MICROBIAL LIGAND RECOGNITION BY INNATE IMMUNE SENSORS

先天免疫传感器识别微生物配体

• 批准号: 7957282
• 负责人: Yorgo Modis
• 金额: $ 1.79万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7957282
• 关键词: Affinity; Agonist; Cell Nucleus; Cell Wall; Characteristics; Communicable Diseases; Complex; Computer Retrieval of Information on Scientific Projects Database; Crystallography; DNA; Engineering; Filament; Flagellin; Funding; Generations; Grant; Human; Immune; Immune response; Immune system; Immunity; Institution; Invaded; Ligand Binding; Ligands; Light; Measures; Molecular; Mutation; Pattern; Production; RNA; Recruitment Activity; Research; Research Personnel; Resources; Signal Transduction; Source; Structure; Synchrotrons; TLR5 gene; TLR8 gene; Testing; Therapeutic; Toll-like receptors; Translating; United States National Institutes of Health; Vaccine Adjuvant; Work; X-Ray Crystallography; antimicrobial; base; cytokine; defense response; design; insight; microbial; milligram; novel vaccines; pathogen; prevent; receptor function; sensor; three dimensional structure; viral DNA

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. Background 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, such as bacterial cell wall components, bacterial filaments, or viral DNA and RNA. Upon ligand binding, TLRs transmit a signal to the nucleus that leads to the production of proinflammatory compounds. These include antimicrobial cytokines, and compounds that recruit the adaptive immune system, which establishes long-term immunity to specific pathogens. Objectives We will determine three-dimensional structures of human TLR5, TLR8 or TLR9, in complex with their ligands¿¿" bacterial flagellin, single-stranded RNA or CpG DNA, respectively. The structures of these complexes will provide critical insight into the molecular basis of pathogen recognition and proinflammatory signal generation. We will express the ectodomains of TLR5/8/9 in milligram quantities and crystallize them in complex with their respective ligands. We will determine three-dimensional structures of the complexes by X-ray crystallography. 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. Relevance Our work will reveal the molecular basis for how pathogen recognition is translated into an immune response signal. Our structures 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.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 背景 我们依靠天生的免疫系统是针对入侵病原体的第一道防线反应。这种免疫反应严重取决于收费受体（TLR）。每个TLR都识别出一种不同的分子模式，该模式是特定病原体的特征，例如细菌细胞壁成分，细菌丝或病毒DNA和RNA。配体结合后，TLR将信号传递到导致促炎化合物产生的细胞核。这些包括抗菌细胞因子以及募集适应性免疫系统的化合物，该系统建立了对特定病原体的长期免疫学。 目标 我们将与其配体的复杂性确定人类TLR5，TLR8或TLR9的三维结构。 我们将在毫克量中表达TLR5/8/9的外生域，并与它们各自的配体复杂化。我们将通过X射线晶体学确定复合物的三维结构。为了测试我们对TLR功能的基于结构的假设，我们将衡量从结构预测到干扰配体结合或信号产生的工程突变的免疫信号传导的影响。我们提出了一项寻求高亲和力TLR配体或激动剂的策略。 关联 我们的工作将揭示病原体识别方式转化为免疫增强信号的分子基础。我们的结构将指导设计合成TLR激动剂的努力，该激动剂可以用作新型的疫苗调节器或免疫调节治疗。这种疗法将为预防和治疗传染病提供一种强大的新手段。