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应答的原代细胞