Genetic Models of Alcoholism

酗酒的遗传模型

• 批准号: 7687326
• 负责人: JOHN C. CRABBE
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687326
• 关键词: Affect; Alcohol dependence; Alcohol withdrawal syndrome; Alcohol-Related Disorders; Alcoholism; Alcohols; Animal Model; Anxiety; Appearance; Area; Behavior; Behavioral; Biological Assay; Brain; Chromosome Mapping; Chronic; Convulsions; Dependence; Development; Diagnosis; Disease; Dose; Drug Addiction; Environmental Risk Factor; Ethanol; Ethanol dependence; Etiology; Family; Female; Funding; Gene Cluster; Gene Expression; Gene Expression Profile; Gene Targeting; Gene-Modified; General Population; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Goals; Grant; Health; Health care facility; Healthcare Systems; High Prevalence; Hospitals; Human; Human Genetics; Inbreeding; Individual; Individual Differences; Knowledge; Laboratories; Leadership; Location; Maintenance; Maps; Measures; Medical center; Mental disorders; Motor; Motor Activity; Mus; Nervous system structure; Nicotine Dependence; Patients; Pattern; Performance; Pharmacotherapy; Phenotype; Physical Dependence; Program Reviews; Reaction; Reporting; Research; Research Personnel; Research Priority; Resistance; Risk; Seizures; Severities; Substance Abuse Detection; Substance Use Disorder; Substance Withdrawal Syndrome; Substance abuse problem; Symptoms; Time; Time Study; Veterans; Withdrawal; Withdrawal Symptom; Woman; alcohol research; alcohol use disorder; base; behavior test; complement C2a; drinking; expectation; male; motor impairment; neurobiological mechanism; peer; preference; problem drinker; programs; research study; response; socioeconomics; trait; vapor

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.

描述（由申请人提供）： 酗酒和酒精依赖是美国退伍军人面临健康问题的重要原因。酗酒是一种多基因和多基因疾病：也就是说，许多基因对增强风险或保护作用有一定作用。总的来说，遗传因素似乎约占个人总风险的一半，另一半来自“环境”因素，例如社会经济、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的统计风险可能会增加。一个重要的目标是能够根据特定基因的知识预测实际的个体风险差异。目前还没有动物模型能够捕捉到全部的酒精戒断症状。在持续资助的 29 年中，该优异评审计划已建立并研究了多种酒精（乙醇）依赖方面的遗传动物模型，并为鉴定第一个影响药物依赖相关行为特征的基因 Mpdz 做出了贡献，影响乙醇戒断癫痫发作。由于小鼠/人类遗传同源性很高（约 85%），小鼠基因图谱能够预测人类基因位置。然而，迄今为止，任何群体对乙醇依赖的几乎所有基因图谱工作都集中在戒断性癫痫发作或酒精偏好饮酒上。从 1999 年开始，我们开始在多个行为领域进行研究，以更广泛地绘制戒断图景。一个重要的目标是确定导致酒精依赖的几种不同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多种行为中的乙醇戒断效应，包括焦虑、活动、运动表现和戒断引起的饮酒； (2) 阐明每种戒断效应的时间进程； (3) 鉴定显示戒断诱导表达变化的基因； (4) 继续支持最广泛使用的乙醇依赖综合征遗传动物模型，即易出现戒断性癫痫发作和抗戒断性癫痫发作的小鼠品系。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，最终将直接提出针对酒精中毒问题的可能药物疗法。 公共卫生相关性： 退伍军人事务部在药物滥用、退伍军人事务部研究优先领域、特别是酒精研究方面的领导地位是众所周知的。退伍军人管理局医院的大部分患者一直被诊断出与酒精相关的疾病。在一项针对在退伍军人管理局医疗中心接受治疗的所有男性退伍军人（n=539,557）一年期间的研究中，近四分之一的人被诊断出与物质相关的诊断，其中 87.7% 被诊断为酒精依赖。女性和男性退伍军人的酒精依赖患病率也比一般人群高得多[*]。包括酒精使用障碍在内的药物滥用是 VA 医疗保健系统中排名前 3 位的诊断之一 [VA Research Currents，2007 年 1 月]。 2008 年 5 月 VHA 药物滥用障碍 (SUD) 情况说明书报道，在 VA 医疗机构就诊的 355,000 名退伍军人除了尼古丁依赖之外还患有 SUD。 [*] Davis TM、Bush KR、Kivlahan DR、Dobie DJ、Bradley KA。 （2003）。对 VA 医疗保健系统中的女性患者进行药物滥用和精神疾病筛查。精神病学服务 54：214-8。