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）：酒精中毒是一种复杂的多因素疾病，具有很强的遗传成分。这种疾病的病因部分是由于对应激反应的遗传差异和乙醇减轻应激的功效的变化。这种相互作用的分子基础将进行研究，导致直接评估的假设，即酒精的压力调解机制共享共同的分子途径与压力。将有可能确定共用机制和单独机制的使用程度。该项目利用最近开发的称为转录组QTL定位的微阵列技术来确定小鼠海马体中基因表达的变异来源。这种方法使全球映射的因素控制转录反应的压力和酒精的修改。将使用具有足够能力用于研究具有小影响或低遗传力的性状的大组长睡眠短睡眠（LXS）重组近交（RI）小鼠品系来定位在介导乙醇和应激之间的冲突中旋转的调节基因座。应激和非应激动物将用乙醇处理或不处理。将在所有RI菌株中测量和绘制行为和生理应激表型。使用寡核苷酸阵列，评估RI组的所有菌株的强制降解和乙醇相关基因表达差异。在这项工作的最后阶段，表达差异的遗传基础的鉴定将使用新的，大规模的转录分析，以确定影响酒精和应激反应的分子，生理和行为表现的主要调控元件和基因网络进行。该项目将为酒精和神经科学研究社区提供公开可用的转录组调控资源。由于该项目的重点是小鼠中自然发生的遗传变异，因此结果可能会扩展到压力-酒精相互作用差异的人群。