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）：酒精中毒发展的重要遗传危险因素是对急性剂量酒精的敏感性。急性酒精反应是初始灵敏度和急性功能耐受性（AFT）的综合作用的函数，其BOT受遗传因素影响。使用近交小鼠菌株，我们一直在使用一种称为快速公差的范式 - 单次暴露于酒精后在24小时内发展出来 - 作为研究急性酒精反应的遗传学的一种工具。我们发现，近交和短的睡眠小鼠菌株（IL和ISS）在使用右后反射测试（LORR）的丧失作为敏感性的措施的能力上有很大差异。这种依赖性差异似乎至少部分是由于对船尾的差异作用而介导的。我们假设快速耐受性的遗传差异是由于基因型依赖性基因表达的差异，酒精介导的对基因表达的影响以及基因序列和结构差异的结果。因此，我们建议利用下一代高通量深度测序技术来利用快速公差模型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）小鼠应变板来研究快速耐受性，初始灵敏度和AFT的遗传学。表达分析将使用定量RNA测序（RNA-Seq）进行，可以通过研究对替代剪接以及对转录物丰度的影响。提出了以下六个具体目标：1）确定LXS RIS中LORR响应的初始灵敏度，尾和快速耐受性之间的关系； 2）在AIM 1中确定的响应的地图定量性状基因座（QTL）； 3）序列ILS和ISS的完整基因组； 4）在LXS RI的大脑中进行表达分析； 5）在AIM 4中鉴定出的基因以及在AIM 2中确定的行为QTL间隔内发生的基因的MAP表达QTL（EQTL）； 6）确认目标4和5中鉴定的基因的表达结果。我们建议这些实验的结果将洞悉急性酒精敏感性的遗传方差的性质。反过来，这将有助于更深入地了解人类酒精中毒的遗传风险。 公共卫生相关性：酒精中毒的启动和维持受环境和遗传因素的影响。该项目旨在确定影响急性酒精敏感性变化的基因，这种特征被认为有助于酒精中毒的遗传风险。这种知识对于完全了解酒精中毒的分子基础以及制定其治疗策略至关重要。