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

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

展开

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.

项目摘要 NLR（核苷酸结合结构域，富含亮氨酸的重复含有蛋白质，也称为NOD样接收器）家族是一个蛋白质的潜水群，可以调节宿主免疫。显示了许多NLR 调节炎性体的形成和控制caspase-1激活，IL-1β/IL-18分泌和炎症细胞死亡。相反，NLR蛋白的子集负调节不同的炎症途径，通常通过抑制性相互作用与关键信号分子。但是，控制的分子机制炎症的阴性调节知之甚少。尤其是NLRC3已显示为负面调节几种关键的炎症途径。例如，已显示NLRC3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 通过调节刺激，抑制I型干扰素产生的胞质核酸刺激贩运。允许NLRC3在潜水员途径中起作用的分子机制知之甚少。了解炎症负调控的分子机制对于生成改善健康的新策略。我的建议的目标1使用经典的生化和细胞生物学研究新型蛋白质 - 蛋白质相互作用与NLRC3的分子决定剂的技术。我们的研究表明这些交互者之一通过重新定位来负调节I型相互作用的生产 NLRC3到细胞皮层。我提出了实验，以研究这些相互作用是如何介导的。在目标2中和我的3个提案，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高级显微镜研究蛋白质定位和运输在NLRC3-的作用介导的抑制细胞途径。