权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
8018116
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/8018116
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.

该提案描述了为期 5 年的指导培训计划，为候选人提供强化培训在慢性中性粒细胞炎症、基质破坏和慢性阻塞性疾病发病机制领域肺部疾病（COPD）将有助于他作为一名独立研究者的发展。这候选人将得到 J. Edwin Blalock 博士和 William Bailey 医学博士的指导，他们是公认的领导者免疫学和慢性阻塞性肺病以及研究咨询委员会。他将推行一项教育计划完成理学硕士学位、参加会议和研讨会以及其他专业课程发展活动。 UAB 的医学系和生理学与生物物理学系提供了理想的选择通过结合最先进的研究设施和出色的职业生涯来培养医师科学家的环境开发资源和广泛的临床基础。候选人将从事一项研究项目中性粒细胞（PMN）流入和气道损伤的新信号通路可能在慢性阻塞性肺病中发挥作用。胶原蛋白的酶促分解释放出三肽 PGP（Pro-Gly-Pro），该三肽对 PMN 具有趋化性体外和体内。 PGP 存在于暴露于雾化 IPS 的动物气道中，并且显着有助于 PMN 的流入。 PGP 的酶促生产是一个逐步过程，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 存在于几乎所有 COPD 患者的支气管肺泡灌洗液和痰液，但不包括对照组或哮喘患者。 COPD 患者（而非对照者）的痰液可以从胶原蛋白离体产生 PGP，这样的 PGP PE 抑制剂 ZPP 会阻止生产。总的来说，这些发现使我们假设 PGP 和 PE 代表 COPD 的新型生物标志物，可能导致疾病以及有吸引力的治疗这些疾病的目标。在本提案中，我们将探讨 PE 在中性粒细胞肺中的重要性使用急性 LPS 诱导的肺部疾病小鼠模型进行炎症。我们将确定促炎物质在此模型中负责产生 PE 的细胞因子和细胞。此外，我们还会评估PGP和PE 作为 COPD 的新型生物标志物和治疗靶点。外行声明：这项研究将寻求开发针对慢性阻塞性肺病（COPD）的新疗法，慢性阻塞性肺病是一种常见且使人衰弱的肺部疾病由吸烟引起的疾病，目前几乎没有有效的治疗方法。