Alternaria proteases and protease defenses in asthma

描述(申请人提供)：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造成。过敏原暴露在过敏性哮喘的发生发展中是必不可少的，但并非所有过敏原都与哮喘有关。过敏性哮喘，尤其是儿童过敏性哮喘的核心过敏原之一是交链孢霉，这是一种常见的霉菌。链格孢霉与更良性的过敏原的一个关键特征是蛋白水解酶活性。交链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。蛋白水解酶有内源性抑制物，包括丝氨酸蛋白酶抑制物(Serpins)和Stefin蛋白酶抑制物。这些抑制物在交链孢菌的作用下会强烈上调。这一应用的中心假设是交链孢属的蛋白水解酶是交链孢属作为哮喘因子所必需的，它直接作用于上皮细胞，但这些作用是由交链孢属诱导的宿主抗蛋白酶调节的。我们将利用蛋白质组学、体外试验和交链孢霉诱导的小鼠肺部炎症模型来评估上皮细胞和宿主抗蛋白水解酶与交链孢霉蛋白水解酶的相互作用，并确定它们在过敏性哮喘发展中的影响。

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.