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: 8048861
• 负责人: Mark Damian Wewers
• 金额: $ 19.06万
• 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 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8048861
• 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-12; 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

DESCRIPTION (provided by applicant): 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-12. This IL- 12 control is important in lung inflammation and in response to infections since IL-12 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-12 for over 2 decades, we are poised to greatly expand the knowledge of this regulation. IL-12 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-12 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. PUBLIC HEALTH RELEVANCE: Most inflammatory disorders (e.g. sepsis, acute lung injury, asthma, lung fibrosis and hardening of the arteries) are, at least in part, induced by overly active caspase-1, an enzyme that is central to releasing inflammatory hormones. In this context, the discovery of a complex of intracellular proteins that control this activation event provides an opportunity for discovery. This project would utilize a novel, high throughput system that we have recently devised to enhance discovery of caspase-1 regulatory components and the promise of finding new treatment approaches to these inflammatory diseases.

描述（由申请人提供）：作为负责确定对吸入病原体和颗粒物的先天免疫反应的主要细胞，需要肺巨噬细胞来对吸入材料相关的风险做出重要的判断。正是由于这个原因，我们长期以来一直对精致的控制肺巨噬细胞超过IL-12着迷。这种IL-12对照在肺部炎症和感染中很重要，因为IL-12代表了与哮喘，ARDS，ARDS，肺炎和肺纤维化一样多样化的肺部炎症的关键决定因素之一。我们努力理解IL-12的巨噬细胞调节已有20多年的历史，我们有望大大扩展这种调节的知识。现在，IL-12法规是对先天宿主机制的革命革命的中心，这些机制使这一中央肺监管事件有望为新发现。 我们以前已经注意到，尽管正常的肺巨噬细胞包含大量的caspase-1并产生IL-12前体，但它们激活Caspase-1中心炎性体的能力受到限制。该控制可能代表了在肺部炎症性疾病中修改的中心调节事件。该提案将利用我们最近创建的一种新型的高通量系统，我们相信我们可以筛选人类的肺巨噬细胞和人类血液单核细胞，用于参与调节caspase-1的关键分子。提出了具体目的以1）优化条件无细胞的炎性体系统，以及2）用于炎症体调节剂的筛选单核细胞和巨噬细胞。我们认为，这种新的炎性体模型将使我们能够在理解这些事件的理解中取得快速的进展，而这些事件对包括哮喘，ARD和肺纤维化在内的大多数炎性肺部疾病至关重要。 公共卫生相关性：大多数炎症性疾病（例如脓毒症，急性肺损伤，哮喘，肺纤维化和动脉硬化）至少部分是由过度活跃的caspase-1诱导的，这是一种释放炎性激素的核心。在这种情况下，控制这种激活事件的细胞内蛋白质的复合物为发现提供了机会。该项目将利用一种新型的高通量系统，我们最近设计出来，以增强CASPASE-1调节成分的发现，并希望找到这些炎症性疾病的新治疗方法。