A novel role for the TLR signaling adaptor TRAM

TLR 信号适配器 TRAM 的新作用

• 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
• 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

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（TLRs）是膜受体，其胞外结构域可以识别从入侵微生物释放的保守分子（如LPS， CpG等）。TLR结合提醒宿主潜在病原体的存在并激活先天免疫。TLR信号通路的遗传突变可导致免疫缺陷和免疫病理。TLRs通过与细胞质接头相互作用，募集下游信号分子，诱导促炎细胞因子和I型干扰素。目前的TLR范式断言，除了TLR3外，所有13种哺乳动物的TLR都通过适配器MyD88向宿主细胞发出信号，而TLR3则通过另一个适配器TRIF通过“不依赖MyD88”的途径发出信号。TLR4也可以通过MyD88独立通路发出信号，因此通过两种不同的桥接适配器之一交替使用，通过MyD88和TRIF唯一地发出信号：TIRAP/Mal招募MyD88或TRAM招募TRIF。在最近对革兰氏阴性菌土拉菌Francisella tularensis的免疫应答研究中，我们发现了一种新的体内信号通路，该通路需要TRAM，但似乎不涉及“myd88独立”的TRIF信号通路。我们在单核细胞增生李斯特菌感染的小鼠模型中观察到类似的途径。这些结果令人惊讶，因为TRAM的唯一已知功能是在经典的myd88非依赖性通路中架起TLR4和TRIF的桥梁。重要的是，TLR2，而不是TLR4，是识别和控制小鼠土拉菌和单核增生乳杆菌感染所必需的。因此，基于我们的初步研究，我们提出TRAM可以将TLR4以外的TLR（如TLR2）连接到免疫激活，从而在TLR信号传导中发挥比以前已知的更广泛的作用。为了验证这一假设，我们将1)阐明在肺兔病小鼠模型中，依赖于tram、不依赖于TLR4的信号通路调控宿主保护反应的机制，2)确定这种新的依赖于tram的信号通路的分子组成、细胞内定位和下游靶点。总之，这些研究将定义一个重要的TLR信号分子的新作用，为如何控制TLR特异性提供新的思路，并扩展当前的TLR范式。提出的研究具有创新性，因为它们将定义一个关键的TLR信号分子的新作用，并修改当前的TLR范式。这一发现具有重要意义，因为该途径是体内重要的免疫激活途径，其阐明可能为TLR信号的治疗操作和促炎提供新的靶点。