Behavioral Genomics of Alcohol Neuroadaptation

酒精神经适应的行为基因组学

• 批准号: 7208071
• 负责人: JOHN C. CRABBE
• 金额: $ 179.39万
• 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/7208071
• 关键词: 1 year old; ARHGEF5 gene; Acute; Address; Adolescent; Adult; Affect; Alcohol Withdrawal Seizures; Alcohol consumption; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Alleles; Alternative Splicing; Animal Behavior; Animal Model; Animals; Anxiety; Appendix; Area; Ataxia; Award; Bacterial Artificial Chromosomes; Base Sequence; Behavior; Behavioral; Behavioral Genetics; Biochemical; Bioinformatics; Biological; Biological Assay; Biometry; Biostatistics Core; Brain; Breathing; Breeding; Buffers; Candidate Disease Gene; Cell Nucleus; Cerebellum; Cerebral cortex; Chromatin Structure; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 4; Chronic; Clinical Research; Clinical Trials; Collaborations; Communities; Complex; Congenic Mice; Congenic Strain; DNA; DNA Methylation; Data; Data Set; Databases; Dependence; Development; Distal; Distant; Drug Addiction; Drug abuse; Education and Outreach; Embryo; Environmental Risk Factor; Epistatic Gene; Ethanol; Ethanol Metabolism; Etiology; Event; Expressed Sequence Tags; Funding; Future; Gas Chromatography; Gene Chips; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Determinism; Genetic Epistasis; Genetic Polymorphism; Genetic Risk; Genome; Genomics; Genotype; Germany; Goals; Grant; Grant Review; Gray unit of radiation dose; Health; Heart; Hippocampus (Brain); Human; Impulsive Behavior; Impulsivity; Inbred Strain; Inbreeding; Individual; Individual Differences; Influentials; Intake; Internet; Intramural Research Program; Investigation; Kidney; Knowledge; Laboratories; Link; Literature; Liver; Location; Macaca mulatta; Maps; Marriage; Mediating; Meta-Analysis; Methods; Metoclopramide; Midbrain structure; Molecular; Molecular Biology; Molecular Genetics; Moods; Mus; National Institute on Alcohol Abuse and Alcoholism; Nature; Neuroendocrinology; Neurosciences; Neurosecretory Systems; Numbers; Online Systems; Oxidoreductase; Pathway interactions; Pentobarbital; Personal Satisfaction; Pharmaceutical Preparations; Phenotype; Physicians; Pilot Projects; Polymerase Chain Reaction; Population; Population Genetics; Positioning Attribute; Postdoctoral Fellow; Process; Production; Program Research Project Grants; Proteins; Psychiatry; Psychopathology; Publishing; Quantitative Trait Loci; Radiation; Range; Rate; Reaction; Recombinant Inbred Strain; Recruitment Activity; Regulation; Relative (related person); Reporting; Research; Research Personnel; Research Project Grants; Resources; Risk; Role; Scanning; Schools; Scientist; Screening procedure; Seizures; Self Administration; Sequence Analysis; Severities; Signal Transduction; Single Nucleotide Polymorphism; Source; Spleen; Standards of Weights and Measures; Steroids; Structure; Students; System; Techniques; Technology; Temperament; Tertiary Protein Structure; Test Result; Testing; Time; Tissues; Touch sensation; Training; Transcript; Transgenic Organisms; Triad Acrylic Resin; Whole Organism; Withdrawal; Work; X Chromosome; alcohol effect; alcohol related gene; alcohol research; alcohol response; alcoholism prevention; alcoholism/alcohol abuse; base; behavior influence; behavioral genomics; behavioral pharmacology; congenic; day; drinking; drug metabolism; frontier; functional genomics; gene interaction; genetic analysis; genetic risk factor; hedonic; high school; human subject; innovation; insight; interest; member; mouse model; mutant; neuroadaptation; nonhuman primate; novel; outreach; pleiotropism; pre-doctoral; preference; problem drinker; progenitor; receptor; research study; response; science education; sedative; success; tool; trait; translational study

DESCRIPTION (provided by applicant): 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 self administration. 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.

描述（由申请人提供）：波特兰酒精研究中心 (PARC) 专注于酒精滥用、酒精中毒和特定酒精相关健康问题（例如戒断性癫痫发作）的病因学和风险预测。我们正在研究的遗传风险和保护性标记将在未来用于预防酗酒。 PARC 的第一个主题是使用行为基因组学策略，通过基因图谱和表达的研究以及新的遗传动物模型的开发，来识别乙醇神经适应的基因。 PARC 的另一个主要主题是探索与乙醇神经适应相关的潜在机制和特征。综合 PARC 和相关项目的研究结果，提出了两个具体假设。第一个是有趣的想法，即戒断和饮酒可能受到某些相同基因的影响。第二个新的假设是，高度冲动是酗酒的一个重要遗传风险因素。五个研究部分、四个核心部分和一个试点项目部分涉及这些主题和假设。教育和外展部分对博士前和博士后学生进行酒精研究培训，向公众传播研究成果，并与小学生到高中生一起参与一系列活动。三个研究项目主要集中于绘制小鼠酒精偏好和戒断基因的数量性状基因座 (QTL)。在当前的资助期间，我们已经追踪了一个QTL，并成功绘制了第一个与酒精相关的行为反应Mpdz的数量性状基因（QTG），该反应影响酒精戒断的严重程度。我们的基因发现方法正在不断发展，主要强调绘制 QTG，QTG 对性状的影响源自基因表达调控的差异。这项努力极大地扩展了我们的生物信息学工作。第四个新组成部分是开发新的冲动行为小鼠模型，建立其遗传基础，并将其与饮酒联系起来。第五个组成部分也是新的，它利用了一大群恒河猴，所有恒河猴都经过全基因组连锁扫描进行了基因分型，并在 3 个月大时进行了与气质相关的特征（例如焦虑）测试。这些动物将在一岁时接受酒精挑战，以确定酒精引起的共济失调和抗焦虑症的个体差异。我们的希望是最终对他们进行酒精自我管理测试，并回顾性地发现酒精自我管理的预测因素。 更新的另一个新特点是一个试点项目，该项目将在 PARC 中进行第一项临床研究，即甲氧氯普胺的临床试验，以观察冲动是否可以预测反应。