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(申请人提供)：作为决定对吸入病原体和颗粒物的早期先天免疫反应的主要细胞，肺巨噬细胞被要求对与吸入物质相关的风险做出重要的判断。正是出于这个原因，我们长期以来一直对肺巨噬细胞对IL-12的精细控制感到着迷。这种IL-12控制在肺部炎症和对感染的反应中很重要，因为IL-12是哮喘、ARDS、肺炎和肺纤维化等疾病中肺部炎症的关键决定因素之一。经过20多年的努力了解巨噬细胞对IL-12的调节，我们准备极大地扩展这一调节的知识。IL-12调节现在处于一场关于先天宿主机制的认识革命的中心，这使得这一中央肺调节事件有望得到新的发现。我们以前已经注意到，尽管正常肺巨噬细胞含有大量的caspase-1并产生IL-12前体，但它们激活以caspase-1为中心的炎症体的能力有限。这一对照很可能代表了肺部炎症性疾病中的一种中央调节事件。这项提议将利用我们最近创建的一种新颖的高通量系统，我们相信该系统将允许我们筛选人肺巨噬细胞和人血单核细胞，以寻找参与caspase-1调控的关键分子。提出了1)优化无细胞炎症体系统的条件和2)筛选单核细胞和巨噬细胞作为炎症体调节剂的具体目标。我们相信，这种新的炎症体模型将使我们在理解这些事件方面取得快速进展，我们认为这些事件是包括哮喘、ARDS和肺纤维化在内的大多数炎症性肺疾病的核心。 与公共卫生相关：大多数炎症性疾病(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caspase-1过度活跃引起的，caspase-1是一种释放炎症激素的关键酶。在这种背景下，控制这一激活事件的细胞内蛋白质复合体的发现为发现提供了机会。该项目将利用我们最近设计的一种新颖的高通量系统，以加强对caspase-1调节组件的发现，并有望找到治疗这些炎症性疾病的新方法。