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Genetics of Alcohol Sensitivity in Rats

大鼠酒精敏感性的遗传学

基本信息

批准号：
8688849
负责人：
RICHARD A RADCLIFFE
金额：
$ 31.06万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-10 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8688849
关键词：
Acute Address Affect Alcoholism Alcohols Area Backcrossings Behavior Behavioral Assay Blood Breeding Candidate Disease Gene Chromosomes, Human, Pair 1 Chromosomes, Human, Pair 2 Complex Data Development Dose Ethanol Gene Expression Gene Structure Genes Genetic Genetic Polymorphism Genetic Risk Genome Genomics Goals High-Throughput DNA Sequencing Human Inbreeding Individual Knowledge Maintenance Maps Mediating Methods Molecular Nature Pathway interactions Population Procedures Proteins Quantitative Trait Loci RNA Sequences Rat Strains Rattus Recombinants Reflex action Risk Risk Factors Spliced Genes Structure System Technology Testing Variant Work alcohol response alcohol reward alcohol sensitivity alcohol use disorder analytical method base comparative congenic drinking behavior gene environment interaction genetic risk factor genetics of alcoholism improved insight next generation sequencing research study response trait transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): An important genetic risk factor for the development of alcoholism is differential sensitivity to an acute dose of alcohol. Using segregating populations derived from selectively bred rat lines, we have mapped quantitative trait loci (QTLs) on rat chromosomes 1 and 2 for an acute response to alcohol, the duration of the loss of righting reflex (LORR). We have subsequently generated congenic and recombinant congenic lines that have confirmed the QTLs while simultaneously reducing their genomic size. We hypothesize that there are one or more genes within the QTL intervals that contribute to genetic variance for LORR through polymorphism- related effects on gene expression and/or on the structure of the genes' products. A second important hypothesis is that these same genes will influence genetic variance in alcohol reward-related behaviors. To address these hypotheses, the project will carry out four Specific Aims: 1) Fine-map the chromosome 1 and 2 QTLs using the recombinant congenic strategy; 2) Identify candidate genes in the fine-mapped areas of the chromosome 1 and 2 QTLs; 3) Identify enriched functional pathways and gene networks that are affected by the QTLs; and 4) Determine if the chromosome 1 and 2 QTLs are pleiotropic with alcohol reward-related behaviors. Contemporary genetic and genomic methods and analytical approaches, including high-throughput DNA and RNA sequencing, will be used to accomplish the goals of the Aims. 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.

描述（由申请人提供）：酒精中毒发展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。使用来自选择性繁殖的大鼠品系的分离群体，我们绘制了大鼠1号和2号染色体上的数量性状位点（QTL），用于对酒精的急性反应，翻正反射（LORR）丧失的持续时间。我们随后产生了同源和重组同源系，已确认的QTL，同时减少其基因组大小。我们假设在QTL区间内有一个或多个基因通过对基因表达和/或基因产物结构的多态性相关影响而促成LORR的遗传方差。第二个重要的假设是，这些相同的基因将影响酒精奖励相关行为的遗传变异。为了解决这些问题，本项目将开展四个具体的研究工作：1）利用重组同源策略精细定位1号染色体和2号染色体上的QTL; 2）在1号染色体和2号染色体上的QTL精细定位区域内鉴定候选基因; 3）鉴定受QTL影响的丰富的功能途径和基因网络;（4）确定第1和第2染色体上的QTL是否与酒精奖励相关行为具有多效性。现代遗传学和基因组学方法和分析方法，包括高通量DNA和RNA测序，将用于实现目标。我们建议，这些实验的结果将提供深入了解急性酒精敏感性的遗传变异的性质。这反过来将有助于更深入地了解人类酗酒的遗传风险。