A novel role for the TLR signaling adaptor TRAM

TLR 信号适配器 TRAM 的新作用

基本信息

批准号：
8535602
负责人：
MICHAEL T BERTON
金额：
$ 17.36万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-24 至 2014-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8535602
关键词：
Bone Marrow Cell membrane Cells Chronic Chronic Disease Complex Confocal Microscopy Development Disease Effector Cell Endosomes Event Extracellular Domain Family Flow Cytometry Francisella tularensis Gram-Negative Bacteria Growth Human Immune Immune Response Genes Immune response Immunologic Deficiency Syndromes In Situ In Vitro Infection Inflammatory Inflammatory Response Inherited Interferon Type I Invaded Lead Light Link Listeria monocytogenes Location Lung Lupus Mass Spectrum Analysis Membrane Microbe Modeling Molecular Mus Mutation Natural Immunity Nature Pathway interactions Pattern recognition receptor Play Receptor Signaling Recruitment Activity Rheumatoid Arthritis Role Signal Pathway Signal Transduction Signaling Molecule Specificity TLR2 gene TLR3 gene TLR4 gene Testing Therapeutic Toll-Like Receptor 1 Toll-like receptors Tularemia Vaccines Work base cytokine immune activation immunopathology in vivo innovation microbial mouse model mutant new therapeutic target novel pathogen public health relevance receptor receptor binding response sensor

项目摘要

DESCRIPTION (provided by applicant): The Toll-like receptors (TLRs) are membrane receptors whose extracellular domains can recognize conserved molecules released from invading microbes (e.g. LPS, CpG, etc). TLR binding alerts the host to the presence of potential pathogens and activates innate immunity. Inherited mutations in TLR signaling pathways can lead to immunodeficiency and immunopathology. TLRs signal cells by interacting with cytoplasmic adaptors that recruit downstream signaling molecules and lead to induction of proinflammatory cytokines and type I interferons. The current TLR paradigm asserts that all 13 mammalian TLRs, except TLR3, signal host cells via the adaptor MyD88, whereas TLR3 signals through a "MyD88-independent" pathway via the alternate adaptor TRIF. TLR4 can also signal via the MyD88-independent pathway and thus uniquely signals through both MyD88 and TRIF by alternate use of one of two different bridging adaptors: TIRAP/Mal to recruit MyD88 or TRAM to recruit TRIF. In recent studies of the immune response to the Gram-negative bacterium Francisella tularensis, we have uncovered a novel signaling pathway in vivo that requires TRAM but does not appear to involve the "MyD88-independent" TRIF signaling pathway. We have observed a similar pathway in a mouse model of Listeria monocytogenes infection. These results were surprising since TRAM's only known function has been to bridge TLR4 to TRIF in the classic MyD88-independent pathway. Importantly, TLR2, and not TLR4, is required for recognition and control of F. tularensis and L. monocytogenes infections in mice. Based on our preliminary studies, therefore, we propose that TRAM can link TLRs other than TLR4 (e.g. TLR2) to immune activation, and thus plays a broader role in TLR signaling than previously known. To test this hypothesis, we will 1) elucidate the mechanism(s) by which TRAM-dependent, TLR4- independent signaling regulates the host protective response in a mouse model of pulmonary tularemia, and 2) define the molecular components, intracellular location and downstream targets of the novel TRAM-dependent signaling pathway. Together, these studies will define a new role for an important TLR signaling molecule, shed new light on how TLR specificity is controlled, and expand the current TLR paradigm. The proposed studies are innovative because they will define a new role for a key TLR signaling molecule and modify the current TLR paradigm. They are significant because this pathway is a critical immune activation pathway in vivo, and its elucidation may provide new targets for therapeutic manipulation of TLR signaling and the pro-inflammatory.

描述（由申请人提供）：Toll样受体（TLR）是膜受体，其细胞外域可以识别从入侵的微生物（例如LPS，CPG等）释放的保守分子。 TLR结合使宿主警告潜在病原体的存在并激活先天免疫。 TLR信号通路中的遗传突变会导致免疫缺陷和免疫病理学。 TLRS信号细胞通过与募集下游信号分子的细胞质适配器相互作用，并导致促炎性细胞因子和I型干扰素的诱导。当前的TLR范式断言，除TLR3以外，所有13个哺乳动物TLR通过适配器MyD88信号宿主细胞，而TLR3通过替代适配器TRIF通过“ MyD88独立的”途径信号。 TLR4还可以通过MyD88独立的途径发出信号，从而通过MYD88和TRIF唯一信号，通过替代使用两个不同的桥接适配器之一：Tirap/Mal以募集MyD88或Tram来招募TRIF。在最近对革兰氏阴性细菌francisella tularensis的免疫反应的研究中，我们发现了一个需要TRAM的新型信号通路，但似乎并不涉及“独立于MyD88独立的” TRIF信号通路。我们已经观察到单核细胞增生李斯特菌的小鼠模型中的类似途径。这些结果令人惊讶，因为电车的唯一已知功能是在经典的MyD88独立途径中桥接TLR4到TRIF。重要的是，在小鼠中识别和控制tlarensis和L.单核细胞增生乳杆菌感染所必需的TLR2，而不是TLR4。因此，基于我们的初步研究，我们建议电车可以将TLR4（例如TLR2）以外的TLR连接到免疫激活，因此在TLR信号传导中起着比以前已知的更广泛的作用。为了检验这一假设，我们将1）阐明依赖TLR4-独立信号传导的机制，在肺部tlo虫的小鼠模型中调节宿主保护反应，并定义2）定义分子成分，细胞内细胞内的位置和新型Tram依赖性信号通路的下游目标。总之，这些研究将定义重要的TLR信号分子的新作用，对如何控制TLR特异性并扩展了当前的TLR范式。提出的研究具有创新性，因为它们将定义关键TLR信号分子的新作用，并修改当前的TLR范式。它们之所以重要，是因为该途径是体内关键的免疫激活途径，其阐明可能为TLR信号传导和促炎性治疗的治疗操作提供了新的目标。