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根据对特定基因的了解来预测风险的实际个体差异。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29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进行研究，开始更广泛地描绘戒断的景观。一个重要的目标是确定负责增加风险的基因，并防止酒精依赖的几种不同症状。为了填补这一空白，本项目将（1）开发更全面的评估分析，以描述多种行为的乙醇戒断效应，包括焦虑，活动，运动表现和戒断诱导的饮酒;（2）阐明这些戒断效应中的每一种的时间过程;（3）鉴定表现出戒断诱导表达变化的基因;和（4）继续支持最广泛使用的乙醇依赖综合征遗传动物模型，戒断性癫痫倾向和戒断性癫痫抵抗小鼠系。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。 公共卫生相关性： VA在药物滥用方面的领导地位，VA研究优先领域，特别是酒精研究是众所周知的。酒精相关的疾病一直被诊断出在VA医院的病人的很大一部分。在一项对所有在VA医疗中心接受治疗的男性退伍军人（n= 539，557）进行的为期一年的研究中，近四分之一的人被诊断为与物质相关的诊断，其中87.7%被诊断为酒精依赖。女性和男性退伍军人也有更高的患病率比一般人群[*]酒精依赖。物质滥用（包括酒精使用障碍）是VA医疗保健系统的前3大诊断之一[VA Research Currents，2007年1月]。2008年5月，VHA物质使用障碍（SUD）情况说明书报告说，355，000名退伍军人在VA卫生设施中出现SUD而不是尼古丁依赖。 [*] Davis TM、Bush KR、Kivlahan DR、Dobie DJ、布拉德利KA。（2003年）的报告。筛选物质滥用和精神疾病的妇女患者在VA卫生保健系统。Psychiatr Serv 54：214-8.

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, based on knowledge about specific genes. There is currently no animal model that captures the full range of alcohol withdrawal symptoms. During 29 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 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 the several different 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 anxiety, activity, motor performance, and withdrawal-induced drinking; (2) elucidate the time course of each of these withdrawal effects; (3) identify genes which demonstrate withdrawal-induced changes in expression; and (4) continue to support the most widely used genetic animal model for ethanol dependence syndromes, the Withdrawal Seizure-Prone and Withdrawal Seizure-Resistant 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. PUBLIC HEALTH RELEVANCE: The VA's leadership in substance abuse, a VA Research Priority Area, and in particular alcohol research is well known. Alcohol-related disorders have consistently been diagnosed in a large proportion of VA hospital patients. In a study of all male veterans (n=539,557) treated at VA medical centers during a one-year period, nearly one-quarter had a substance-related diagnosis, and of those, 87.7% were diagnosed with Alcohol Dependence. Female and male veterans also have much higher prevalence rates than the general population [*] for Alcohol Dependence. Substance abuse including alcohol use disorders is among the top 3 diagnoses in the VA healthcare system [VA Research Currents, January, 2007]. The May, 2008 VHA Substance Use Disorder (SUD) Factsheet reported that 355,000 veterans who presented at VA health facilities had SUD other than nicotine dependence. [*] Davis TM, Bush KR, Kivlahan DR, Dobie DJ, Bradley KA. (2003). Screening for substance abuse and psychiatric disorders among women patients in a VA Health Care System. Psychiatr Serv 54:214-8.