Alternaria proteases and protease defenses in asthma

过敏性哮喘是一种影响数百万人生活的疾病，由临床、环境、生物和遗传因素的关键交叉点造成。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。一种过敏原的核心发展过敏性哮喘，特别是在儿童中，是链格孢，一种常见的霉菌。链格孢菌区别于更良性过敏原的一个关键特征是蛋白酶活性。链格孢属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。存在蛋白酶的内源性抑制剂，包括丝氨酸蛋白酶抑制剂（Serpin）和Stefin蛋白酶抑制剂。这些抑制剂强烈上调与链格孢暴露。本申请的中心假设是链格孢属蛋白酶是链格孢属通过直接靶向上皮而充当哮喘原所必需的，但这些作用由链格孢属诱导的宿主抗蛋白酶调节。我们将利用蛋白质组学、体外试验和链格孢菌诱导的肺部炎症小鼠模型来评估上皮细胞和宿主抗蛋白酶与链格孢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.