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.

作为决定早期先天免疫反应的主要细胞， 吸入的病原体和颗粒，肺巨噬细胞需要使 重要的判断要求与吸入材料相关的风险。正是由于这个 这也是我们长期以来对微妙的控制肺巨噬细胞着迷的原因， 超过IL-1。这种IL- 1调控在肺部炎症和对 感染，因为IL-1是肺部炎症的关键决定因素之一， 各种疾病，如哮喘、ARDS、肺炎和肺纤维化。具有 为了了解巨噬细胞对IL-1的调节，我们已经研究了20多年， 大大扩展了对这一规定的了解。IL-1调节现在处于 关于先天宿主机制的理解革命的中心， 这个中央肺调节事件准备好了新的发现。 我们以前注意到，虽然正常的肺巨噬细胞含有 大量的caspase-1和产生IL-1前体，它们在其功能上受到限制。 激活以caspase-1为中心的炎性小体的能力。这种控制很可能 代表在肺炎性疾病中被改变的中心调节事件。这 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类肺部巨噬细胞和人类血液 单核细胞中参与caspase-1调节的关键分子。具体 提出的目的是1）优化无细胞炎性小体系统的条件和2） 筛选单核细胞和巨噬细胞中的炎性体调节剂。我们认为 这种新的炎性小体模型将使我们能够在 我们认为这些事件是大多数炎症性肺部疾病的核心， 包括哮喘、ARDS和肺纤维化的疾病。