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

描述(由申请人提供)：建立有效的免疫反应的能力对人类健康至关重要。Toll样受体(TLRs)是表达在吞噬细胞和其他细胞上的跨膜蛋白，作为微生物感染的传感器。最近的研究强调了TLRs在先天免疫和获得性免疫中的重要性，因为TLR信号缺陷的小鼠在控制细菌和病毒感染方面存在缺陷。尽管已经鉴定了TLR信号转导所需的几个基因，但对TLR信号复合体是如何组装的以及组装是如何调控的还缺乏一个清晰的图景。这项提案将研究TLR信号转导的细胞和分子方面。我们将集中在四个重要的TLR接头蛋白的定位和募集到带有激活的TLR的膜上的特征。将识别和突变介导适配器定位和TLRs募集的顺式作用结构域，作为解决适配器定位在TLR信号中的功能意义的手段。调节接头定位的反式作用因子将被确定，特别是磷脂酰肌醇对运输的调节。这个项目的成功完成将对TLR信号转导的细胞控制以及免疫机制产生重要的影响。

DESCRIPTION (provided by applicant): 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 identification 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 yield important insight into cellular control of TLR signal transduction and thus, mechanisms of immunity.