Initiation of Toll-like Receptor Signaling

性状（由申请方提供）：通过识别病毒、微生物和真菌成分，Toll样受体（TLR）在提醒宿主存在感染性微生物方面发挥关键作用。为了响应这些非自身结构，TLR激活细胞内信号级联，最终定制以保护宿主免受入侵病原体的类型。在TLR家族的10个成员中，TLR 2需要TLR 1或TLR 6来识别、区分和启动对多种微生物组分的应答。定制的宿主应答通过募集对所接合的TLR特异性的衔接子分子来实现。本文拟通过合成受体激动剂和受体结构域交换实验，研究微生物诱导TLR 2与TLR 1、TLR 6、MyD 88和TIRAP/MAL.TLR1和TLR 6在激动剂识别中的功能、相互作用和机制。消除内源性受体或衔接子分子表达/活性对信号传导和全局基因诱导的影响进行了评估，以描述病原体诱导的细胞活化过程中每个信号传导组分的具体作用。信号启动的机制是通过亚细胞运动，物理相互作用和蛋白质修饰的受体和它们的适配器分子的激动剂遇到的结果的研究。

DESCRIPTION (provided by applicant): Through the recognition of viral, microbial and fungal components, Toll-like receptors (TLRs) serve the critical role of alerting the host to the presence of infectious organisms. In response to these non-self structures, TLRs activate intracellular signaling cascades that are ultimately tailored to protect the host from the type of invading pathogen. Among the ten member TLR family, TLR2 requires TLR1 or TLR6 to recognize, discriminate and initiate responses to a wide variety of microbial components. Tailored host responses are achieved by recruitment of adaptor molecules specific for the TLRs that are engaged. The studies proposed here address the precise function, physical interactions and mechanism of microbial induced activation of TLR2 in association with TLR1, TLR6 and the adaptor molecules MyD88 and TIRAP/MAL. The specific function of TLR1 and TLR6 with respect to agonist discrimination and the structural basis of this discrimination are assessed through the use of synthetic agonists and receptor domain swapping experiments. The effect of abrogating endogenous receptor or adaptor molecule expression/activity on signaling and global gene induction is evaluated in order to delineate the specific role of each signaling component during pathogen-induced cellular activation. The mechanism underlying signal initiation is addressed through studies of the subcellular movement, physical interactions and protein modifications of the receptors and their adaptor molecules as a result of agonist encounter.