Regulation of lung host defense by inflammasome modifiers

炎症小体调节剂对肺宿主防御的调节

• 批准号: 8204686
• 负责人: Mark Damian Wewers
• 金额: $ 22.88万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-08 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204686
• 关键词: Acute Lung Injury; Adaptor Signaling Protein; Adult Respiratory Distress Syndrome; Apoptosis; Arteries; Asthma; Biochemical; Breathing; Caspase; Caspase-1; Cell model; Cell-Free System; Cells; Cleaved cell; Complex; Cytosol; Dimerization; Disease; Enzymes; Event; Fibrosis; Hormones; Host Defense; Human; Immune response; Infection; Inflammatory; Interleukin-18; Invaded; Judgment; Knowledge; Lung; Lung Inflammation; Lung diseases; Modeling; Molecular; Natural Immunity; Oranges; Particulate; Pattern; Phagocytes; Pneumonia; Proteins; Pulmonary Fibrosis; Regulation; Risk; Role; Sepsis; System; Testing; Toll-like receptors; Work; cofactor; fascinate; high risk; innate immune function; interest; macrophage; marenostrin; monocyte; novel; pathogen; receptor; response; sensor

As the primary cell responsible for deciding the early innate immune response to inhaled pathogens and particulates, the lung macrophage is required to make important judgment calls about the risks associated with inhaled materials. It is for this reason that we have been long fascinated by the delicate control lung macrophages have over IL-1¿. This IL- 1¿ control is important in lung inflammation and in response to infections since IL-1¿ represents one of the key determinants of lung inflammation in disorders as diverse as asthma, ARDS, pneumonia and pulmonary fibrosis. Having worked to understand macrophage regulation of IL-1¿ for over 2 decades, we are poised to greatly expand the knowledge of this regulation. IL-1¿ regulation is now at the center of a revolution of understanding about innate host mechanisms that make this central lung regulatory event poised for new discovery. We have previously noted that although normal lung macrophages contain abundant amounts of caspase-1 and generate IL-1¿ precursor, they are limited in their ability to activate the caspase-1 centered inflammasome. This control is likely to represent a central regulatory event that is modified in lung inflammatory diseases. This proposal will take advantage of our recent creation of a novel, high throughput system that we believe will allow us to screen human lung macrophages and human blood monocytes for key molecules that participate in the regulation of caspase-1. Specific aims are proposed to 1) optimize the conditions cell-free inflammasome system and 2) screen monocytes and macrophages for modulators of the inflammasome. We believe that this new inflammasome model will allow us to make rapid progress in the understanding of these events which we believe are central to most inflammatory lung disorders including asthma, ARDS, and pulmonary fibrosis.

作为负责决定早期先天免疫反应的原代细胞 吸入的病原体和颗粒物，需要肺巨噬细胞 为此，需要对与吸入物质相关的风险做出重要判断。 我们长期以来对肺部巨噬细胞的微妙控制着迷的原因 超过 IL-1¿ .这个IL-1¿控制对于肺部炎症和响应很重要 IL-1以来的感染¿是肺部炎症的关键决定因素之一 哮喘、ARDS、肺炎和肺纤维化等多种疾病。 致力于了解巨噬细胞对 IL-1 的调节20多年来，我们蓄势待发 大大扩展了有关 IL-1 的知识。监管现在处于 关于先天宿主机制的理解革命的中心，使 这一中央肺调节事件为新的发现做好了准备。 我们之前已经注意到，虽然正常的肺巨噬细胞含有 大量的 caspase-1 并生成 IL-1¿前身，他们的能力有限 这种控制可能会激活以 caspase-1 为中心的炎症小体。 这代表了肺部炎症疾病中发生改变的中心调节事件。 该提案将利用我们最近创建的一种新颖的高通量系统 我们相信这将使我们能够筛选人肺巨噬细胞和人类血液 单核细胞参与 caspase-1 特异性调节的关键分子。 建议的目标是 1) 优化无细胞炎性体系统的条件和 2) 我们相信筛选单核细胞和巨噬细胞的炎症小体调节剂。 这种新的炎症小体模型将使我们能够在 了解这些我们认为是大多数肺部炎症的核心事件 疾病包括哮喘、ARDS 和肺纤维化。