Fibrinolytic Pathways in Lung Injury and Repair

肺损伤和修复中的纤溶途径

• 批准号: 6895401
• 负责人: Steven Idell
• 金额: $ 153.49万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6895401
• 关键词: clinical research; fibrin; fibrinolysis; lung injury; regeneration

DESCRIPTION (provided by applicant): Abnormalities in the plasminogen activator (PA) pathways have been implicated in the pathogenesis of acute lung (All) and pleural injury. Recent interventional trials suggest that targeting these pathways can reduce mortality in sepsis and protect against acute lung or pleural injury. The Project Leaders of this PPG have developed evidence that these pathways can influence ALI and pleural injury through newly recognized mechanisms. However the pathogenic mechanisms that link the PA pathways to ALI and pleural injury are poorly understood and are likely to involve non-proteolytic signal-transducing pathways. Our thematic objective is to address this gap by defining novel mechanisms by which urokinase (uPA), its receptor (uPAR), other novel uPA receptors and its inhibitor PAI-1 influence the course of inflammation, remodeling of transitional matrix and accelerated fibrosis in ALI and pleural injury. In Project 1, pathways that regulate PAI-1 and uPAR expression by the.mesothelium at the posttranscriptional level will be defined and a novel fibrinolytic intervention to prevent pleural loculation will be further evaluated. Project 2 will elucidate novel posttranscriptional mechanisms by which uPA and uPAR are regulated by the lung epithelium. Project 3 will define novel pathways by which uPA interacts with cell surface signaling adapter molecules to regulate pulmonary vasoconstriction and lung edema after ALI and ascertain the role of defensin in the process. These interactive projects derive from active programs directed by experienced Project Leaders and are now oriented to our thematic objective. In vitro, in vivo and interventional methods will be used. This PPG will accelerate the acquisition of new, clinically relevant information that will hasten the development of better treatments for ALI and/or pleural injury.

描述（由申请人提供）：纤溶酶原激活剂（PA）途径的异常与急性肺（All）和胸膜损伤的发病机制有关。 最近的介入试验表明，针对这些途径可以降低败血症的死亡率并预防急性肺或胸膜损伤。 该 PPG 的项目负责人已经开发出证据，表明这些途径可以通过新认识的机制影响 ALI 和胸膜损伤。 然而，PA 途径与 ALI 和胸膜损伤相关的致病机制尚不清楚，并且可能涉及非蛋白水解信号转导途径。 我们的主题目标是通过定义尿激酶 (uPA)、其受体 (uPAR)、其他新型 uPA 受体及其抑制剂 PAI-1 影响 ALI 和胸膜损伤中炎症过程、移行基质重塑和加速纤维化的新机制来解决这一差距。 在项目 1 中，将定义在转录后水平调节间皮 PAI-1 和 uPAR 表达的途径，并将进一步评估预防胸膜形成的新型纤溶干预措施。 项目 2 将阐明肺上皮调节 uPA 和 uPAR 的新转录后机制。 项目 3 将定义 uPA 与细胞表面信号传导接头分子相互作用的新途径，以调节 ALI 后的肺血管收缩和肺水肿，并确定防御素在此过程中的作用。 这些互动项目源自经验丰富的项目负责人指导的活跃计划，现在面向我们的主题目标。 将使用体外、体内和介入方法。 该 PPG 将加速获取新的临床相关信息，从而加速针对 ALI 和/或胸膜损伤的更好治疗方法的开发。