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Roles of Peptidases in Chronic Airway Inflammation

肽酶在慢性气道炎症中的作用

基本信息

批准号：
7931085
负责人：
GEORGE H CAUGHEY
金额：
$ 50.01万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-11 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7931085
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

项目摘要

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.

在发炎的气道中，上皮结构、基质、腺体和血管的改变会促进阻塞