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）： 新描述的胶原片段脯氨酸-甘氨酸-脯氨酸（PGP）驱动慢性中性粒细胞炎症反应，并且似乎在慢性阻塞性肺病（COPD）发病机制中发挥作用。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生成 PGP 所需的蛋白水解级联的最后一步。因此，PE 似乎代表了未来 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，因此对这种蛋白酶在肺部疾病中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 PI 实验室的新证据来填补这一知识空白，证明 PE 是通过外泌体从气道上皮细胞释放的。该应用重点关注香烟烟雾 (CS) 暴露和 COPD 中 PE 表达和 PGP 生成的独特前馈途径，特别强调内源 CXCR 配体信号传导。该提案中的目标在主题上是相互关联的（通过高质量的体外、体内模型和离体临床标本），并且经过精心设计，以提高我们对该途径及其与慢性阻塞性肺疾病（COPD）肺部疾病的相关性的理解。具体目标 1a 将检查 CXC 配体对原代气道上皮细胞 PE 的调节和释放，强调 PE 通过外泌体释放的潜力，确定参与释放的细胞内途径，并确定这种释放对胶原体外 PGP 生成的影响。具体目标 1b 将确定香烟烟雾 (CS) 对 PE 和 PGP 产生调节的影响，并用新型治疗化合物专门针对 CXC 受体和 PE。这笔资助的第二个目标将集中于 PE 抑制作为 COPD 慢性 CS 模型的治疗方法。这将利用 PE 的基因删除（PREP-/- 小鼠）进行检查，以检查观察到的炎症反应和慢性 CS 暴露的表型是否有所改善。该模型还将在测试一种新的 PE 抑制剂 S-17092 时进行检查，该抑制剂目前正在进行神经退行性疾病的临床试验，作为 COPD 肺部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检查从 COPD 患者身上收集临床生物样本，以确定与没有肺部疾病的个体相比是否存在富含 PE 的外泌体和 PGP 肽。这些目标的成功完成将加深人们对细胞外环境中 PE 的调节和释放及其不受约束的蛋白酶活性的下游影响的了解。在此过程中，这些研究可能会开发出一种新的慢性阻塞性肺病生物标志物和治疗靶点。