Genetic Analysis of Ethanol-Mediated Stress Reduction

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压力源的反应的遗传差异和乙醇在减轻压力方面的功效的变化。将研究这种相互作用的分子基础，从而直接评估酒精介导压力的机制与压力源具有共同的分子途径这一假设。将有可能确定采用共享机制和单独机制的程度。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中基因表达变异的来源。这种方法可以对控制应激转录反应的因子进行全局映射，并通过酒精对其进行修饰。大量具有足够能力研究小效应或低遗传力性状的LXS重组自交系小鼠将被用于定位介导乙醇与应激之间冲突的调控位点。应激动物和非应激动物将用乙醇治疗或不治疗。所有RI菌株的行为和生理应激表型将被测量和绘制。使用寡核苷酸阵列，将评估所有RI组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，将使用新的、大规模的转录分析来确定表达差异的遗传基础，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。该项目将为酒精和神经科学研究界提供公开可用的转录组调控资源。由于该项目关注的是小鼠体内自然发生的遗传变异，因此其结果很可能扩展到具有压力-酒精相互作用差异的人类群体。

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.