P2X7 and the Inflammasome Pathways in Lung Inflammation

P2X7 和肺部炎症中的炎症小体通路

基本信息

批准号：
7476118
负责人：
Beverly H Koller
金额：
$ 29.9万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7476118
关键词：
2,4-Dinitrophenol Abbreviations Acute Adenosine Alcian Blue Alveolar Amino Acids Aminopterin Animals Antibodies Antigens Apoptosis Apoptotic Asthma Bacterial Artificial Chromosomes Binding Biotin Bone Marrow Caspase-1 Cell Line Cell Surface Receptors Cells Complex Cyclization Cytoplasmic Protein Cytosol DNA Nucleotidylexotransferase Development Disease Dissociation ES Cell Line Endotoxins Enzymes Event Excision Family Fluorescence-Activated Cell Sorting Gated Ion Channel Gene Family Genes Genetic Recombination HMGB1 Protein HMGB1 gene Hanks Balanced Salt Solution Hypoxanthine Hypoxanthines IgE Immune response In Situ Nick-End Labeling Inflammatory Response Interferons Interleukin-1 Interleukin-18 Interleukins Intravenous Ion Channel Irrigation Label Lead Leucine Ligands Lipopolysaccharides Lung Lung Inflammation Mediating Modeling Molds Mus Necrosis Neomycin Nuclear Numbers Ovalbumin P2X-receptor PTGS2 gene Pathogenesis Pathway interactions Pattern Recognition Periodic acid Schiff stain method Phosphate Buffer Physiology Play Polymerase Chain Reaction Production Prostaglandin-Endoperoxide Synthase Purinoceptor Recruitment Activity Resolution Role Saline Stem Cell Factor Stimulus TNF gene Testing Thymidine Toll-like receptors Tumor Necrosis Factor-alpha Tumor Necrosis Factors airway hyperresponsiveness allergic airway disease anakinra cyclooxygenase 1 cytokine dinitrophenyl disease characteristic environmental agent human TNF protein interleukin-18 binding protein intraperitoneal macrophage marenostrin mast cell neutrophil novel numb protein receptor recombinase response tripolyphosphate

项目摘要

A large number of studies indicate that environmental stimuli impact the pathogenesis of asthma both by triggering acute events and by molding the developing adaptive immune responses characteristic of this disease. Much of our study of the immune response of the asthmatic lung to innate stimuli such as endotoxin has focused on the role of the Toll receptors, cell surface molecules which through pattern recognition alert the cell in response to the presence of foreign agents. Recent studies by a number of labs, including that of our collaborator Dr. Ting, have identified a novel family of genes, initially termed CATERPILLER genes, which play a critical role in the response of cells to environmental insults. These genes encode cytoplasmic proteins characterized by pyrin, nuclear binding, and leucine-rich domains, similar to those found in Toll receptors. In response to various stimuli, a number of these proteins have been shown to assemble into complexes termed "inflammasomes" which help to orchestrate the response of the cell to the environmental threat. In the case of complexes formed with three of the CATERPILLER genes, Nlrpl, cryopyrin/Mrp3, and Nlrc4/lpaf1, this response includes the production of cytokines and the initiation of events that lead to necrosis or apoptosis. Previous studies by our group have shown that ATP is required for the maturation and release of IL-1(3 from endotoxin primed mouse macrophages and, furthermore, that this is mediated by ATP activation of the ion channel, P2X7. A model has emerged in which activation of P2X7 leads to alteration in intracellular K+, which in turn leads to activation of some inflammasomes. More recently, it has been suggested that P2X7 recruits the hemichannel pannexin-1 and that this complex mediates the passage of bacterial molecules from the endosomal compartment to the host cytosol leading to inflammasome activation. The overall hypothesis of this application is that the activation of the P2X7/inflammosome pathway plays an important part in the response of cells to environmental stimuli, regulating both the maturation and release of the family of IL-1 cytokines and modulating the apoptotic response of the lung to these stimuli. This pathway, therefore, can contribute both to the pathogenesis of asthma as well as to disease exacerbations triggered by environmental stimuli.

大量研究表明，环境刺激通过以下方式影响哮喘的发病机制：触发急性事件并塑造其发展中的适应性免疫反应特征疾病。我们的大部分研究都是关于哮喘肺对先天刺激的免疫反应，例如内毒素主要关注 Toll 受体的作用，细胞表面分子通过模式识别提醒细胞对外来物质的存在做出反应。许多实验室最近的研究，包括我们的合作者丁博士，已经确定了一个新的基因家族，最初被称为卡特彼勒基因，在细胞对环境损害的反应中发挥着关键作用。这些基因编码以吡啶、核结合和富含亮氨酸结构域为特征的细胞质蛋白，类似 Toll 受体中发现的那些。为了响应各种刺激，许多这样的蛋白质已被证明组装成称为“炎性体”的复合物，有助于协调细胞的反应环境威胁。在与三个 CATERPILLER 基因 Nlrpl 形成复合物的情况下， Cryopyrin/Mrp3 和 Nlrc4/lpaf1，这种反应包括细胞因子的产生和启动导致坏死或凋亡的事件。我们小组之前的研究表明，ATP 是内毒素引发的小鼠巨噬细胞中 IL-1(3 的成熟和释放，此外，这是由离子通道 P2X7 的 ATP 激活介导。已经出现了一个模型，其中 P2X7 的激活导致细胞内 K+ 的改变，进而导致一些炎症小体的激活。更多的最近，有人提出 P2X7 招募半通道 pannexin-1，并且该复合物介导细菌分子从内体区室到宿主细胞质的通道，从而导致炎症小体激活。该应用程序的总体假设是激活 P2X7/炎症小体通路在细胞对环境刺激的反应中发挥重要作用，调节 IL-1 细胞因子家族的成熟和释放并调节细胞凋亡肺部对这些刺激的反应。因此，该途径可以促进以下疾病的发病机制：哮喘以及环境刺激引发的疾病恶化。