Roles of Peptidases in Chronic Airway Inflammation

肽酶在慢性气道炎症中的作用

• 批准号: 8239548
• 负责人: GEORGE H CAUGHEY
• 金额: $ 32.84万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239548
• 关键词: Adoptive Transfer; Alleles; Allergic; Allergic inflammation; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Apical; Architecture; Asthma; Autoimmune Process; Bacteria; Bacterial Infections; Cell Communication; Cell Culture Techniques; Cells; Chronic; Chronic Bronchitis; Cystic Fibrosis; Defect; Development; Disease; Employee Strikes; Epithelial; Epithelial Cells; Epithelium; Exhibits; Failure; Fibrosis; Functional disorder; Genes; Genetic Variation; Genetic screening method; Genotype; Gland; Goals; Grant; Haplotypes; Host Defense; Human; Hydration status; Image; Immune; Individual; Infection; Inflammation; Inherited; Integrins; Ions; Leukocytes; Life; Linkage Disequilibrium; Lipids; Lung; Maintenance; Membrane; Microbe; Modeling; Mus; Mycoplasma; Mycoplasma Infections; Obstruction; Pathology; Peptide Hydrolases; Peritonitis; Phospholipase; Pneumonia; Predisposition; Process; Regulation; Research; Resistance; Resolution; Role; Severities; Testing; Time; Toxin; Tryptase; Variant; Work; airway inflammation; airway remodeling; antimicrobial; base; human PRSS8 protein; in vivo Model; inhibitor/antagonist; killings; mast cell; monolayer; mouse model; novel strategies; prevent; septic

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.

在发炎的血管中，上皮结构、基质、腺体和血管的变化促进了阻塞 以及慢性支气管炎和哮喘的高分泌。这个项目检验了肽酶 控制慢性气道炎症的重塑和其他方面的消退。它使用新颖的方法 例如用基于活性的探针靶向活细胞中的肽酶，探测免疫细胞与 慢性感染小鼠模型的真实的时间成像，并探索 肥大细胞肽酶对人类哮喘的影响。目的1是确定气道上皮肽酶的作用 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 毒素屏障功能的失效导致慢性感染和重塑，如囊性纤维化。要求1 研究验证了前列腺素对通道离子通量和完整性的支持是由膜控制的假设 锚定、激活、抑制和脱落。目的二是确定肥大细胞肽酶在解决 炎症肥大细胞产物可能会造成伤害，但小鼠研究表明，它们也可以促进从 脓毒性腹膜炎和肺炎。通过帮助解决感染，它们的整体效果可以是抗炎的。 目的2验证肥大细胞肽酶促进慢性炎症消退的假说。目标3 确定肥大细胞类胰蛋白酶缺乏对慢性气道炎症影响。胰蛋白酶是 与过敏性和自身免疫性炎症的气道重塑有关， 感染，因此有可能产生并解决炎症。我们最近的研究揭示了 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的数量。通过探索基因型和哮喘之间的联系， 不仅与慢性炎症有关，而且与感染加重有关， 研究验证了类胰蛋白酶基因型差异导致哮喘遗传变异的假设 严重性和可重复性。总的来说，拟议的研究预计将确定机制，表明 以前未探索的预防或逆转慢性气道炎症病理学的策略。