Behavioral Genomics of Alcohol Neuroadaptation

酒精神经适应的行为基因组学

• 批准号: 7338329
• 负责人: JOHN C. CRABBE
• 金额: $ 173.66万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7338329
• 关键词: 1 year old; ARHGEF5 gene; Address; Adolescent; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Animal Behavior; Animal Model; Animals; Anxiety; Appendix; Area; Ataxia; Behavioral; Behavioral Genetics; Biochemical; Bioinformatics; Biological Assay; Biostatistics Core; Breathing; Chromosome Mapping; Clinical Research; Clinical Trials; Congenic Strain; Data; Data Set; Dependence; Development; Education and Outreach; Ethanol; Etiology; Funding; Future; Gas Chromatography; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Risk; Genome; Genotype; Goals; Grant; Grant Review; Health; Human; Impulsive Behavior; Impulsivity; Individual; Individual Differences; Influentials; Link; Literature; Macaca mulatta; Maps; Meta-Analysis; Metoclopramide; Molecular; Molecular Biology; Molecular Genetics; Moods; Mus; National Institute on Alcohol Abuse and Alcoholism; Neuroendocrinology; Neurosciences; Numbers; Pharmaceutical Preparations; Pilot Projects; Psychiatry; Psychopathology; Quantitative Trait Loci; Range; Recruitment Activity; Research; Research Personnel; Research Project Grants; Resources; Risk; Role; Scanning; Schools; Screening procedure; Seizures; Self Administration; Severities; Single Nucleotide Polymorphism; Students; Temperament; Testing; Tissues; Training; Withdrawal; alcohol related gene; alcohol research; alcohol response; alcoholism prevention; alcoholism/alcohol abuse; base; behavioral genomics; behavioral pharmacology; drinking; genetic risk factor; high school; human subject; mouse model; neuroadaptation; nonhuman primate; novel; outreach; preference; problem drinker; response; science education; trait

The Portland Alcohol Research Center (PARC) focuses on the etiology and prediction of risk of alcohol abuse, alcoholism, and specific alcohol-related health problems (e.g., withdrawal seizures). The genetic risk and protective markers that we are studying will be of utility in the future for prevention of alcoholism. The first theme of the PARC is to use behavioral genomics strategies, through studies of gene mapping and expression, and development of new genetic animal models, to identify genes underlying ethanol neuroadaptation. The other main PARC theme is exploring mechanisms underlying and traits related to ethanol neuroadaptation. Two specific hypotheses have developed from the synthesis of PARC and related projects' findings. The first is the intriguing idea that withdrawal and drinking may be influenced by some of the same genes. The second emergent hypothesis is that high impulsivity is a significant genetic risk factor for high alcohol drinking. Five research components, four core components, and a pilot project component address these themes and hypotheses. An Education and Outreach component trains pre and postdoctoral students in alcohol research, disseminates research findings to the public, and engages in a range of activities with elementary-to-high school students. Three research projects focus intensively on mapping quantitative trait loci (QTLs) for alcohol preference and withdrawal genes in mice. During the current period of funding, we have pursued one QTL and have successfully mapped the first quantitative trait gene (QTG) for an alcohol-related behavioral response, Mpdz, which influences alcohol withdrawal severity. Our gene finding approaches are evolving to include a major emphasis on mapping QTGs whose effects on the trait are derived from differences in regulation of gene expression. This effort has led to a significant expansion in our bioinformatics efforts. A fourth, new component is developing novel mouse models for impulsive behavior, establishing their genetic basis, and relating them to alcohol consumption. The fifth component, also new, takes advantage of access to a large colony of rhesus monkeys, all of whom have been genotyped in a full-genome linkage scan, and were tested at 3 months old for temperament-related traits (e.g., anxiety). These animals will be given an alcohol challenge at 1 year old to determine individual differences in alcohol-induced ataxia and anxiolysis. Our hope is to test them eventually for alcohol self-administration, and retrospectively to discover predictors of alcohol selfadministration. The other new feature in the renewal is a pilot project that will perform the first clinical study in the PARC, a clinical trial of metoclopramide, to see whether impulsivity predicts response.

波特兰酒精研究中心（PARC）重点介绍了酒精风险的病因和预测 滥用，酗酒和与酒精有关的健康问题（例如，戒断癫痫发作）。遗传风险 我们正在研究的保护标记将来将有效用，以预防酒精中毒。这 PARC的第一个主题是通过研究基因映射使用行为基因组学策略 以及新遗传动物模型的表达和发展，以鉴定基因 乙醇神经加热。另一个主要的PARC主题是探索基础和特征的机制 与乙醇神经适应有关。从PARC的合成中提出了两个特定的假设 和相关项目的发现。首先是一个有趣的想法，即戒断和饮酒可能受到影响 通过一些相同的基因。第二个出现的假设是，高冲动性是一种重要的遗传 高饮酒的危险因素。五个研究组件，四个核心组件和一个试点项目 组件解决这些主题和假设。教育和外展成分训练前和 博物馆研究的博士后学生，向公众传播研究结果，并从事 与小学生的一系列活动。三个研究项目的重点是 绘制小鼠酒精偏好和戒断基因的定量性状基因座（QTL）。在 当前的资金时期，我们追求了一个QTL，并成功映射了第一个QTL 用于酒精相关的行为反应MPDZ的定量性状基因（QTG），它影响 戒酒的严重程度。我们的基因发现方法正在不断发展，以包括对 映射对性状影响的QTG来自基因表达调节的差异。这 努力导致了我们的生物信息学努力的显着扩展。第四个新组件正在开发 新颖的小鼠模型，用于冲动行为，建立遗传基础并将其与酒精有关 消耗。第五个组成部分（也是新的）利用了进入大型恒河所的机会 猴子，所有的猴子都在全基因组链接扫描中进行了基因分型，并在3个月大时进行了测试 对于与气质相关的特征（例如焦虑）。这些动物将在1岁时受到酒精挑战 确定酒精引起的共济失调和抗焦虑分析的个体差异。我们的希望是测试他们 最终为了自我管理，并回顾性地发现酒精自我管理的预测指标。 续约中的另一个新功能是一个试点项目，该项目将进行第一个临床研究 在PARC中，是甲氧氯普胺的临床试验，以查看冲动性是否预测了反应。