INIA: Genetic Analysis of Alcohol Consumption and Stress

INIA：酒精消耗和压力的基因分析

• 批准号: 6927660
• 负责人: Daniel Goldowitz
• 金额: $ 4.8万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6927660
• 关键词: alcoholic beverage consumption; alcoholism /alcohol abuse; animal breeding; anxiety; behavior test; behavioral /social science research tag; behavioral genetics; biotechnology; cooperative study; corticosterone; drug withdrawal; functional /structural genomics; gene expression; gene mutation; gene targeting; genetic manipulation; genetic mapping; genetic screening; laboratory mouse; microarray technology; nitrosourea; phenotype; quantitative trait loci; site directed mutagenesis; stress; substance abuse related behavior

DESCRIPTION (provided by applicant): The genetic basis of the neuroadaptive response to stress and anxiety relative to alcohol abuse is poorly understood. In this Research Component of the INIA, a wide net will be cast to identify genes important to neuroadaptation and alcohol abuse by using ethyl nitrosourea (ENU)-induced mutations of male mouse germ cells and subsequent breeding to screen for dominant and homozygous recessive mutations that result in aberrant alcohol-related phenotypes. Microarray and gene mapping studies are proposed to chart the molecular pathways and the specific genes that are involved in alcohol-related phenotypes. In addition, specially constructed congenic lines of mice will be used as reagents to better map loci responsible for quantitative trait loci (QTLS) and serve as reagents for gene identification in an ENU-mutagenesis program. In Aim, 1, ongoing NIH-supported mutagenesis program will be identifying mutants with abnormal fear conditioning behavior and a wide range of aberrant alcohol phenotypes and these mutants will be further explored for a) corticosterone levels following acute ethanol administration and b) stress-induced reinstatement of ethanol consumption. A concerted effort will be made in Aim 2 to identify the genetic basis of quantitative trait (QTLS) for alcohol-related behaviors by targeted mutagenesis of mouse chromosomes 1 and 4. Male congenic or consomic mice that span the withdrawal and drinking QTLs on Chr 1 and 4 will mutagenized with ENU. Test class mice, identified by molecular markers, will be phenotyped for 2-bottle choice, withdrawal or corticosterone levels following ethanol administration. Mice that show aberrant behavior in any of these tasks would be candidates to bear a mutation in a gene responsible for the relevant QTL. These studies should provide insights into the genetic bases of stress-alcohol interactions, and provide molecular clues to rational therapeutic approaches to curing alcoholism.

描述（由申请人提供）： 对压力和焦虑的神经适应性反应的遗传基础 人们对酗酒知之甚少。在 INIA 的这个研究部分中， 将广泛撒网来识别对神经适应重要的基因 使用乙基亚硝基脲 (ENU) 诱导的雄性小鼠突变酗酒 生殖细胞和随后的育种以筛选显性和纯合子 导致异常酒精相关表型的隐性突变。 提出了微阵列和基因图谱研究来绘制分子图谱 与酒精相关的途径和特定基因 表型。此外，专门构建的同源系小鼠将被 用作试剂来更好地绘制负责数量性状基因座的基因座 (QTLS) 并用作 ENU 诱变中基因鉴定的试剂 程序。在目标 1 中，正在进行的 NIH 支持的诱变计划将是 识别具有异常恐惧调节行为和广泛范围的突变体 异常酒精表型和这些突变体将被进一步探索 a) 急性乙醇给药后皮质酮水平和 b) 压力诱导的乙醇消耗恢复。齐心协力将 目标 2 确定数量性状 (QTLS) 的遗传基础 通过小鼠染色体 1 的定向诱变来控制与酒精相关的行为 4.跨越戒断和饮酒的雄性同类或同类小鼠 Chr 1 和 Chr 4 上的 QTL 将用 ENU 进行诱变。测试级小鼠，由 分子标记，将进行表型分析以进行 2 瓶选择、退出或 乙醇给药后皮质酮水平。老鼠展示 这些任务中任何一个的异常行为都将成为突变的候选者 位于负责相关 QTL 的基因中。这些研究应该提供 深入了解压力与酒精相互作用的遗传基础，并提供 治疗酒精中毒的合理治疗方法的分子线索。