可能的药物疗法来治疗酒精中毒的潜在问题。

DESCRIPTION (provided by applicant): Alcoholism and alcohol dependence are important contributors to health problems facing US veterans. Alcoholism is a multigenic and polygenic disease: that is, many genes contribute modest effects to enhance risk or protection. Together, genetic factors appear to contribute approximately half of an individual's total risk, with the other half coming from "environmental" factors, such as socioeconomic, family, and peer attributes. We can now only predict that an individual may be at an increased statistical risk based on his or her genetic relationships to alcoholics. One important goal is to be able to predict actual individual differences in risk, base on knowledge about specific genes. There is currently no animal model that captures the full range of alcohol withdrawal symptoms. During 34 years of continuous funding, this Merit Review Program has established and studied a number of genetic animal models for aspects of alcohol (ethanol) dependence, and has contributed to the identification of the first gene influencing a drug-dependence related behavioral trait, Mpdz, influencing ethanol withdrawal seizures. Because of the high degree of mouse/human genetic homology (approx. 85%), genes mapped in mice are able to predict human gene locations. However, to date, nearly all gene mapping efforts for ethanol dependence by any group have focused on either withdrawal seizures or alcohol preference drinking. Beginning in 1999, we began studies in several behavioral domains (motor impairment, anxiety, activity, increased drinking after withdrawal) to start mapping the landscape of withdrawal more broadly. An important goal is to identify the genes responsible for increased risk for and protection against additional symptoms of alcohol dependence. In filling this gap, this project will (1) develop more comprehensive assessment assays to describe ethanol withdrawal effects across multiple behaviors, including pain sensitivity, anhedonia/depression, learning & memory /cognitive impairment, thermal disruption, and reinforcement; (2) elucidate the time course of each of these withdrawal effects; (3) use brain microinjection to test whether a specific neural circuit underlies one withdrawal behavior, exacerbated drinking; (4) sequence the exomes of the most widely used genetic animal model for ethanol dependence syndromes, the Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) mouse lines and their Controls (WSC), to identify potentially informative sequence variants (SNVs); (5) using generational strategies, including an F2 cross of WSP x WSR, identify SNVs that segregate with various withdrawal symptoms; and (6) continue to support the WSP, WSR, WSC, and inbred iWSP and iWSR mouse lines. These studies, through identification of gene targets that are affected by alcohol dependence and withdrawal symptoms, will ultimately directly suggest possible pharmacotherapies for the problems underlying alcoholism.