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因素。酒精中毒是一种多基因和多基因疾病：也就是说，许多基因贡献适度的影响，以提高风险或保护。总的来说，遗传因素似乎贡献了个体总风险的大约一半，另一半来自“环境”因素，如社会经济，家庭和同伴属性。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处于更高的统计风险中。一个重要的目标是能够预测风险的实际个体差异，基于对特定基因的了解。目前还没有动物模型能够捕捉到酒精戒断症状的全部范围。 在34年的持续资助中，该Merit Review Program建立并研究了许多酒精（乙醇）依赖方面的遗传动物模型，并有助于确定第一个影响药物依赖相关行为特征的基因Mpdz，影响乙醇戒断发作。由于小鼠/人的高度遗传同源性（约。85%），在小鼠中定位的基因能够预测人类基因的位置。 然而，到目前为止，几乎所有的酒精依赖的基因图谱工作都集中在戒断发作或酒精偏好饮酒上。从1999年开始，我们开始在几个行为领域（运动障碍、焦虑、活动、戒断后饮酒增加）进行研究，开始更广泛地绘制戒断的图景。一个重要的目标是确定负责增加酒精依赖风险和防止其他症状的基因。为了填补这一空白，该项目将（1）开发更全面的评估分析，以描述乙醇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，热破坏和强化;（2）阐明每种戒断效应的时间过程;（3）采用脑内微量注射技术检测一种戒断行为、加重饮酒是否存在特定的神经回路;（4）对用于乙醇依赖综合征的最广泛使用的遗传动物模型的外显子组进行测序，易戒断性惊厥（WSP）和抗戒断性惊厥（WSR）小鼠品系及其对照（WSC），以鉴定潜在的信息序列变体（SNV）;（5）使用世代策略，包括WSP × WSR的F2杂交，鉴定具有各种戒断症状的分离的SNV;和（6）继续支持WSP、WSR、WSC和近交iWSP和iWSR小鼠品系。 这些研究，通过识别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.