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) 专注于酒精风险的病因学和预测 滥用、酗酒和特定的与酒精相关的健康问题（例如戒断性癫痫发作）。遗传风险 我们正在研究的保护性标记将来可用于预防酗酒。这 PARC 的第一个主题是通过基因图谱研究使用行为基因组学策略 和表达以及新的遗传动物模型的开发，以确定潜在的基因 乙醇神经适应。 PARC 的另一个主要主题是探索潜在的机制和特征 与乙醇神经适应有关。 PARC 的综合提出了两个具体假设 以及相关项目的调查结果。第一个是有趣的想法，即戒断和饮酒可能会受到影响 由一些相同的基因。第二个新出现的假设是，高冲动性是一种重要的遗传因素。 大量饮酒的危险因素。五个研究部分、四个核心部分和一个试点项目 组件解决这些主题和假设。教育和外展部分对预习和外展进行培训 从事酒精研究的博士后学生，向公众传播研究成果，并从事 与小学生到高中学生一起开展的一系列活动。三个研究项目集中关注 绘制小鼠酒精偏好和戒断基因的数量性状位点（QTL）。期间 本期资助，我们已经追踪了一个QTL并成功定位了第一个QTL 与酒精相关的行为反应的数量性状基因（QTG）Mpdz，它影响 酒精戒断的严重程度。我们的基因寻找方法正在不断发展，主要强调 绘制QTG，其对性状的影响源自基因表达调控的差异。这 我们的努力极大地扩展了我们的生物信息学工作。第四个新组件正在开发中 研究冲动行为的新型小鼠模型，建立其遗传基础，并将其与酒精联系起来 消耗。第五个组成部分也是新的，利用了一大群恒河猴的优势 猴子，所有猴子均已通过全基因组连锁扫描进行基因分型，并在 3 个月大时进行了测试 与气质相关的特征（例如焦虑）。这些动物将在 1 岁时接受酒精挑战 确定酒精引起的共济失调和焦虑症的个体差异。我们的希望是测试它们 最终进行酒精自我管理，并回顾性地发现酒精自我管理的预测因素。 更新的另一个新功能是一个试点项目，该项目将进行首次临床研究 在 PARC 中，一项甲氧氯普胺的临床试验，旨在观察冲动是否可以预测反应。