Genetic Studies of Alcohol Tolerance

酒精耐受性的遗传学研究

• 批准号: 8371962
• 负责人: RICHARD A RADCLIFFE
• 金额: $ 12.99万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-20 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8371962
• 关键词: Acute; Alcoholism; Alcohols; Alternative Splicing; Animal Model; Behavior; Behavioral; Behavioral Genetics; Brain; Cerebellum; Complex; Control Groups; DNA Sequence; Data; Development; Dose; Ethanol; Gene Expression; Genes; Genetic; Genetic Models; Genetic Risk; Genome; Genotype; Goals; Haplotypes; Human; Hybrids; Inbred Strains Mice; Inbreeding; Individual; Knowledge; Laboratory mice; Maintenance; Maps; Measures; Mediating; Methodology; Modeling; Molecular; Molecular Genetics; Molecular Profiling; Mouse Strains; Mus; Nature; Procedures; Prosencephalon; Quantitative Trait Loci; RNA; RNA Sequences; Recombinant Inbred Strain; Recombinants; Reflex action; Risk; Risk Factors; Saline; Sampling; Sleep; Structure; Technology; Testing; Transcript; Variant; alcohol exposure; alcohol response; alcohol sensitivity; alcohol use disorder; base; comparative; drinking behavior; gene environment interaction; genetic risk factor; genetics of alcoholism; genome sequencing; hypnotic; improved; insight; instrument; next generation; progenitor; research study; response; structural genomics; tool; trait

DESCRIPTION (provided by applicant): An important genetic risk factor for the development of alcoholism is differential sensitivity to an acute dose of alcohol. Acute alcohol responses are a function of the combined effects of initial sensitivity and acute functional tolerance (AFT), bot of which are influenced by genetic factors. Using inbred mouse strains, we have been using a paradigm known as rapid tolerance - tolerance that develops within 24 hrs following a single exposure to alcohol - as a tool to investigate the genetics of acute alcohol responses. We have found that the Inbred Long and Short Sleep mouse strains (ILS and ISS) differ considerably in their ability to develop rapid tolerance using the loss of righting reflex test (LORR) as the measure of sensitivity. This strain- dependent difference appears to be mediated at least partly by differential effects on AFT. We hypothesize that genetic variance in rapid tolerance occurs as a result of genotype-dependent differences in baseline gene expression, in alcohol-mediated effects on gene expression, and in differences in gene sequence and structure. Thus, we propose to exploit the rapid tolerance model to examine the molecular and genetic basis of acute responses using Next Generation high-throughput deep sequencing technologies. The genetics of rapid tolerance, initial sensitivity, and AFT will be investigated using the LXS recombinant inbred (RI) mouse strain panel which was derived from the ILS and ISS. Expression profiling will be conducted using quantitative RNA sequencing (RNA-seq) with which it is possible to investigate effects on alternative splicing as well as on transcript abundance. The following six Specific Aims are being proposed: 1) determine relationships between initial sensitivity, AFT, and rapid tolerance for the LORR response in the LXS RIs; 2) map quantitative trait loci (QTLs) for the responses determined in Aim 1; 3) sequence the full genomes of the ILS and ISS; 4) conduct expression profiling in the brains of the LXS RIs; 5) map expression QTLs (eQTLs) for genes identified in Aim 4 and for genes that occur within the behavioral QTL intervals determined in Aim 2; and 6) confirm expression results for genes identified in Aims 4 and 5. We propose that the results of these experiments will offer insight into the nature of genetic variance for acute alcohol sensitivity. This in turn will contribute to a deeper understanding of genetic risk for human alcoholism. PUBLIC HEALTH RELEVANCE: The initiation and maintenance of alcoholism is influenced by both environmental and genetic factors. This project aims to identify genes that influence variation in acute alcohol sensitivity, a trait that is thought to contribute to genetic risk for alcoholism. Such knowledge is essential for a complete understanding of the molecular basis of alcoholism and for the development of new or improved strategies for its treatment.

描述（由申请人提供）：形成酒精中毒的一个重要遗传风险因素是对急性剂量酒精的不同敏感性。急性酒精反应是初始敏感性和急性功能耐受性 (AFT) 综合作用的函数，其中 bot 受到遗传因素的影响。使用近交系小鼠品系，我们一直在使用一种称为快速耐受性的范式（单次接触酒精后 24 小时内形成的耐受性）作为研究急性酒精反应遗传学的工具。我们发现，近交长睡眠小鼠品系和短睡眠小鼠品系（ILS 和 ISS）在使用翻正反射丧失测试（LORR）作为敏感性衡量标准来产生快速耐受性的能力方面存在显着差异。这种应变依赖性差异似乎至少部分是由对 AFT 的差异效应介导的。我们假设快速耐受性的遗传变异是由于基线基因表达的基因型依赖性差异、酒精介导的基因表达影响以及基因序列和结构的差异而发生的。因此，我们建议利用快速耐受模型，使用下一代高通量深度测序技术来检查急性反应的分子和遗传基础。将使用源自 ILS 和 ISS 的 LXS 重组近交 (RI) 小鼠品系组来研究快速耐受性、初始敏感性和 AFT 的遗传学。将使用定量 RNA 测序 (RNA-seq) 进行表达谱分析，通过该测序可以研究对选择性剪接以及转录本丰度的影响。提出以下六个具体目标： 1) 确定 LXS RI 中 LORR 响应的初始灵敏度、AFT 和快速耐受性之间的关系； 2) 绘制目标 1 中确定的响应的数量性状位点 (QTL)； 3) 对ILS和ISS的全基因组进行测序； 4) 对 LXS RI 的大脑进行表达谱分析； 5) 绘制目标 4 中确定的基因和目标 2 中确定的行为 QTL 区间内出现的基因的表达 QTL (eQTL)； 6) 确认目标 4 和 5 中确定的基因的表达结果。我们建议这些实验的结果将深入了解急性酒精敏感性遗传变异的本质。这反过来将有助于更深入地了解人类酗酒的遗传风险。 公共卫生相关性：酗酒的发生和持续受到环境和遗传因素的影响。该项目旨在识别影响急性酒精敏感性变异的基因，这种特征被认为会导致酗酒的遗传风险。这些知识对于全面了解酗酒的分子基础以及制定新的或改进的治疗策略至关重要。