A novel role for the TLR signaling adaptor TRAM

TLR 信号适配器 TRAM 的新作用

• 批准号: 8304012
• 负责人: MICHAEL T BERTON
• 金额: $ 22.19万
• 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 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8304012
• 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; 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. PUBLIC HEALTH RELEVANCE: A complete understanding is needed of the signaling pathways that control immune responses to microbial infections and that regulate the harmful inflammatory responses observed in chronic diseases such as rheumatoid arthritis and Lupus. The proposed studies will characterize a novel role for the TRAM signaling molecule, known for its role in immune responses to infections. The results will provide valuable information for the development of better therapeutics to enhance vaccines and to treat chronic inflammatory diseases.

描述(申请人提供)：Toll样受体(TLRs)是一种膜受体，其胞外结构域可以识别入侵微生物(如内毒素、CpG等)释放的保守分子。TLR结合提醒宿主注意潜在病原体的存在，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通过与细胞质适配器相互作用来向细胞发出信号，后者招募下游信号分子，并导致促炎细胞因子和I型干扰素的诱导。目前的TLR范式认为，除TLR3外，所有13种哺乳动物的TLR都通过接头MyD88向宿主细胞发出信号，而TLR3通过另一种接头TRIF通过“MyD88不依赖”的途径发出信号。TLR4也可以通过MyD88不依赖的途径发出信号，因此通过交替使用两个不同的桥接接头之一：TIRAP/MAL来招募MyD88或TRAM来招募TRIF，从而通过MyD88和TRIF来唯一地发出信号。在最近对革兰氏阴性杆菌的免疫反应的研究中，我们在体内发现了一条新的信号通路，它需要TRAM，但似乎不涉及“MyD88非依赖的”TRIF信号通路。我们在单核细胞增多性李斯特菌感染的小鼠模型中观察到了类似的途径。这些结果令人惊讶，因为TRAM唯一已知的功能是在经典的MyD88非依赖途径中连接TLR4和TRIF。重要的是，TLR2，而不是TLR4，是识别和控制图拉氏丝虫病和单核细胞增多症小鼠感染所必需的。因此，根据我们的初步研究，我们认为TRAM可以将TLR4以外的TLR(如TLR2)与免疫激活联系起来，从而在TLR信号转导中发挥比已知更广泛的作用。为了验证这一假设，我们将1)阐明TRAM依赖的、TLR4不依赖的信号转导调节肺图拉热症小鼠宿主保护反应的机制(S)，2)确定TRAM依赖的新的信号通路的分子组成、细胞内定位和下游靶点。总之，这些研究将为一个重要的TLR信号分子定义一个新的角色，揭示TLR特异性是如何控制的，并扩展目前的TLR范式。拟议的研究具有创新性，因为它们将为关键的TLR信号分子定义新的角色，并修改当前的TLR范式。它们具有重要意义，因为该途径是体内关键的免疫激活途径，其阐明可能为TLR信号转导和促炎作用的治疗操作提供新的靶点。 公共卫生相关性：需要完全了解控制对微生物感染的免疫反应的信号通路，以及调节在类风湿性关节炎和狼疮等慢性病中观察到的有害炎症反应的信号通路。拟议的研究将表征TRAM信号分子的一个新角色，该分子以其在感染免疫反应中的作用而闻名。这一结果将为开发更好的治疗方法以增强疫苗和治疗慢性炎症性疾病提供有价值的信息。