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（申请人提供）：Toll样受体（TLR）是膜受体，其胞外结构域可以识别入侵微生物释放的保守分子（例如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 信号通路的遗传性突变可导致免疫缺陷和免疫病理学。 TLR 通过与细胞质接头相互作用向细胞发出信号，这些接头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 范式断言，除 TLR3 外，所有 13 种哺乳动物 TLR 均通过接头 MyD88 向宿主细胞发出信号，而 TLR3 通过替代接头 TRIF 通过“MyD88 独立”途径发出信号。 TLR4 还可以通过 MyD88 独立途径发出信号，因此通过交替使用两种不同的桥接接头之一，通过 MyD88 和 TRIF 发出独特的信号：TIRAP/Mal 招募 MyD88 或 TRAM 招募 TRIF。在最近对革兰氏阴性细菌土拉弗朗西斯菌免疫反应的研究中，我们发现了一种新的体内信号通路，它需要 TRAM，但似乎不涉及“MyD88 独立”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 唯一已知的功能是在经典的 MyD88 独立途径中将 TLR4 桥接至 TRIF。重要的是，识别和控制小鼠体内土拉杆菌和单核细胞增生利斯特氏菌感染需要 TLR2，而不是 TLR4。因此，根据我们的初步研究，我们提出TRAM可以将TLR4以外的TLR（例如TLR2）与免疫激活联系起来，从而在TLR信号传导中发挥比之前已知的更广泛的作用。为了检验这一假设，我们将 1) 阐明 TRAM 依赖性、TLR4 独立信号传导在肺兔热病小鼠模型中调节宿主保护反应的机制，2) 定义新型 TRAM 依赖性信号传导途径的分子成分、细胞内位置和下游靶点。总之，这些研究将为重要的 TLR 信号分子定义新的作用，为 TLR 特异性的控制提供新的思路，并扩展当前的 TLR 范式。拟议的研究具有创新性，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。它们很重要，因为该途径是体内关键的免疫激活途径，其阐明可能为 TLR 信号传导和促炎的治疗操作提供新靶点。