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Prolyl endopeptidase, a novel protease important in lung inflammation

脯氨酰内肽酶，一种在肺部炎症中重要的新型蛋白酶

基本信息

批准号：
8420461
负责人：
Philip James O'Reilly
金额：
$ 13.31万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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：
2010-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8420461
关键词：
Acute Advisory Committees Alveolar Animals Area Biological Markers Biophysics Bronchoalveolar Lavage Fluid CXC Chemokines Cells Chemicals Chronic Chronic Obstructive Airway Disease Chronic lung disease Clinical Clinical Research Collagen Development Diagnosis Disease Doctor of Philosophy Early Diagnosis Early treatment Education Environment Evaluation Exposure to Generations Grant Human IL8 gene Immunology In Vitro Inflammation Inflammatory Lead Lung Lung Inflammation Lung diseases Master of Science Medicine Mentors Metalloproteases Methods Modeling Pathogenesis Patients Peptide Hydrolases Physicians Physiology Play Prevention Process Production Protease Inhibitor Public Health Reaction Research Research Personnel Research Project Grants Resources Right Ventricular Hypertrophy Role Scientist Signal Pathway Smoking Sputum Staging Stimulus Testing Training Training Programs United States aerosolized analog base career development cigarette smoking cofactor cytokine in vivo induced pluripotent stem cell mouse model neutrophil novel pre-clinical programs prolinal prolyl oligopeptidase prolyl-glycyl-proline prolyl-prolyl-glycine receptor binding research clinical testing research facility response symposium therapeutic target

项目摘要

This proposal describes a 5 year mentored training program to provide the candidate with intensive training in the areas of chronic neutrophilic inflammation, matrix destruction and pathogenesis of chronic obstructive pulmonary disease (COPD) which will facilitate his development as an independent investigator. The candidate will be mentored by J. Edwin Blalock PhD and William Bailey, MD who are recognized leaders in immunology and COPD and by a research advisory committee. He will pursue a program of education by completing a Masters of Science degree, attending conferences and seminars and additional professional development activities. The Departments of Medicine and Physiology & Biophysics at UAB provide the ideal environment for training physician-scientists by combining state of the art research facilities, excellent career development resources and a broad clinical base. The candidate will engage in a research project studying a new pathway signaling neutrophil (PMN) influx and damage to the airways that may play a role in COPD. Enzymatic breakdown of collagen releases a tripeptide PGP (Pro-Gly-Pro) that is chemotactic for PMN in vitro and in vivo. PGP is found in the airways of animals exposed to aerosolized IPS and markedly contributes to PMN influx. The enzymatic production of PGP is a stepwise process initially involving matrix metalloproteases with prolyl endopeptidase (PE) catalyzing the final reaction. PGP is present in bronchoalveolar lavage fluids and sputum from virtually all COPD patients but not controls or asthmatics. Sputum from COPD patients but not controls can generate PGP ex vivo from collagen and such PGP production is blocked by the PE inhibitor, ZPP. Collectively, these findings lead us to hypothesize that PGP and PE represent novel biomarkers for COPD that may contribute to disease as well as attractive therapeutic targets in these disorders. In this proposal, we will explore the importance of PE in neutrophilic lung inflammation using a mouse model of acute LPS-induced lung disease. We will identify the pro-inflammatory cytokines and cells responsible for generation of PE in this model. In addition, we will evaluate PGP and PE as novel biomarkers and therapeutic targets for COPD. Lay statement: This research will seek to develop new therapies for COPD, a common and debilitating lung disease caused by smoking for which there are few effective treaments.

该提案描述了一个为期5年的指导培训计划，为候选人提供强化培训