Genetics of Alcohol Sensitivity in Rats

大鼠酒精敏感性的遗传学

基本信息

批准号：
8107853
负责人：
RICHARD A RADCLIFFE
金额：
$ 32.02万
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 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8107853
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 DNA Sequence Data Development Dose Ethanol Gene Expression Gene Expression Profile Gene Structure Genes Genetic Genetic Polymorphism Genetic Risk Genome Genomics Goals 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 public health relevance research study response trait

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. 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。使用从选择性繁殖的大鼠系中得出的分离种群，我们在大鼠染色体1和2上绘制了定量性状基因座（QTL），以急性反应，这是对酒精的急性反应，这是右后反射（LORR）损失的持续时间。随后，我们产生了先天性和重组的先天性线，这些品系证实了QTL，同时降低了它们的基因组大小。我们假设QTL间隔内存在一个或多个基因，这些基因通过多态性的相关影响对基因表达和/或基因产物的结构有助于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与酒精奖励相关行为的遗传差异。为了解决这些假设，该项目将执行四个具体的目的：1）使用重组持续策略对染色体1和2 QTL进行细微地图； 2）确定染色体1和2 QTL的精细图区域中的候选基因； 3）确定受QTL影响的丰富功能途径和基因网络； 4）确定染色体1和2 QTL是否具有与酒精奖励相关行为的多效性。当代遗传和基因组方法和分析方法（包括高通量DNA和RNA测序）将用于实现目标的目标。我们建议这些实验的结果将为急性酒精敏感性的遗传差异的性质提供深入的了解。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。