Genetic Analysis of Ethanol-Mediated Stress Reduction

描述(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源的反应的遗传差异以及乙醇在减轻压力方面的效果的差异。这种相互作用的分子基础将被研究，导致对酒精调节压力的机制与应激源共享共同的分子途径的假设的直接评估。将有可能确定采用共享和独立机制的程度。该项目利用最近开发的一种名为转录-QTL作图的微阵列技术来识别小鼠海马区基因表达的变异来源。这种方法可以对控制应激反应和酒精修饰的转录反应的因素进行全球定位。长睡眠短睡眠(LXS)重组近交系小鼠具有足够的能力研究小效应或低遗传力的性状，将被用来定位调节乙醇和应激之间的调节基因座。应激和非应激的动物将被乙醇处理或不治疗。将对所有RI菌株的行为和生理应激表型进行测量和定位。使用寡核苷酸阵列，RI小组的所有菌株都将被评估与压力和酒精相关的基因表达差异。在这项工作的最后阶段，将使用新型的大规模转录分析来识别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，以确定表达差异的遗传基础。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控资源。因为这个项目关注的是老鼠身上自然发生的遗传变异，所以结果可能会扩展到压力-酒精相互作用存在差异的人类群体。

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.