INIA: Genetic Analysis of Alcohol Consumption and Stress

描述（由申请人提供）： 应激和焦虑相关神经适应性反应的遗传基础 对酗酒的了解很少。在INIA的研究部分， 将撒下一张大网，以确定对神经适应重要的基因， 乙基亚硝基脲（ENU）致雄性小鼠酒精滥用突变 生殖细胞和随后的育种筛选显性和纯合子 导致异常酒精相关表型的隐性突变。 微阵列和基因定位研究提出了图表的分子 参与酒精相关疾病的通路和特定基因 表型此外，将特别构建小鼠的同类系， 用作试剂以更好地绘制负责数量性状基因座的基因座 （QTLS），并用作ENU诱变中的基因鉴定试剂。 程序.在Aim，1中，正在进行的NIH支持的诱变项目将被 识别具有异常恐惧条件反射行为的突变体， 异常的酒精表型，这些突变体将进一步探讨， a）急性乙醇给药后的皮质酮水平，和B） 压力导致的乙醇消费恢复。协调一致的努力将 确定数量性状的遗传基础 通过小鼠1号染色体的定向突变来研究酒精相关行为 和4.跨越戒断和饮酒的雄性同类或同类小鼠 用ENU诱变Chr 1和Chr 4上的QTL。试验级小鼠，通过 分子标志物，将进行2瓶选择、退出或 乙醇给药后的皮质酮水平。老鼠表现出 这些任务中的任何一个的异常行为都可能是携带突变的候选者 在一个负责相关QTL的基因中。这些研究将提供 深入了解压力-酒精相互作用的遗传基础，并提供 合理治疗酒精中毒的分子线索。

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.