Regulation of pathogen sensing and inflammation by NLR proteins

NLR 蛋白对病原体感应和炎症的调节

基本信息

批准号：
9812277
负责人：
Beckley K Davis
金额：
$ 37.9万
依托单位：
FRANKLIN AND MARSHALL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9812277
关键词：
Affect Affinity Chromatography Attenuated Autoimmune Diseases Autoimmunity Binding Biochemical Biological Biological Response Modifiers CASP1 gene Cell Death Cells Chronic Complex Confocal Microscopy Coupled Cytosol Data Development Disease Endoplasmic Reticulum Epithelial Cells Equilibrium FMNL1 gene Family Generations Genetic Transcription Goals Health Host Defense Immune Immune signaling Immunity Immunologics In Situ Infection Inflammasome Inflammation Inflammatory Insulin-Like Growth Factor I Interferon Type I Interferons Interleukin-1 beta Interleukin-18 Leucine Leucine-Rich Repeat Link Location Malignant Neoplasms Mass Spectrum Analysis Measures Mediating Metabolic Diseases Metabolic syndrome Microscopy Molecular N-terminal NF-kappa B Natural Immunity Nuclear Envelope Nucleic Acids Nucleotides Pathogen detection Pathway interactions Patients Pattern Pattern Recognition Pattern recognition receptor Post-Translational Protein Processing Production Protein Binding Domain Proteins Publishing RNA Interference Receptor Signaling Regulation Resolution Role Scaffolding Protein Series Signal Pathway Signal Transduction Signaling Molecule Small Interfering RNA T-Cell Receptor TRAF6 gene Techniques Wegener&apos s Granulomatosis Western Blotting Yeasts adaptive immunity base cell cortex cytokine design experimental study immunopathology improved insight knock-down macrophage novel pathogen prevent protein function protein protein interaction receptor recruit response scaffold screening spatiotemporal trafficking tumorigenesis yeast two hybrid system

项目摘要

Project Summary The NLR (nucleotide-binding domain, leucine-rich repeat containing protein, also known as NOD-like receptor) family is a diverse group of proteins that functions to regulate host immunity. Many of the NLRs have been shown to regulate inflammasome formation and control caspase-1 activation, IL-1β/IL-18 secretion and inflammatory cell death. In contrast a subset of NLR proteins negatively regulates different inflammatory pathways, typically via inhibitory interactions with key signaling molecules. Nonetheless the molecular mechanisms that control the negative regulation of inflammation are poorly understood. NLRC3 in particular has been shown to negatively regulate several key inflammatory pathways. For example, NLRC3 has been shown to inhibit NF-κB and PI3K pathways in response to TLR (or IGF-1R) signaling and proinflammatory cytokine secretion; alternatively, NLRC3 inhibits type I interferon production in response to cytosolic nucleic acid stimulation by regulating STING trafficking. The molecular mechanisms to allow for NLRC3 to function in diverse pathways are poorly understood. Understanding the molecular mechanisms of negative regulation of inflammation will be necessary for the generation of new strategies to improve health. Aim 1 of my proposal uses classic biochemical and cell biological techniques to examine the molecular determinants of novel protein-protein interactors with NLRC3. Our studies suggest that one of these interactors negatively regulates type I interferon production possibly by relocating NLRC3 to the cell cortex. I propose experiments to investigate how these interactions are mediated. In Aim 2 and 3 of my proposal, we will investigate the role of these protein-protein interactions using siRNA knockdown experiments and advanced microscopy to investigate the role of protein localization and trafficking in NLRC3- mediated inhibition of cellular pathways.

项目概要 NLR（核苷酸结合域，富含亮氨酸重复序列的蛋白质，也称为 NOD 样受体） NLR 家族是一组具有调节宿主免疫功能的多样化蛋白质。调节炎症小体形成并控制 caspase-1 激活、IL-1β/IL-18 分泌和炎症相反，NLR 蛋白的一个子集通常负向调节不同的炎症途径。然而，通过与关键信号分子的抑制性相互作用来控制。人们对炎症的负调节知之甚少，尤其是 NLRC3 已被证明具有负调节作用。例如，NLRC3 已被证明可以抑制 NF-κB 和 PI3K。响应 TLR（或 IGF-1R）信号传导和促炎细胞因子分泌的途径；或者，NLRC3 通过调节 STING 抑制响应胞质核酸刺激的 I 型干扰素产生 NLRC3 在多种途径中发挥作用的分子机制尚不清楚。了解炎症负调节的分子机制对于我的建议的目标 1 使用经典的生物化学和细胞生物学来产生新的策略来改善健康。我们的研究利用 NLRC3 来检查新型蛋白质-蛋白质相互作用分子的分子决定因素。表明这些相互作用因子之一可能通过重新定位来负调节 I 型干扰素的产生在目标 2 中，我建议进行实验来研究这些相互作用是如何介导的。和我的提案 3 中，我们将使用 siRNA 敲低研究这些蛋白质-蛋白质相互作用的作用实验和先进的显微镜研究NLRC3-中蛋白质定位和运输的作用介导的细胞通路抑制。