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)： 新近发现的胶原片段Pro-Glyine-Proline(PGP)可驱动慢性中性粒细胞炎症反应，在COPD发病机制中起重要作用。Prolyl endopeptidase(PE)是一种特别重要的丝氨酸蛋白酶，因为它被证明催化了从胶原合成PGP所需的蛋白水解级联反应的最后一步。因此，PE似乎是未来COPD相关治疗的一个非常有吸引力的新靶点。然而，由于对PE在慢性炎症中的作用的认识还很新，在肺部疾病的背景下对这种蛋白酶的调节的某些基本方面仍然知之甚少。这项修订后的提案将通过强调来自PI实验室的新证据来填补这一知识空白，这些证据表明PE通过外体从呼吸道上皮细胞中释放出来。这一应用侧重于香烟烟雾(CS)暴露和COPD中PE表达和Pgp产生的独特前馈途径，并特别强调内源性CXCR配体信号。该提案中的目标在主题上相互关联(通过高质量的体外、体内模型和体外临床标本)，并经过精心设计，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。具体目标1a将研究CXC配体对原代呼吸道上皮细胞PE的调节和释放，强调PE通过外切体释放的潜力，确定参与释放的细胞内途径，并确定这种释放对体外胶原生成PGP的影响。具体目标1b将确定香烟烟雾(CS)对PE和Pgp产生的调节作用，并通过新的治疗化合物特异性靶向CXC受体和PE。这笔赠款的第二个目标将集中在PE抑制作为COPD慢性CS模型的治疗方法上。这将利用PE(prep-/-小鼠)的基因缺失进行检查，以检查慢性CS暴露是否改善了观察到的炎症反应和表型。这一模型还将用于测试一种新的PE抑制剂S-17092，该药目前正在进行神经退行性疾病的临床试验，作为这种慢性阻塞性肺疾病模型的主要抗炎治疗药物。最终目标将涉及通过支气管镜收集COPD患者的临床生物标本，以确定与没有肺部疾病的人相比，富含PE的外切体和PGP多肽的存在。这些目标的成功完成将使人们更好地了解PE在细胞外环境中的调节和释放，以及其不受限制的蛋白酶活性的下游影响。通过这样做，这些研究可能会导致开发一种新的COPD生物标记物和治疗靶点。