Genetic Analysis of Ethanol-Mediated Stress Reduction

乙醇介导的减压的遗传分析

• 批准号: 7071287
• 负责人: LU LU
• 金额: $ 41.09万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7071287
• 关键词: adrenocorticotropic hormone; alcoholism /alcohol abuse; anxiety; behavior test; behavioral /social science research tag; behavioral genetics; cooperative study; ethanol; gene environment interaction; gene expression; gene expression profiling; genetic susceptibility; hippocampus; hyperthermia; hypothalamic pituitary adrenal axis; laboratory mouse; linkage mapping; microarray technology; oligonucleotides; physiologic stressor; psychological stressor; quantitative trait loci; restraint; adrenocorticotropic hormone; alcoholism /alcohol abuse; anxiety; behavior test; behavioral /social science research tag; behavioral genetics; cooperative study; ethanol; gene environment interaction; gene expression; gene expression profiling; genetic susceptibility; hippocampus; hyperthermia; hypothalamic pituitary adrenal axis; laboratory mouse; linkage mapping; microarray technology; oligonucleotides; physiologic stressor; psychological stressor; quantitative trait loci; restraint

DESCRIPTION (provided by applicant): Alcoholism is a complex multi-factorial disease with a strong genetic component. The etiology of this disease is due in part to genetic differences in responses to stressors and to variation in the efficacy of ethanol in stress reduction. The molecular basis of this interaction will be studied, leading to a direct evaluation of the hypothesis that mechanisms of stress mediation by alcohol share common molecular pathways with stressors. It will be possible to determine the degree to which shared and separate mechanisms are employed. The project exploits a recently developed microarray technology called transcriptome-QTL mapping to identify the sources of variation in gene expression in the mouse hippocampus. This method enables global mapping of factors controlling the transcriptional response to stress and its modification by alcohol. A large panel of Long Sleep by Short Sleep (LXS) recombinant inbred (RI) strains of mice with sufficient power for the study of traits with small effect or low heritability will be used to map the regulatory loci revolved m mediating the infraction between ethanol and stress. Stressed and unstressed animals will be treated with ethanol or left untreated. Behavioral and physiological stress phenotypes will be measured and mapped in all RI strains. Using oligonucleotide arrays, all strains of the RI panel will be assessed for stress and ethanol related gene expression differences. In the final stage of this work, the identification of the genetic basis of expression differences will be carried out using the novel, large-scale transcriptional analysis to identify major regulatory elements and gene networks that influence the molecular, physiological and behavioral manifestations of alcohol and stress response. This project will generate publicly available transcriptome regulation resources for the alcohol and neuroscience research communities. Because this project focuses on naturally occurring genetic variation in the mouse, the results are likely to extend to human populations with differences in the stress-alcohol interaction.

描述（申请人提供）：酒精中毒是一种复杂的多因素疾病，具有强大的遗传成分。该疾病的病因部分是由于对压力源的反应和乙醇在减轻压力减轻疗效的差异的部分原因。将研究这种相互作用的分子基础，从而直接评估酗酒的压力介导机制与应激源共享常见的分子途径。可以确定采用共享和单独的机制的程度。该项目利用了一种新近开发的微阵列技术，称为Transcriptome-QTL映射，以识别小鼠海马中基因表达的变异来源。该方法实现了控制压力转录反应及其通过酒精修饰的因素的全球映射。长时间睡眠（LXS）重组近交（RI）菌株的长时间睡眠，具有足够功能，用于研究具有较小效果或遗传力较低的性状的足够功能，以绘制介导乙醇和压力之间的违规的调节基因座。压力和无压力动物将用乙醇处理或未经治疗。将在所有RI菌株中测量和映射行为和生理压力表型。使用寡核苷酸阵列，将对RI面板的所有菌株进行应力和乙醇相关基因表达差异的评估。在这项工作的最后阶段，将使用新颖的大规模转录分析来鉴定表达差异的遗传基础，以识别影响酒精和压力反应的分子，生理和行为表现的主要调节元素和基因网络。该项目将为酒精和神经科学研究社区生成公开可用的转录组调节资源。由于该项目的重点是小鼠中自然存在的遗传变异，因此结果可能会扩展到人类种群，而应力 - 酒精相互作用差异。