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29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进行研究，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几种不同症状的风险增加和保护作用的基因。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，包括焦虑、活动、运动表现和戒断诱导饮酒；(2)阐明每种戒酒影响的时间进程；(3)确定显示戒断诱导表达变化的基因；以及(4)继续支持酒精依赖综合征最广泛使用的遗传动物模型，即易戒断和耐戒断的小鼠系。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。 公共卫生相关性： 退伍军人管理局在药物滥用方面的领导作用是众所周知的，这是退伍军人事务部研究的优先领域，特别是酒精研究。在退伍军人医院的患者中，有很大一部分人一直被诊断为与酒精相关的疾病。在一项对退伍军人医疗中心接受治疗的所有男性退伍军人(n=539,557人)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有关，其中87.7%被诊断为酒精依赖。女性和男性退伍军人的酒精依赖患病率也远远高于普通人群[*]。包括酒精使用障碍在内的物质滥用是退伍军人医疗保健系统的前三大诊断之一[退伍军人研究动态，2007年1月]。2008年5月，VHA物质使用障碍(SUD)情况说明书报告称，在退伍军人管理局就诊的355,000名退伍军人患有除尼古丁依赖以外的其他物质使用障碍。[*]Davis TM，Bush KR，Kivlahan Dr，Dobie DJ，Bradley Ka。(2003)。在退伍军人保健系统中对女性患者进行药物滥用和精神障碍的筛查。精神病学家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.