MICROBIAL LIGAND RECOGNITION BY INNATE IMMUNE SENSORS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们依靠先天免疫系统作为抵御入侵病原体的第一道防线。这种免疫反应严重依赖Toll样受体(TLRs)。每个TLR识别不同的分子模式，这是特定病原体的特征。在配体结合时，TLRs向细胞核传递信号，导致致炎化合物的产生。我们将确定TLR与其配体形成的络合物的三维结构。这种结构将为病原体识别和促炎信号产生的分子基础提供关键的洞察力。为了测试我们关于TLR功能的基于结构的假设，我们将测量从结构预测的干扰配体结合或信号生成的工程突变对免疫信号的影响。我们提出了一种寻找高亲和力TLR配体或激动剂的策略。我们的工作将揭示病原体识别如何转化为免疫反应信号的分子基础。我们的结构将指导设计合成TLR激动剂的努力，这些激动剂可以用作新型疫苗佐剂，或作为免疫调节疗法。这种疗法将为预防和治疗传染病提供一种强有力的新手段。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We rely on our innate immune system as the first line of defense response against invading pathogens. This immune response is critically dependent on the Toll-like receptors (TLRs). Each TLR recognizes a different molecular pattern that is characteristic of specific pathogens. Upon ligand binding, TLRs transmit a signal to the nucleus that leads to the production of proinflammatory compounds. We will determine three-dimensional structures of a TLR in complex with its ligand. This structure will provide critical insight into the molecular basis of pathogen recognition and proinflammatory signal generation. To test our structure-based hypotheses on TLR function, we will measure the effect on immune signaling of engineered mutations that are predicted from the structures to interfere with ligand binding or signal generation. We propose a strategy to seek high-affinity TLR ligands, or agonists. Our work will reveal the molecular basis for how pathogen recognition is translated into an immune response signal. Our structure will guide efforts to design synthetic TLR agonists, which could serve as novel vaccine adjuvants, or as immunomodulatory therapeutics. Such therapeutics would provide a powerful new means to prevent and treat infectious diseases.