Cellular and molecular aspects of Toll-like receptor signal transduction.

项目摘要 建立有效免疫反应的能力对人类健康至关重要。Toll样受体(TLRs) 是在吞噬细胞和其他细胞上表达的跨膜蛋白，这些细胞充当微生物的传感器 感染。最近的研究强调了TLRs在先天性和获得性免疫中的重要性，因为 缺乏TLR信号的小鼠在控制细菌和病毒感染方面存在缺陷。尽管 鉴定了TLR信号所需的几个基因，清楚地了解了TLR信号是如何复杂的 都是组装的，缺乏对组装的监管。这项提案将调查蜂窝和 TLR信号转导的分子方面。我们将重点介绍四个基本要素的特征 TLR接头蛋白的定位和募集到含有激活的TLR的膜上。 介导接头定位和TLR招募的顺式作用结构域将被识别和突变 作为一种手段来解决适配器本地化在TLR信号中的功能意义。反演戏 调节适配器本地化的因素将被确定，特别是运输调节 通过磷脂酰肌醇。该项目的成功完成将对蜂窝手机产生重要的影响 控制TLR信号转导，从而控制免疫机制。

Project Summary The ability to mount an effective immune response is critical for human health. Toll-like receptors (TLRs) are transmembrane proteins expressed on phagocytes and other cells that act as sensors of microbial infection. Recent studies have underscored the importance of TLRs in innate and adaptive immunity as mice deficient in TLR signaling have defects in controlling bacterial and viral infections. Despite the indentification of several genes required for TLR signaling, a clear picture of how TLR signaling complexes are assembled and how assembly is regulated is lacking. This proposal will investigate cellular and molecular aspects of TLR signal transduction. We will focus on the characterization of the four essential TLR adaptor proteins in terms of their localization and recruitment to membranes bearing activated TLRs. Cis-acting domains that mediate adaptor localization and recruitment to TLRs will be identified and mutated as a means of addressing the functional significance of adaptor localization in TLR signaling. Trans-acting factors that regulate adaptor localization will be identified with a particular focus on the transport regulation by phosphoinositides. The successful completion of this project will yeild important insight into cellular control of TLR signal transduction and thus, mechanisms of immunity.