MICROBIAL LIGAND RECOGNITION BY INNATE IMMUNE SENSORS

先天免疫传感器识别微生物配体

• 批准号: 7955157
• 负责人: Yorgo Modis
• 金额: $ 1.68万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7955157
• 关键词: Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Cell Wall; Cells; Complex; Computer Retrieval of Information on Scientific Projects Database; Crystallization; Event; Family; Filament; Funding; Goals; Grant; Immune; Immune response; Immune system; Infection; Inflammatory; Institution; Leucine-Rich Repeat; Ligand Binding; Ligands; Medical; Molecular; Nucleic Acids; Organism; Pattern; Process; Property; Proteins; RNA Helicase; Research; Research Personnel; Resources; Signal Transduction; Source; Structure; Surface; Techniques; Therapeutic; Toll-like receptors; Translating; United States National Institutes of Health; Vaccine Adjuvant; Work; X-Ray Crystallography; antimicrobial; cell type; design; insight; microbial; molecular recognition; novel; pathogen; programs; protein expression; receptor; sensor; structural biology

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. Most organisms rely on an innate immune system as their first line of defense against infection. Within the innate immune system, the Toll-like receptors (TLRs), a family of evolutionarily ancient receptors found on the surface of many cell types, are critical for pathogen recognition outside the cell. About 12 TLRs recognize structures specific to pathogens, such as bacterial cell wall components, bacterial filament proteins, or certain types of nucleic acid. This recognition event initiates a signal inside the cell, which induces the rapid secretion of antimicrobial and inflammatory proteins. Inside the cell, the NOD proteins and RNA helicases such as MDA5 recognize similar pathogen-associated structures to those recognized by TLRs. Remarkably, given the structural diversity of the structures that they recognize, all TLRs and NODs rely on a "leucine-rich repeat" (LRR) domain to recognize pathogen-associated structures. The overall goal of our research program on innate immune sensors is to understand how they recognize conserved molecular patterns in pathogens, and how this recognition is translated into an innate immune response. Our structural approach will provide unique insights into these important processes. First, we aim to determine the structure of one or more TLR-ligand complexes, by X-ray crystallography. Alternative crystallization targets are NOD-ligand or helicase-RNA complexes. We propose to use novel protein expression techniques to maximize protein yields. Our structures will likely define novel principles of molecular recognition. By revealing the conformational changes associated with ligand binding, the structures will provide insight on how pathogen recognition is translated into a signal in the cell that elicits an immune response. Our work will also guide efforts to design synthetic agonists or antagonists with immunomodulatory properties. Such compounds would have a wide range of medical applications, particularly as vaccine adjuvants or anti-inflammatory therapeutics.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 大多数生物体依靠先天免疫系统作为其抵抗感染的第一道防线。在先天免疫系统中，Toll样受体（TLR）是在许多细胞类型表面发现的一个进化上古老的受体家族，对于细胞外的病原体识别至关重要。大约12个TLR识别病原体特异性结构，如细菌细胞壁成分、细菌细丝蛋白或某些类型的核酸。这种识别事件在细胞内启动信号，诱导抗菌和炎症蛋白的快速分泌。在细胞内，NOD蛋白和RNA解旋酶如MDA 5识别与TLR识别的病原体相关结构相似的结构。值得注意的是，考虑到它们识别的结构的结构多样性，所有TLR和NOD都依赖于“富含亮氨酸重复”（LRR）结构域来识别病原体相关结构。 我们对先天免疫传感器的研究计划的总体目标是了解它们如何识别病原体中的保守分子模式，以及这种识别如何转化为先天免疫反应。我们的结构方法将为这些重要过程提供独特的见解。首先，我们的目标是通过X射线晶体学确定一个或多个TLR-配体复合物的结构。备选的结晶靶标是NOD-配体或解旋酶-RNA复合物。我们建议使用新的蛋白质表达技术，以最大限度地提高蛋白质产量。我们的结构可能会定义新的分子识别原理。通过揭示与配体结合相关的构象变化，这些结构将提供关于病原体识别如何转化为细胞中激发免疫反应的信号的见解。我们的工作也将指导设计具有免疫调节特性的合成激动剂或拮抗剂的努力。此类化合物将具有广泛的医学应用，特别是作为疫苗佐剂或抗炎治疗剂。