Alternaria proteases and protease defenses in asthma

描述（由申请人提供）：过敏性哮喘是一种影响数百万人生活的疾病，是由临床、环境、生物和遗传因素的关键交叉点造成的。过敏原暴露对过敏性哮喘的发展至关重要，但并非所有过敏原都与哮喘有关。过敏性哮喘的一个核心过敏原，特别是在儿童中，是一种常见的霉菌。与良性过敏原相比，交替菌的一个关键特征是蛋白酶活性。交替菌中的蛋白酶通过破坏上皮细胞紧密连接、激活上皮细胞和增加肺部炎症来增加其生物活性。有内源性蛋白酶抑制剂，包括丝氨酸蛋白酶抑制剂（Serpins）和Stefin蛋白酶抑制剂。这些抑制剂在暴露于交替孢菌时被强烈上调。本应用的中心假设是交替菌蛋白酶对交替菌起到直接靶向上皮的喘息剂作用至关重要，但这些作用是由交替菌诱导的宿主抗蛋白酶调节的。我们将利用蛋白质组学、体外实验和交替菌诱导的小鼠肺部炎症模型来评估上皮和宿主抗蛋白酶与交替菌蛋白酶的相互作用，并确定它们对过敏性哮喘发展的影响。

DESCRIPTION (provided by applicant): Allergic asthma is a disease that impacts the lives of millions and is created by critical intersections of clinical, environmental, biologic, and genetic factors. Allergen exposure is essential to the development of allergic asthma, but not all allergens associate with asthma. One allergen central to the development of allergic asthma, especially in children, is Alternaria, a common mold. A critical feature of Alternaria differentiating it from more benign allergens is protease activity. The proteases in Alternaria increase its biological activity by disrupting epithelial cell tight junctions, activating epithelial cells, and increasing lung inflammation. There are endogenous inhibitors of proteases, including SERine Protease INhibitors (Serpins) and Stefin protease inhibitors. These inhibitors are strongly upregulated with Alternaria exposure. The Central Hypothesis of this application is that Alternaria proteases are essential to Alternaria acting as an asthmagen by directly targeting the epithelium but these effects are modulated by Alternaria-induced host antiproteases. We will utilize proteomics, in vitro assays, and murine models of Alternaria-induced lung inflammation to assess the interaction of the epithelium and host antiproteases with Alternaria proteases and determine their impact on the development of allergic asthma.