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: 7569436
• 负责人: JONATHAN C KAGAN
• 金额: $ 24.9万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 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 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7569436
• 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; Role; Signal Transduction; Site; Toll-like receptors; Trans-Activators; Transgenic Mice; Virus Diseases; in vivo; insight; microbial; pressure; receptor; sensor

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.

项目摘要 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细胞上表达的跨膜蛋白，它们充当微生物的传感器 感染。最近的研究强调了TLR在先天和适应性免疫中的重要性 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。尽管有 TLR信号传导所需的几个基因的缩进，清楚地了解了TLR信号传导如何复合物 是组装的，并且缺少组装方式。该建议将研究细胞和 TLR信号转导的分子方面。我们将专注于四个必需品的特征 TLR适配器蛋白在其定位和募集到具有激活TLR的膜上的定位和募集。 将识别和突变，将介导适配器定位和募集到TLR的顺式作用域 作为解决TLR信号中适配器定位的功能意义的一种手段。跨性别 将确定调节适配器定位的因素，并特别关注运输法规 通过磷酸肌醇。该项目的成功完成将使人们对蜂窝的重要见解 控制TLR信号转导，因此是免疫机制。

项目成果

Regulation of lipopolysaccharide-induced translation of tumor necrosis factor-alpha by the toll-like receptor 4 adaptor protein TRAM.

Toll 样受体 4 接头蛋白 TRAM 对脂多糖诱导的肿瘤坏死因子-α 翻译的调节。

• DOI: 10.1159/000324833
• 发表时间: 2011
• 期刊: Journal of innate immunity
• 影响因子: 5.3
• 作者: Wang,Lijian;Trebicka,Estela;Fu,Ying;Waggoner,Lisa;Akira,Shizuo;Fitzgerald,KatherineA;Kagan,JonathanC;Cherayil,BobbyJ
• 通讯作者: Cherayil,BobbyJ

Defining the subcellular sites of innate immune signal transduction.

• DOI: 10.1016/j.it.2012.06.005
• 发表时间: 2012-09
• 期刊: Trends in immunology
• 影响因子: 16.8
• 作者: Kagan JC

"Complementing" toll signaling.

“补充”收费信号。

• DOI: 10.1126/scisignal.3120pe15
• 发表时间: 2010
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Kagan,JonathanC