Innate Immunity in Allergic Airway Inflammation of Asthma

描述(由申请人提供)： 哮喘是一种慢性炎症综合征，表现为呼吸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，哮喘在全世界的患病率和严重性都有所增加。目前的数据强烈表明炎症是哮喘表型的主要标志。哮喘呼吸道炎症的发生和传播有多种因素，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日益被人们所认识。在此背景下，本中心建议的总体目标是探讨先天免疫关键因素对哮喘过敏性炎症的作用机制。该中心在方案上注重翻译研究，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，包括人类主题调查、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。我们的计划涉及三个独立但互补的先天免疫因素，这三个因素有助于哮喘的过敏性呼吸道炎症。这些因子是一氧化氮、环境蛋白水解酶和内源性金属蛋白酶。项目1将重点阐明iNOS在哮喘气道炎症中过度产生NO的机制。它还评估了iNOS翻译抑制剂在哮喘小鼠模型中的使用。项目2将确定由过敏原激活的最早的先天免疫信号通路，过敏原为随后的过敏性肺部疾病提供条件。此外，它还将确定家庭环境中的过敏性蛋白水解酶与儿童哮喘发展之间的关系。项目3将确定关键基质蛋白酶和蛋白多糖在协调肺内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清除肺部炎症细胞中的作用。这三个项目都研究哮喘患者和哮喘的小鼠模型。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。CORE B(动物核心)协助研究人员进行与哮喘小鼠模型的开发和测试相关的所有研究。Core C处理中心研究人员的原代细胞培养、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的病理生理学和潜在治疗方法的了解。

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.