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

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（由申请人提供）：酗酒是一种复杂的多因素疾病，具有很强的遗传因素。这种疾病的病因部分是由于对压力源反应的遗传差异以及乙醇减轻压力功效的差异所致。将研究这种相互作用的分子基础，从而直接评估酒精的应激调节机制与应激源具有共同的分子途径的假设。将有可能确定共享机制和独立机制的使用程度。该项目利用最近开发的一种称为转录组 QTL 作图的微阵列技术来识别小鼠海马体基因表达变异的来源。该方法能够对控制对压力的转录反应及其通过酒精的修饰的因素进行全局映射。一大组长睡眠短睡眠（LXS）重组近交（RI）小鼠品系具有足够的能力来研究影响小或遗传力低的性状，将用于绘制介导乙醇和乙醇之间的干扰的调节基因座。压力。应激和未应激的动物将用乙醇治疗或不治疗。将对所有 RI 菌株的行为和生理应激表型进行测量和绘制。使用寡核苷酸阵列，将评估 RI 组的所有菌株的应激和乙醇相关基因表达差异。在这项工作的最后阶段，将利用新颖的大规模转录分析来鉴定表达差异的遗传基础，以确定影响酒精和酒精的分子、生理和行为表现的主要调控元件和基因网络。应激反应。该项目将为酒精和神经科学研究界生成公开的转录组调控资源。由于该项目重点关注小鼠中自然发生的遗传变异，因此结果可能会扩展到压力与酒精相互作用存在差异的人类群体。