Mechanisms of Gene Regulation by MicroRNAs

描述（由申请人提供）：这些研究将集中于哺乳动物细胞中 microRNA 介导的 mRNA 降解，目的是了解 microRNA 加速脱腺苷化作为其 mRNA 靶标降解的早期步骤的机制，以及 mRNA 脱腺苷化和衰变对 microRNA 基因调控的贡献。使用培养的哺乳动物细胞作为模型系统和分子生物学方法作为分析工具，我们将研究有助于 microRNA 定向去腺苷化的蛋白质、它们彼此结合的方式以及这些相互作用对 miRNA 功能的重要性。此外，我们将研究 mRNA 环境对 microRNA 影响 mRNA 稳定性程度的影响。最后，我们将探讨 microRNA 识别 mRNA 中靶位点的机制。这些研究的结果应该增强我们对目前人们知之甚少的真核基因调控的广泛机制的了解。这些知识最终对于理解在某些情况下被认为与 microRNA 功能缺陷有关的疾病的病因学以及提高 RNA 干扰作为医学疗法的功效应该是有价值的。外行语言声明：人们越来越认识到人类细胞中数百种不同的 microRNA 在基因调控中发挥着关键作用。其他证据表明 microRNA 对于病毒感染很重要，并且 microRNA 功能缺陷可能导致癌症和先天性异常。拟议的研究最终应该对于了解与 microRNA 功能或功能障碍相关的疾病的病因学以及提高基于小 RNA 分子的医学疗法的疗效具有价值。

DESCRIPTION (provided by applicant): These investigations will focus on microRNA-mediated mRNA degradation in mammalian cells, with the goal of understanding the mechanism by which microRNAs expedite deadenylation as an early step in the degradation of their mRNA targets and the contribution of mRNA deadenylation and decay to gene regulation by microRNAs. Using cultured mammalian cells as model systems and molecular biological methods as analytical tools, we will investigate the proteins that contribute to microRNA-directed deadenylation, the manner in which they associate with one another, and the importance of those interactions for miRNA function. In addition, we will examine the impact of mRNA context on the degree to which microRNAs influence mRNA stability. Finally, we will explore the mechanism by which microRNAs identify their target sites in mRNA. The results of these studies should enhance our knowledge of a widespread mechanism of eukaryotic gene regulation that presently is poorly understood. This knowledge should ultimately be of value for understanding the etiology of diseases thought in some instances to be related to defects in microRNA function and for improving the efficacy of RNA interference as a medical therapy. Lay language statement: There is growing awareness that the hundreds of distinct microRNAs in human cells play key roles in gene regulation. Additional evidence suggests that microRNAs are important for viral infection and that defects in microRNA function can contribute to cancer and congenital abnormalities. The proposed research should eventually be of value for understanding the etiology of diseases related to microRNA function or dysfunction and for improving the efficacy of medical therapies based on small RNA molecules.