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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：
7786785
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/7786785
关键词：
Acute Advisory Committees Alveolar Animals Area Arts 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 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 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.

本建议书描述了一个为期5年的指导培训计划，为候选人提供强化培训在慢性嗜酸性炎症、基质破坏和慢性阻塞性肺疾病的发病机制方面，肺疾病（COPD），这将有助于他作为一名独立研究者的发展。的候选人将由J. Edwin Blalock博士和William Bailey博士指导，他们是公认的领导者，免疫学和COPD研究咨询委员会。他将通过以下方式开展教育计划：完成科学硕士学位，参加会议和研讨会，以及其他专业发展活动。UAB的医学和生理学与生物物理学系提供了理想的通过结合最先进的研究设施，优秀的职业生涯，发展资源和广泛的临床基础。候选人将从事研究项目，研究一种新的信号通路，中性粒细胞（PMN）流入和气道损伤可能在COPD中发挥作用。胶原蛋白的酶促分解释放三肽PGP（Pro-Gly-Pro），其对中性粒细胞具有趋化性，体外和体内。PGP存在于暴露于雾化IPS的动物的气道中，有助于PMN流入。PGP的酶促生产是一个逐步的过程，最初涉及基质金属蛋白酶与脯氨酰内肽酶（PE）催化最终反应。PGP存在于支气管肺泡灌洗液和痰液来自几乎所有的COPD患者，而不是对照或哮喘患者。来自COPD患者而非对照的痰液可以从胶原蛋白离体产生PGP，并且这种PGP 生产被PE抑制剂ZPP阻断。总的来说，这些发现使我们假设PGP 和PE代表了COPD的新生物标志物，可能有助于疾病以及有吸引力的治疗这些疾病中的靶点。在这个建议中，我们将探讨PE在嗜肺动脉高压中的重要性。使用急性LPS诱导的肺疾病的小鼠模型观察炎症。我们会找出促炎因子在该模型中，细胞因子和负责产生PE的细胞。此外，我们将评估PGP和PE 作为COPD的新型生物标志物和治疗靶点。 Lay声明：这项研究将寻求开发COPD的新疗法，COPD是一种常见的使人衰弱的肺由吸烟引起的疾病，几乎没有有效的治疗方法。