Regulation of lung host defense by inflammasome modifiers

描述（由申请人提供）：肺巨噬细胞作为决定吸入病原体和颗粒的早期先天免疫反应的主要细胞，需要对吸入物质相关的风险做出重要的判断。正是由于这个原因，我们长期以来一直着迷于肺巨噬细胞对IL-12的微妙控制。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、急性呼吸窘迫综合征、肺炎和肺纤维化等多种疾病中肺部炎症的关键决定因素之一。在了解巨噬细胞对IL-12的调节已有20多年的历史，我们准备大大扩展这种调节的知识。IL-12的调控现在处于对先天宿主机制的理解革命的中心，这使得这个中央肺调控事件有了新的发现。我们之前已经注意到，尽管正常的肺巨噬细胞含有大量的caspase-1并产生IL-12前体，但它们激活caspase-1中心炎性体的能力有限。这种控制可能代表了在肺部炎症性疾病中被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，我们相信该系统将使我们能够筛选人肺巨噬细胞和人血液单核细胞，以寻找参与caspase-1调节的关键分子。具体的目标是提出1)优化条件无细胞炎性小体系统和2)筛选单核细胞和巨噬细胞的炎性小体调节剂。我们相信，这种新的炎性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大多数炎症性肺部疾病（包括哮喘，ARDS和肺纤维化）的核心。

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.