Genetic Models of Alcoholism

酗酒的遗传模型

• 批准号: 8258636
• 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/8258636
• 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）： 酒精中毒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，许多基因对增强风险或保护产生了适度的影响。总之，遗传因素似乎贡献了一个人总风险的一半，另一半来自“环境”因素，例如社会经济，家庭和同伴属性。现在，我们只能预测，基于其与酒精中毒的遗传关系，个人可能面临统计风险的增加。一个重要的目标是基于对特定基因的知识来预测风险中的实际个体差异。目前没有动物模型可以捕获各种戒酒症状。在29年的持续资金中，该优点审查计划已建立并研究了许多遗传动物模型，以实现酒精（乙醇）依赖性方面，并有助于鉴定影响药物依赖性相关行为性状MPDZ的第一个基因MPDZ，从而影响了乙醇撤离癫痫发作。由于小鼠/人类遗传同源性的高度（约85％），在小鼠中映射的基因能够预测人类基因位置。但是，迄今为止，几乎所有小组对乙醇依赖的基因映射工作都集中在戒断或酒精偏爱饮酒上。从1999年开始，我们开始在几个行为领域进行研究，以更广泛地开始绘制撤离的景观。一个重要的目标是确定负责增加风险的基因，并保护酒精依赖的几种不同症状。在填补这一空白时，该项目将（1）制定更全面的评估测定法，以描述多种行为的乙醇提取效果，包括焦虑，活动，运动表现和戒断诱导的饮酒； （2）阐明每种戒断效应的时间过程； （3）确定表现出戒断诱导的表达变化的基因； （4）继续支持最广泛使用的乙醇依赖性遗传动物模型，戒断癫痫发作和戒断癫痫发作的小鼠系。通过鉴定受酒精依赖和戒断症状影响的基因靶标，这些研究最终将直接提出可能针对酒精中毒的问题的药物治疗。 公共卫生相关性： VA在药物滥用，VA研究优先领域以及尤其是酒精研究方面的领导才能众所周知。在大部分VA医院患者中，始终诊断出与酒精有关的疾病。在一项对在VA医疗中心治疗的所有男性退伍军人（n = 539,557）的研究中，将近四分之一的诊断均具有物质相关的诊断，其中87.7％被诊断为酒精依赖性。对于酒精依赖性，女性和男性退伍军人的患病率也比一般人群高得多。滥用饮酒障碍在内的药物滥用是VA医疗保健系统的前三名诊断之一[VA研究电流，2007年1月]。 2008年5月，VHA药物使用障碍（SUD）Factsheet报告说，在VA卫生设施中介绍的355,000名退伍军人除尼古丁依赖外。 [*] Davis TM，Bush KR，Kivlahan DR，Dobie DJ，Bradley KA。 （2003）。在VA医疗保健系统中，在女性患者中筛查药物滥用和精神疾病。 Psychiatr Serv 54：214-8。