Cellular Signaling by Double-Stranded RNA

本项目将研究双链RNA在细胞内的信号传递。Dsrna是一种强有力的调节剂。 酶的激活和转录信号。它的细胞活动与细胞的功能有关 干扰素系统，通常是细胞对病毒感染反应的中介物。它作为一个标记的身份 最近发现的病毒感染的受体Toll样受体3(TLR3)， 它是先天免疫系统的一个组成部分，对各种感染性病原体做出反应。其他内容 对dsrna的生物学作用的兴趣是由于sirna的使用增加而引起的，这是很短的。 DsRNA，作为一种实验工具。我们项目的总体目标是确定人类的曲目 由dsRNA和病毒激活天然免疫系统而诱导的基因，并描绘 使用生化和遗传工具的相应信号通路。具体地说，我们将分析 DsRNA、仙台病毒和干扰素诱导转录的汇聚和发散途径 为此目的，我们将使用微阵列分析由以上诱导的基因 各种突变细胞系中的试剂在相关信号通路的已知成分中存在缺陷。我们会 确定新观察到的TLR3酪氨酸磷酸化需要的生化基础 调节dsRNA产生的信号。我们还将研究生化、细胞和生理方面的 多功能蛋白激酶蛋白激活剂PACT、细胞内受体PKR的功能 DsRNA。PACT在通过TLRs调节先天免疫反应方面的可能作用也将是 调查过了。成功完成拟议的项目将有助于更好地了解 哺乳动物先天免疫系统的作用机制及其如何调节宿主与病毒的相互作用 和细胞生长。

Cellular signaling by double-stranded RNA will be investigated in this project. DsRNA is a potent regulator of enzyme activation and transcriptional signaling. Its cellular actions are connected to the functioning of the interferon system and often it is a mediator of the cellular responses to virus infection. Its identity as a marker of viral infection has been reinforced by the recent discovery of its receptor, the Toll-like receptor 3 (TLR3), which is a component of the innate immune system that responds to various infectious agents. Additional interests in the biological actions of dsRNA have risen from the increasing usage of siRNA, which are short dsRNAs, as an experimental tool. The overall objective of our project is to identify the repertoire of human genes induced by activation of the innate immune system by dsRNA and viruses and to delineate the corresponding signaling pathways using biochemical and genetic tools. Specifically, we will analyze the convergent and divergent pathways used by dsRNA, Sendai virus and interferons to induce transcription of overlapping sets of genes For this purpose, we will use microarray analyses of genes induced by the above agents in various mutant cell lines defective in known components of relevant signaling pathways. We will determine the biochemical basis of the newly observed need of tyrosine phosphorylation of TLR3 in mediating signals generated by dsRNA. We will also investigate the biochemical, cellular and physiological functions of PACT, the protein activator of the multi-functional protein kinase, PKR, an intracellular receptor of dsRNA. A possible role of PACT in mediating innate immune responses through TLRs will also be investigated. Successful completion of the proposed project will lead to a better understanding of the mechanism of action of the mammalian innate immune system and how it regulates host-virus interactions and cell growth.