Genetic Models of Alcoholism

酗酒的遗传模型

• 批准号: 8810582
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8810582
• 关键词: Acute; Affect; Afghanistan; Air; Alcohol dependence; Alcohol withdrawal syndrome; Alcohol-Related Disorders; Alcoholism; Alcohols; Anhedonia; Animal Model; Animals; Anxiety; Area; Basal Ganglia; Behavior; Behavioral; Behavioral Assay; Biological Assay; Brain; Chromosome Mapping; Convulsions; Dependence; Development; Diagnosis; Disease; Dose; Drug Addiction; Drug Use Disorder; Enrollment; Environmental Risk Factor; Ethanol; Ethanol dependence; Etiology; Family; Female; Funding; Gene Targeting; General Population; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Genetic study; Genomics; Genotype; Goals; Grant; Health; Healthcare; High Prevalence; Hospitals; Human; Human Genetics; Impaired cognition; Inbreeding; Individual; Individual Differences; Iraq; Knowledge; Lateral; Leadership; Learning; Location; Maps; Measures; Memory; Mental Depression; Microinjections; Motor; Mus; Nicotine Dependence; Pain; Patients; Performance; Pharmacotherapy; Phenotype; Play; Primary Health Care; Program Reviews; Psychological reinforcement; Quantitative Trait Loci; Relapse; Research; Research Personnel; Research Priority; Resistance; Risk; Role; Seizures; Severities; Substance Use Disorder; Substance Withdrawal Syndrome; Substance abuse problem; Substantia nigra structure; Symptoms; Testing; Time; Update; Variant; Veterans; Withdrawal; Withdrawal Symptom; alcohol effect; alcohol misuse; alcohol research; alcohol sensitivity; alcohol use disorder; anxiety-like behavior; base; behavior test; drinking; exome sequencing; genetic variant; hedonic; interest; male; motor impairment; neural circuit; patient population; peer; peer influence; preference; problem drinker; programs; public health relevance; putamen; relating to nervous system; research study; response; segregation; 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, 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.

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。一个重要的目标是能够预测风险中的实际个体差异，基于有关特定基因的知识。目前没有动物模型可以捕获各种戒酒症状。 在34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，以依靠酒精（乙醇）依赖性方面，并有助于鉴定出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（运动障碍，焦虑，活动，戒断后增加饮酒）开始研究，以开始更广泛地绘制撤离的景观。一个重要的目标是确定负责增加风险的基因，并防止其他酒精依赖症状。在填补这一空白时，该项目将（1）开发更全面的评估测定法，以描述多种行为的乙醇戒断效应，包括疼痛敏感性，Anhedonia /抑郁症，学习与记忆 /认知障碍，热中断和增强型； （2）阐明每种戒断效应的时间过程； （3）使用大脑显微注射来测试特定的神经回路是否是一种戒断行为的基础，加剧了饮酒； （4）序列乙醇依赖性综合征最广泛使用的遗传动物模型的外观，戒断癫痫发作（WSP）和抗戒断癫痫发作（WSR）小鼠系及其对照（WSC），以识别潜在的信息序列变体（SNVS）； （5）使用世代相传的策略，包括WSP X WSR的F2交叉，识别出具有各种戒断症状的SNV； （6）继续支持WSP，WSR，WSC和INBRED IWSP和IWSR鼠标线。 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。