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

Toll 样受体信号转导的细胞和分子方面。

• 批准号: 7224426
• 负责人: JONATHAN C KAGAN
• 金额: $ 9万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7224426
• 关键词: Adaptor Signaling Protein; Address; Alleles; Binding; Biological; Cells; Complex; Data; Defect; Development; Essential Genes; Genes; Genetic; Health; Human; Immune response; Immunity; Infection; Integral Membrane Protein; Mediating; Membrane; Molecular; Mus; Mutate; MyD88 protein; Phagocytes; Phagosomes; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Proteins; Receptor Signaling; Recruitment Activity; Regulation; Research Personnel; Role; Signal Transduction; Site; Toll-like receptors; Trans-Activators; Transgenic Mice; Virus Diseases; in vivo; insight; intracellular protein transport; microbial; pressure; programs; protein localization location; receptor; sensor

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.

描述（由申请人提供）：实现有效免疫反应的能力对于人类健康至关重要。 Toll样受体（TLR）是在吞噬细胞和其他充当微生物感染传感器的细胞上表达的跨膜蛋白。最近的研究强调了TLR在先天和适应性免疫中的重要性，因为缺乏TLR信号传导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信号传导所需的几个基因，但缺少TLR信号传导复合物以及如何调节组装的清晰图片。该建议将研究TLR信号转导的细胞和分子方面。我们将专注于四个必需TLR衔接蛋白的表征，从它们的定位和募集到带有活化TLR的膜上的特征。介导适配器定位和募集到TLR的顺式作用域将被识别并突变，以解决TLR信号中适配器定位的功能意义的一种手段。调节适配器定位的跨作用因子将被识别为磷酸肌醇的转运调节。该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见解。

项目成果

Common mechanisms activate plant guard receptors and TLR4.

常见机制激活植物保护受体和 TLR4。

• DOI: 10.1016/j.it.2014.08.009
• 发表时间: 2014
• 期刊: Trends in immunology
• 影响因子: 16.8
• 作者: Kagan,JonathanC

Endosomes as platforms for NOD-like receptor signaling.

• DOI: 10.1016/j.chom.2014.05.001
• 发表时间: 2014-05-14
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Bonham KS;Kagan JC
• 通讯作者: Kagan JC