Prolyl Endopeptidase-Mediated Matrix Remodeling and Inflammation in COPD

脯氨酰内肽酶介导的慢性阻塞性肺病基质重塑和炎症

• 批准号: 8734624
• 负责人: AMIT GAGGAR
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8734624
• 关键词: Accounting; Address; Admission activity; Aging; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Biological Markers; Biology; Biopsy; Blood Circulation; Bronchoalveolar Lavage; Bronchoscopy; CXCR; Cause of Death; Characteristics; Chronic; Chronic Obstructive Airway Disease; Cleaved cell; Clinical; Clinical Trials; Collagen; Collection; Cytosol; Development; Diagnosis; Disease; Disease Progression; Environment; Environmental air flow; Enzymes; Epithelial Cells; Extracellular Matrix; Functional disorder; Future; Generations; Genetic; Glycine; Goals; Grant; Health; Healthcare Systems; Human; IL8RA gene; IL8RB gene; Immunofluorescence Immunologic; Immunology; Impairment; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Response; Information Systems; Injury; Interleukin-8B Receptor; Knowledge; Laboratories; Lead; Ligands; Link; Lung diseases; Matrix Metalloproteinases; Mediating; Metalloproteases; Modeling; Molecular Target; Morbidity - disease rate; Mucociliary Clearance; Mus; Natural Immunity; Neurodegenerative Disorders; Neutrophil Infiltration; Outcome; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Phenotype; Play; Population; Prevalence; Prevention; Production; Proline; Protease Inhibitor; Proteins; Proteomics; Pulmonary Inflammation; Pulmonology; Regulation; Research; Role; Serine Protease; Signal Transduction; Site; Specimen; Staining method; Stains; Stimulus; Testing; Therapeutic; Treatment Cost; United States; Veterans; Work; airway epithelium; burden of illness; cigarette smoking; cost; disease phenotype; disorder control; environmental tobacco smoke exposure; extracellular; feeding; human disease; improved; in vivo Model; insight; lung injury; mortality; neutrophil; novel; novel therapeutics; patient population; prolyl oligopeptidase; public health relevance; receptor; therapeutic target

DESCRIPTION (provided by applicant): The newly described collagen fragment proline-glycine-proline (PGP) drives chronic neutrophilic inflammatory responses and appears to play a role in COPD pathogenesis. Prolyl endopeptidase (PE) is a particularly important serine protease because it has been shown to catalyze the final step in a proteolytic cascade required to generate PGP from collagen. Consequently, PE would seem to represent a very attractive new target for future therapeutics related to COPD. However because recognition of the role of PE in chronic inflammation is so new, certain fundamental aspects of the regulation of this protease in the context of lung disease remains poorly understood. This revised proposal will fill in this void of knowledge by highlighting new evidence from the PI's laboratory demonstrating that PE is released from airway epithelial cells via exosomes. This application focuses on a unique feed-forward pathway of PE expression and PGP generation in cigarette smoke (CS) exposure and COPD with particular emphasis on endogenous CXCR ligand signaling. The aims in this proposal are thematically linked to each other (through high quality in vitro, in vivo models and ex vivo clinicl specimens) and are carefully crafted to improve our understanding of this pathway and its relevance to COPD lung disease. Specific aim 1a will examine the regulation and release of PE from primary airway epithelial cells by CXC ligands, highlighting the potential of PE release via exosomes, identifying the intracellular pathways involved in the release, and determining the impact of this release on ex vivo PGP generation from collagen. Specific aim 1b will determine the impact of cigarette smoke (CS) on the regulation of PE and PGP production, with specific targeting of CXC receptors and PE with novel therapeutic compounds. The second aim of this grant will focus on PE inhibition as a therapeutic approach in a chronic CS model of COPD. This will be examined utilizing a genetic deletion of PE (the PREP-/- mouse) to examine if there is amelioration of the observed inflammatory response and phenotype with chronic CS exposure. This model will also be examined in testing a new PE inhibitor S- 17092, currently in clinical trials for neurodegenerative disease, as a lead anti-inflammatory therapeutic in this model of COPD lung disease. The final aim will involve the collection of clinical biospecimens via bronchoscopy from patients with COPD to determine the presence of PE-rich exosomes and PGP peptides compared to individuals without lung disease. The successful completion of these aims will lead to an increased understanding of the regulation and release of PE in the extracellular environment and the downstream effects of its unfettered protease activity. In doing so, these studies may result in the development of a new biomarker and therapeutic target for COPD.

描述（由申请人提供）： 新描述的胶原蛋白片段脯氨酸 - 甘氨酸 - 丙酸酯（PGP）驱动慢性嗜中性炎症反应，并且似乎在COPD发病机理中起作用。脯氨酰内肽酶（PE）是一种特别重要的丝氨酸蛋白酶，因为它已被证明可以催化从胶原蛋白产生PGP所需的蛋白水解级联反应。因此，PE似乎代表了与COPD相关的未来治疗剂的一个非常有吸引力的新目标。但是，由于对PE在慢性炎症中的作用的认识是如此新，因此在肺部疾病的背景下，该蛋白酶调节的某些基本方面仍然很少了解。这项修订后的提案将通过强调PI实验室的新证据来填补这一知识，证明PE通过外泌体从气道上皮细胞释放出来。该应用集中在香烟烟雾（CS）暴露和COPD中的PE表达和PGP产生的独特前进途径和COPD中，并特别强调内源性CXCR配体信号传导。该提案的目的是从主题上相互联系（通过体外高质量，体内模型和Ex Vivo诊所标本），并精心制作以提高我们对这一途径及其与COPD肺部疾病的相关性的理解。具体的目标1A将检查CXC配体从原发气道上皮细胞中PE的调节和释放，从而强调了通过外泌体释放PE的潜力，从而鉴定了释放中涉及的细胞内途径，并确定了该释放对胶原的Ex Vivo PGP生成的影响。特定的目标1B将确定香烟烟雾（CS）对PE和PGP产生的调节的影响，并具有CXC受体的特定靶向和PE的特异性靶向。该赠款的第二个目标将集中在慢性CS模型中，将PE抑制作为一种治疗方法。通过使用PE（PREP - / - 小鼠）的遗传缺失来检查这是否可以改善观察到的炎症反应和慢性CS暴露的表型，对此进行检查。该模型还将在测试新的PE抑制剂S-17092（目前正在神经退行性疾病的临床试验中）作为铅抗炎治疗中的临床试验进行检查。与没有肺部疾病的个体相比，最终目标将涉及通过COPD患者的支气管镜检查收集COPD患者的临床生物测量，以确定富含PE的外泌体和PGP肽的存在。这些目标的成功完成将导致对细胞外环境中PE的调节和释放的了解以及其不受限制的蛋白酶活性的下游效应。这样，这些研究可能会导致开发新的生物标志物和COPD治疗靶标。