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：
8220838
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/8220838
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.

本建议书描述了一项为期5年的指导培训计划，为应聘者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中的作用肺部疾病(COPD)，这将促进他作为独立调查员的发展。这个候选人将由J.Edwin Blalock博士和William Bailey医学博士指导，他们是公认的免疫学和慢性阻塞性肺病以及一个研究咨询委员会。他将通过以下方式继续教育计划完成理学硕士学位，参加会议和研讨会，以及其他专业人员发展活动。UAB的医学和生理生物物理学系提供了理想的结合最先进的研究设施，培养医生-科学家的环境，卓越的职业生涯发展资源和广阔的临床基础。应聘者将参与一项研究项目中性粒细胞(PMN)进入和损伤呼吸道的新途径可能在COPD中起作用。胶原蛋白的酶降解释放三肽PGP(Pro-Gly-Pro)，它对中性粒细胞有趋化作用体外和体内。在雾化吸入IPS的动物的呼吸道中发现了PGP，并显著促进了PMN的流入。PGP的酶促生产是一个最初涉及基质的分步过程金属蛋白酶与脯氨酰内肽酶(PE)共同催化最终的反应。PGP存在于几乎所有COPD患者的支气管肺泡灌洗液和痰，但不包括对照组或哮喘患者。慢性阻塞性肺疾病患者的痰而不是对照组的痰在体外可以从胶原和这样的PGP产生PGP 生产受到PE抑制剂ZPP的阻碍。总而言之，这些发现使我们假设PGP 和PE是COPD的新生物标志物，可能有助于疾病和有吸引力的治疗这些疾病的靶标。在这个方案中，我们将探讨PE在中性粒细胞肺中的重要性炎症采用急性脂多糖诱导的小鼠肺部疾病模型。我们将确定促炎因素在这个模型中，细胞因子和细胞负责PE的产生。此外，我们还将评估PGP和PE 作为COPD的新生物标志物和治疗靶点。 Lay声明：这项研究将寻求开发治疗COPD的新疗法，COPD是一种常见的、令人衰弱的肺吸烟引起的疾病，几乎没有有效的治疗方法。