Regulation of Lung Epithelial Fibrinolysis by Urokinase

尿激酶对肺上皮纤溶的调节

• 批准号: 6947206
• 负责人: Sreerama Shetty
• 金额: $ 26.55万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6947206
• 关键词: enzyme induction /repression; fibrin; fibrinolysis; genetic transcription; immunocytochemistry; lung injury; plasminogen activator; plasminogen activator inhibitors; protein purification; receptor expression; respiratory epithelium; thrombin; tissue /cell culture; urokinase

DESCRIPTION (provided by applicant): Disordered fibrin turnover and extravascular fibrin deposition have been implicated in the pathogenesis of lung injury and repair and lung cancer. Lung epithelial cells contribute to remodeling of extravascular fibrin by elaboration of urokinase (uPA), the urokinase receptor (uPAR) and plasminogen activator inhibitor-1 (PAl-1). Abnormal expression of these molecules in lung injury and neoplasia disrupts local fibrin turnover, potentiates local inflammation, and promotes organization of transitional fibrin with eventual fibrosis. We recently found that uPA induces expression of uPAR by lung epithelial cells. We now demonstrate that exogenous uPA also induces uPA and PAI-1 expression by these cells. These studies clearly show that lung epithelial cells regulate the uPA-uPAR-PAI-1 system by novel pathways about which little is currently understood. Our preliminary data show that posttranscriptional regulation contributes to uPA-mediated autoinduction as well as that of uPAR and PAI-1. Our central hypothesis is that novel pathways by which uPA regulates its own expression as well as that of uPAR and PAI-1 by lung epithelial cells are crucial in the pathogenesis of acute lung injury, its repair and lung cancer. Our objective is to elucidate the regulatory mechanisms by which uPA induces expression of these molecules. We will accomplish the objective in four specific aims. In Aim 1, we will determine if uPA induces epithelial cell uPAR at both transcriptional or posttranscriptional levels and define the responsible mechanisms. In Aim 2, we will determine the mechanism by which a-thrombin blocks uPA-mediated uPAR induction. In Aims 3 and 4, we will determine the mechanisms by which uPA induces its own expression as well as that of PAl-1, respectively, in lung epithelial cells. We will use a wide range of molecular, immunohistochemical, protein purification, and cell culture techniques with which we are experienced to complete the proposed work. These studies will increase our understanding of novel mechanisms by which the lung epithelium regulates the uPA-uPAR-PAI-1 system. This information could hasten the development of new, mechanism-based interventions for lung disorders, including acute lung injury or lung neoplasia.

描述（申请人提供）：纤维蛋白转换紊乱和血管外纤维蛋白沉积与肺损伤和修复以及肺癌的发病机制有关。肺上皮细胞通过尿激酶（uPA）、尿激酶受体（uPAR）和纤溶酶原激活物抑制剂-1 （PAl-1）的表达参与血管外纤维蛋白的重塑。这些分子在肺损伤和肿瘤中的异常表达破坏了局部纤维蛋白的转换，增强了局部炎症，促进了移行纤维蛋白的组织，最终导致纤维化。我们最近发现uPA诱导肺上皮细胞表达uPAR。我们现在证明外源性uPA也诱导这些细胞表达uPA和PAI-1。这些研究清楚地表明，肺上皮细胞通过目前知之甚少的新途径调节uPA-uPAR-PAI-1系统。我们的初步数据表明，转录后调控有助于upa介导的自诱导，以及uPAR和PAI-1的自诱导。我们的中心假设是，uPA调节其自身以及uPAR和PAI-1在肺上皮细胞中的表达的新途径在急性肺损伤、其修复和肺癌的发病机制中至关重要。我们的目的是阐明uPA诱导这些分子表达的调控机制。我们将从四个方面来具体实现这一目标。在目的1中，我们将确定uPA是否在转录或转录后水平诱导上皮细胞uPAR，并确定相关机制。在Aim 2中，我们将确定a-凝血酶阻断upa介导的uPAR诱导的机制。在目标3和目标4中，我们将分别确定uPA在肺上皮细胞中诱导其自身表达和PAl-1表达的机制。我们将使用广泛的分子，免疫组织化学，蛋白质纯化和细胞培养技术，我们有经验来完成拟议的工作。这些研究将增加我们对肺上皮调节uPA-uPAR-PAI-1系统的新机制的理解。这一信息可以加速开发新的、基于机制的肺疾病干预措施，包括急性肺损伤或肺肿瘤。

项目成果

Post-transcriptional regulation of plasminogen activator inhibitor type-1 expression in human pleural mesothelial cells.

人胸膜间皮细胞中纤溶酶原激活剂抑制剂 1 型表达的转录后调节。

• DOI: 10.1165/rcmb.2009-0046oc
• 发表时间: 2010
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: Shetty,Sreerama;Velusamy,Thirunavukkarasu;Shetty,RashmiS;Marudamuthu,AmarnathS;Shetty,ShwethaK;Florova,Galina;Tucker,Torry;Koenig,Kathy;Shetty,Praveenkumar;Bhandary,YashodharP;Idell,Steven
• 通讯作者: Idell,Steven