RNA Mediated Genetic Interference in C. elegans

描述(申请人提供)：RNA干扰(RNAi)已成为靶向抑制基因表达的重要新工具。RNAi方法学正在加速多个领域的基础医学研究，并具有许多潜在的临床应用。然而，我们对RNAi的基本机制仍有许多认识上的差距。本研究旨在了解RNAi并改进相关的基因沉默技术。我们现在对RNAi的核心机制有了一个基本的概述，并了解了相关机制在各种动植物的基因组维持和发育基因调控中是如何重要的。拟议的研究将解决以下问题：(I)RNAi沉默机制是如何触发的？(Ii)采用类似机制的RNAi和发育途径如何调节不同的结果、信使核糖核酸的破坏、翻译抑制和转录沉默？以及(Iii)哪些额外的基因产物在RNAi和相关途径中发挥作用？这些问题将以线虫秀丽线虫为模型系统，用一套完整的分子、生化和遗传学方法来解决。这些研究的发现将促进我们对RNAi和包括人类在内的其他生物中相关途径的理解，并可能导致改进遗传干扰技术。此外，RNAi的遗传机制与古老的基因调控机制有关，因此可能与人类发育和疾病的许多方面有关。

DESCRIPTION (provided by applicant): RNA interference (RNAi) has become an important new tool for the targeted inhibition of gene expression. RNAi methodologies are accelerating basic medical research in numerous fields and have many potential clinical applications. However, there are still many gaps in our understanding of the basic mechanism of RNAi. The research proposed here is directed at understanding RNAi and improving related technologies for gene silencing. We now posses a basic outline of the core mechanism of RNAi, and an understanding of how related mechanisms are important in genome maintenance and developmental gene regulation in a variety of animals and plants. The proposed studies will address the following questions: (i) How are RNAi silencing mechanisms triggered? (ii) How do the RNAi and developmental pathways, which employ similar mechanisms, mediate distinct outcomes, mRNA destruction, translation inhibition and transcriptional silencing? and (iii) what additional gene products function in RNAi and related pathways? These questions will be addressed with an integrated set of molecular, biochemical and genetic methods using the nematode Caenorhabditis elegans as a model system. The findings from these studies will advance our understanding of RNAi and of related pathways in other organisms including humans and may lead to improved genetic interference technologies. Moreover, the genetic mechanisms of RNAi are related to ancient gene-regulatory mechanisms and are thus likely to be relevant to many aspects of human development and disease.