Innate Immunity in Allergic Airway Inflammation Asthma

描述（由申请人提供）： 哮喘是一种慢性炎症综合征，表现为气道阻塞和气道高反应性。在过去的30年里，越来越多的证据表明，哮喘在世界范围内的流行率和严重程度都有所增加。目前的数据强烈暗示炎症是哮喘表型的主要标志。哮喘气道炎症的发生和发展有多种因素，包括遗传因素和环境因素。近年来，天然免疫在哮喘气道炎症中的作用越来越受到重视。在此背景下，本中心的总体目标是研究先天免疫的关键因素对哮喘变应性炎症的机制。该中心的重点是翻译研究，并采用多学科方法。该中心的优势在于创始研究人员在多个学科的独特而互补的专业知识，包括人类受试者研究，分子细胞生物学，细胞因子生物学，细胞转导，免疫学和生理学。我们的计划解决了三个独立但互补的先天免疫因素，有助于哮喘的过敏性气道炎症。这些因子是一氧化氮、环境蛋白酶和内源性金属蛋白酶。项目一将致力于阐明哮喘气道炎症中iNOS过量产生NO的机制。它还评估了iNOS翻译抑制剂在哮喘小鼠模型中的应用。项目2将确定由过敏原激活的最早的先天免疫信号传导途径，该途径使肺适应随后的过敏性肺病。此外，它将确定过敏性蛋白酶在家庭环境和儿童哮喘的发展之间的关系。项目3将定义关键基质蛋白酶和蛋白聚糖在协调肺中免疫细胞和非免疫细胞之间的串扰以及协调过敏性炎症的进展和从肺中清除炎性细胞中的作用。这三个项目都研究哮喘患者以及哮喘小鼠模型。三个核心支持中心。行政核心（核心A）全面负责管理中心的所有科学和行政方面。核心B（动物核心）协助研究人员进行与哮喘小鼠模型开发和测试相关的所有研究。核心C处理中心研究者的原代细胞培养、组织处理和成像需求。在这个高度互动的中心，研究结果将增加我们对哮喘病理生理学和潜在治疗的理解。

DESCRIPTION (provided by applicant): Asthma is a chronic inflammatory syndrome that manifests through airway obstruction and airway hyper-responsiveness. Over the past 30 years evidence has accumulated that asthma has increased in prevalence and severity worldwide. Current data strongly implicate inflammation, as a major hallmark of the asthma phenotype. There are many factors that contribute to the initiation and propagation of airway inflammation of asthma including genetic and environmental factors. Recently, innate immunity has been increasingly recognized to play a significant role in airway inflammation of asthma. In this context, the overall objective of this Center proposal is to investigate the mechanisms of key factors of innate immunity to the allergic inflammation of asthma. The Center has a programmatic focus on translational research and utilizes a multidisciplinary approach. The strength of the Center lies in the unique yet complementary expertise of the founding investigators in several disciplines including human subject investigation, molecular cell biology, cytokine biology, cellular transduction, immunology, and physiology. Our program addresses three independent yet complementary factors of innate immunity that contribute to the allergic airway inflammation of asthma. These factors are nitric oxide, environmental proteases, and endogenous metalloproteinases. Project 1 will focus on elucidation of the mechanisms of overproduction of NO by iNOS in airway inflammation of asthma. It also evaluates the use of iNOS translational inhibitors in a mouse model of asthma. Project 2 will determine the earliest innate immune signaling pathway activated by allergens that conditions the lung for subsequent allergic lung disease. Further, it will determine the relationship between allergenic proteinases in home environments and the development of childhood asthma. Project 3 will define the role of key matrix proteinases and proteoglycans in coordinating the crosstalk between immune and non-immune cells in the lung and in orchestrating the progression of allergic inflammation and clearance of inflammatory cells from lung. All three projects study asthma patients as well as mouse models of asthma. Three cores support the Center. The Administrative Core (Core A) has the overall responsibility of managing all scientific and administrative aspects of the Center. Core B (Animal Core) assists investigators in all studies related to the development and testing of a mouse model of asthma. Core C handles primary cell culture, tissue processing and imaging needs of Center investigators. The results of the studies, in this highly interactive Center, will increase our understanding of the pathophysiology and potential therapy for asthma.