Genome-wide identification of miRNAs associated with alcoholism endophenotypes

酒精使用障碍是美国的一个主要健康和社会问题，超过1800万美国人符合酒精滥用或依赖的诊断标准。人类和动物研究都表明，遗传和环境因素，除了它们的相互作用，在酒精中毒的发展中起着重要作用。该项目的目标是在小鼠模型系统中识别与酒精中毒相关的遗传因素，以了解使个体易患该疾病的机制和推断途径。该项目的具体目标是研究通过microRNA（miRNA）活性和结合调节的变异如何影响小鼠大脑中的基因表达调控，并与酒精中毒相关性状（或内表型）相关。LXS小鼠组将构成我们工作的基础，是一个大型重组近交系小鼠组，除了广泛的行为测试外，还进行了高通量基因表达和高密度基因分型分析。特别是，所检查的行为内表型将是对乙醇敏感性、耐受性和消耗的易感性。发掘潜力 为寻找miRNA基因调控的候选者，我们的研究目标包括在LXS板上生成高通量miRNA表达谱数据，并使用新的生物信息学技术将这些数据与基因分型资源、基因表达数据和行为测试结果相结合。将进行分子测定以验证有希望的候选物并定位脑区域效应。在LXS面板上为其他研究者生成有价值的miRNA数据资源将是研究过程中的重要交付成果。为了实现我们的目标，我们组建了一个多学科的调查团队，他们在小鼠酒精相关行为测试、miRNA调控、基因表达分析和小鼠遗传学方面拥有丰富的知识和经验。在该项目结束时，将预测和验证与酒精反应和摄入倾向相关的特定miRNA和相应mRNA的作用。这些结果将提供有关酒精中毒遗传风险因素的机制见解，这些信息可用于未来的个性化医疗和其他治疗和诊断目的。

DESCRIPTION (provided by applicant): Alcohol use disorders are a major health and social problem in the United States, with more than 18 million Americans who meet the diagnostic criteria for alcohol abuse or dependence. Both human and animal studies show that genetic and environmental factors, in addition to their interaction, play an important role in the development of alcoholism. The goal of this project is to identify genetic factors related to alcoholism in a mouse model system in order to understand mechanisms and inferred pathways predisposing individuals to the disease. The specific objective of this project is to examine how variation modulated through micro RNA (miRNA) activity and binding affects gene expression regulation in the brains of mice and is associated with alcoholism related traits (or endophenotypes). The LXS mouse panel will form the basis of our work and is a large recombinant inbred panel with has been subject to high-throughput gene expression and high-density genotyping profiling, in addition to extensive behavioral testing. In particular, the examined behavioral endophenotypes will be the predisposition to ethanol sensitivity, tolerance and consumption. To discover potential candidates for miRNA gene regulation, our research aims include the generation of high-throughput miRNA expression profiling data on the LXS panel and the use of novel bioinformatics techniques to integrate these data with the genotyping resources, gene expression data and behavioral testing results. Molecular assays will be performed to validate promising candidates and to localize brain region effects. Generating valuable miRNA data resources on the LXS panel for other investigators will be an important deliverable during the course of the study. To accomplish our objectives, a multidisciplinary investigative team has been assembled with extensive knowledge and experience in alcohol-related behavioral testing in mice, miRNA regulation, gene expression analysis and mouse genetics. At the conclusion of this project, the role of specific miRNA, and respective mRNA, associated with the predisposition to alcohol response and intake will be predicted and validated. These results will give mechanistic insight regarding genetic risk factors for alcoholism, information that can be used in the future for personalized medicine and other therapeutic and diagnostic purposes.