Roles of Peptidases in Chronic Airway Inflammation

在炎症性静脉曲张中，上皮结构、基质、腺体和血管的变化促进梗阻。 慢性支气管炎和哮喘的高分泌。这个项目测试了多肽酶的假说 控制慢性气道炎症的重塑和其他方面的消退。它使用了新的方法 例如用基于活性的探针靶向活细胞中的多肽酶，探测免疫细胞与 在慢性感染小鼠模型中进行实时成像，并探索基因变异在慢性感染中的作用 肥大细胞多肽酶对人类哮喘的影响。目标1是确定主路上皮多肽酶的作用 前列腺素在慢性感染中的应用。上皮的完整性和水解性对于防御微生物和 毒素。屏障功能的丧失会导致慢性感染和重构，如囊性纤维化。目标1 研究证实前列腺素支持动脉内离子流量和完整性的假说是由膜控制的 锚定、伸展、抑制和脱落。目标2是确定肥大细胞肽酶在分解过程中的作用 火热的黑手党。肥大细胞产品会造成伤害，但小鼠研究表明，它们也可以促进来自 感染性腹膜炎和肺炎。通过帮助消除感染，它们的总体效果可以是消炎的。 目的2研究验证肥大细胞肽酶促进慢性炎症消退的假说。目标3 目的是确定肥大细胞类胰蛋白酶缺乏对慢性呼吸道炎症的影响。类胰酶是 与过敏性和自身免疫性炎症的气道重塑和细菌防御有关 感染，因此有可能产生和消退炎症。我们最近的工作揭示了 功能失调的人类类胰蛋白酶很常见，而且个体和人群在 继承的活性类胰蛋白酶基因的数量。通过探索基因和哮喘之间的联系，一个 不仅与慢性炎症有关的疾病，而且与感染加剧有关的疾病，建议 研究验证了类胰蛋白酶基因差异导致哮喘遗传变异的假说 严重性和易感性。总体而言，拟议的研究预计将确定以下机制： 以前未曾探索过的预防或逆转慢性气道炎病理的策略。

In inflamed ainvay, 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 ainway inflammafion. It uses novel approaches such as targeting peptidases in living cells with acfivity-based probes, probing immune cell interactions with real time imaging in mouse models of chronic infection, and exploring contribufions of genetic variation in mast cell peptidases to human asthma. Aim 1 is to determine roles of the ainway epithelial peptidase prostasin in chronic infection. Epithelial integrity and hydrafion is essenfial for defense against microbes and toxins. Failure of barrier funcfion leads to chronic infection and remodeling, as in cystic fibrosis. Aim 1 studies test the hypothesis that prostasin support of ainway ion flux and integrity is controlled by membrane anchoring, acfivafion, inhibition and shedding. Aim 2 is to determine roles of mast cell peptidases in resolving inflammafion. 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 pepfidases promote resolufion of chronic inflammation. Aim 3 is to determine impact of mast cell tryptase deficiency on chronic ainway 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 populafions vary strikingly in number of active tryptase genes inherited. By exploring connecfions between genotype and asthma, a disease associated not only with chronic inflammafion but with exacerbation by infection, the proposed studies test the hypothesis that differences in tryptase genotype contribute to inherited variafion in asthma severity and suscepfibility. Overall, the proposed studies are expected to identify mechanisms that suggest previously unexplored strategies to prevent or reverse the pathology of chronic airway inflammation.