Genome-wide identification of miRNAs associated with alcoholism endophenotypes

与酗酒内表型相关的 miRNA 的全基因组鉴定

• 批准号: 9121378
• 负责人: Katherina Kechris-Mays
• 金额: $ 34.88万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9121378
• 关键词: Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; American; Animal Model; Animals; Area; Base Pairing; Behavioral; Binding; Bioinformatics; Biological Assay; Biological Models; Brain; Brain region; Cataloging; Catalogs; Chromosome Mapping; Consumption; Data; Data Sources; Detection; Development; Diagnostic; Disease; Environmental Risk Factor; Ethanol; Exhibits; Family; Future; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Generations; Genetic; Genetic Transcription; Genetic study; Genomic Segment; Genotype; Goals; Health; Human; Inbred Mouse; Inbreeding; Individual; Informatics; Intake; Knowledge; Luciferases; Mammals; Maps; Mediating; Messenger RNA; Methods; MicroRNAs; Mining; Modeling; Molecular; Molecular Profiling; Mouse Strains; Mus; Neurons; Pathway interactions; Phenotype; Play; Polymorphism Analysis; Predisposition; Quantitative Trait Loci; Recombinants; Regulation; Research; Research Personnel; Resources; Reverse Transcriptase Polymerase Chain Reaction; Role; Site; Social Problems; Structure; Techniques; Test Result; Testing; Therapeutic; Transcript; Translations; Twin Multiple Birth; United States; Untranslated RNA; Validation; Variant; Work; alcohol effect; alcohol research; alcohol response; alcohol sensitivity; alcohol use disorder; base; behavior test; density; endophenotype; experience; experimental analysis; gene product; genetic risk factor; genetic variant; genome-wide; genome-wide analysis; human subject; innovation; insight; meetings; miRNA expression profiling; mouse model; multidisciplinary; novel; personalized medicine; trait; web site

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.

描述（由申请人提供）：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。人类和动物研究表明，遗传和环境因素除了相互作用之外，在酗酒的发生中也发挥着重要作用。该项目的目标是在小鼠模型系统中识别与酗酒相关的遗传因素，以便了解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微小 RNA (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，以及如何与酗酒相关性状（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组，除了广泛的行为测试外，还经过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、耐受性和消耗的倾向。去发现潜力 作为 miRNA 基因调控的候选者，我们的研究目标包括在 LXS panel 上生成高通量 miRNA 表达谱数据，并使用新型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整合。将进行分子测定来验证有前途的候选者并定位大脑区域的影响。在 LXS panel 上为其他研究人员生成有价值的 miRNA 数据资源将是研究过程中的重要成果。为了实现我们的目标，我们组建了一个多学科研究团队，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酗酒遗传风险因素的机制见解，这些信息可在未来用于个性化医疗和其他治疗和诊断目的。