Roles of Peptidases in Chronic Airway Inflammation

在慢性支气管炎和哮喘的气道炎症中，上皮结构、基质、腺体和血管的变化促进阻塞和分泌过多。这个项目测试的假设，肽酶控制解决重塑和其他方面的慢性气道炎症。它使用了新的方法，如以活性为基础的探针靶向活细胞中的肽酶，在慢性感染的小鼠模型中用真实的时间成像探测免疫细胞相互作用，以及探索肥大细胞肽酶的遗传变异对人类哮喘的贡献。目的1探讨气道上皮肽酶前列腺素在慢性感染中的作用。上皮完整性和水合作用对于防御微生物和毒素至关重要。屏障功能的失效导致慢性感染和重塑，如囊性纤维化。目的1研究验证前列腺素对气道离子通量和完整性的支持是由膜锚定、激活、抑制和脱落控制的假设。目的2是确定肥大细胞肽酶在解决炎症反应中的作用。肥大细胞产物可能会造成伤害，但小鼠研究表明，它们也可以促进脓毒性腹膜炎和肺炎的生存。通过帮助解决感染，它们的整体效果可以是抗炎的。 目的2研究验证肥大细胞肽酶促进慢性炎症消退的假设。目的3：探讨肥大细胞类胰蛋白酶缺乏对慢性气道炎症的影响。胰蛋白酶参与过敏性和自身免疫性炎症中的气道重塑以及对细菌感染的防御，因此具有产生和消除炎症的潜力。我们最近的工作表明，功能失调的人类类胰蛋白酶是常见的，个体和人群在遗传的活性类胰蛋白酶基因数量上有显著差异。通过探索基因型与哮喘（一种不仅与慢性炎症相关，而且与感染加重相关的疾病）之间的联系，拟议的研究验证了类胰蛋白酶基因型差异导致哮喘严重程度和易感性遗传变异的假设。总的来说，这些拟议的研究预计将确定机制，建议以前未探索的策略，以预防或逆转慢性气道炎症的病理。

In inflamed airway, changes in epithelial architecture, matrix, glands, and vessels promote obstruction and hypersecretion in chronic bronchitis and asthma. This project tests the hypothesis that peptidases control resolution of remodeling and other aspects of chronic airway inflammation. It uses novel approaches such as targeting peptidases in living cells with activity-based probes, probing immune cell interactions with real time imaging in mouse models of chronic infection, and exploring contributions of genetic variation in mast cell peptidases to human asthma. Aim 1 is to determine roles of the airway epithelial peptidase prostasin in chronic infection. Epithelial integrity and hydration is essential for defense against microbes and toxins. Failure of barrier function leads to chronic infection and remodeling, as in cystic fibrosis. Aim 1 studies test the hypothesis that prostasin support of airway ion flux and integrity is controlled by membrane anchoring, activation, inhibition and shedding. Aim 2 is to determine roles of mast cell peptidases in resolving inflammation. Mast cell products can Inflict harm, but mouse studies suggest they also promote survival from septic peritonitis and pneumonia. By helping to resolve infection, their overall effect can be anti-inflammatory. Aim 2 studies test the hypothesis that mast cell peptidases promote resolution of chronic inflammation. Aim 3 is to determine impact of mast cell tryptase deficiency on chronic airway inflammation. Tryptases are implicated in airway remodeling in allergic and autoimmune inflammation and in defense against bacterial infection and thus have the potential to produce as well as to resolve inflammation. Our recent work reveals that dysfunctional human tryptases are common and that Individuals and populations vary strikingly in number of active tryptase genes inherited. By exploring connections between genotype and asthma, a disease associated not only with chronic inflammation but with exacerbation by infection, the proposed studies test the hypothesis that differences in tryptase genotype contribute to inherited variation in asthma severity and susceptibility. Overall, the proposed studies are expected to identify mechanisms that suggest previously unexplored strategies to prevent or reverse the pathology of chronic airway inflammation.