Control of Fibrinolysis by the Lung Epithelium

肺上皮对纤维蛋白溶解的控制

• 批准号: 7492131
• 负责人: Sreerama Shetty
• 金额: $ 37.48万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7492131
• 关键词: 3' Untranslated Regions; Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Alveolar; Alveolar Macrophages; Binding Proteins; Cell surface; Cells; Clinical; Code; Complement; Complementary DNA; Complex; Data; Defensins; Deposition; Depressed mood; Development; Disease; Elements; Epithelial; Epithelial Cells; Epithelium; Fibrin; Fibrinolysis; Fibroblasts; Fibrosis; Goals; HNRPAB human, protein; Hamman-Rich syndrome; Heterogeneous-Nuclear Ribonucleoprotein Group C; Hyperoxia; Hypoxia; Impairment; Interstitial Lung Diseases; Lung; Lung Inflammation; Mediating; Messenger RNA; Molecular; Neoplasms; Pathogenesis; Pathway interactions; Patients; Phosphoglycerate Kinase; Plasminogen; Plasminogen Activator Inhibitor 1; Pleural; Pneumonia; Process; Proteins; Proteolysis; Publishing; Regulation; Research Personnel; Role; Signal Transduction; Specificity; Stimulation of Cell Proliferation; Structure of parenchyma of lung; System; Time; Urokinase; Urokinase Plasminogen Activator Receptor; Work; cell motility; comparative; cytokine; genetic regulatory protein; improved; injured; injury and repair; lung Carcinoma; lung injury; mRNA Stability; novel; novel therapeutics; programs; receptor; receptor expression; repaired; response

The urokinase (uPA)-uPA receptor (uPAR) system is implicated in the pathogenesis of pulmonary inflammation and neoplasia via proteolytic remodeling, nonproteolytic signaling and regulation of cell migration and mitogenesis. In patients with acute lung injury (All), depressed uPA-mediated fibrinolytic activity promotes alveolar fibrin deposition, favoring accelerated fibrotic repair. We recently demonstrated that lung epithelial cells regulate both uPA and uPAR at the posttranscriptional level of mRNA stability. We hypothesize that expression of uPA and uPAR by lung epithelial cells is regulated via these newly appreciated posttranscriptional pathways to influence epithelial cell responses germane to All and its repair. Our objective is to elucidate these pathways. These pathways are poorly understood at this time, representing an important gap in our understanding of the pathogenesis of ALL Our preliminary data support the hypothesis and show that phosphoglycerate kinase (PGK) and other newly appreciated uPAR and uPA mRNA binding protein-mRNA interactions control uPAR and uPA expression by lung epithelial cells. Our Specific Aims are: 1) To determine how PGK and another newly recognized uPAR mRNA coding region binding protein regulate uPAR expression in lung epithelial cells. 2) To elucidate the role of newly recognized 3'-untranslated region (3'UTR) uPAR mRNA-binding protein interactions on uPAR expression. 3) To determine mechanism(s) by which PGK and hnRNPC, another putative regulatory protein, regulate cytokine mediated expression of uPAR in lung epithelial cells. 4) To clone the cDNA for the uPA mRNABp and determine how it regulates uPA expression in lung epithelial cells. These studies will extend our - understanding of mechanisms by which lung epithelial cells regulate uPAR and uPA expression and hasten the development of novel therapeutics for ALI and its repair.

尿激酶 (uPA)-uPA 受体 (uPAR) 系统通过蛋白水解重塑、非蛋白水解信号传导以及细胞迁移和有丝分裂的调节参与肺部炎症和肿瘤的发病机制。在急性肺损伤患者（全部）中，uPA 介导的纤溶活性降低会促进肺泡纤维蛋白沉积，有利于加速纤维化修复。我们最近证明，肺上皮细胞在转录后水平的 mRNA 稳定性上调节 uPA 和 uPAR。我们假设肺上皮细胞表达 uPA 和 uPAR 通过这些新近认识的转录后途径进行调节，从而影响上皮细胞对 All 及其修复的密切反应。我们的目标是阐明这些途径。目前对这些途径知之甚少，这代表我们对 ALL 发病机制的理解存在重要差距。我们的初步数据支持这一假设，并表明磷酸甘油酸激酶 (PGK) 和其他新认识的 uPAR 和 uPA mRNA 结合蛋白-mRNA 相互作用控制 uPAR和肺上皮细胞的uPA表达。我们的具体目标是： 1) 确定 PGK 和另一个新的 识别的uPAR mRNA编码区结合蛋白调节肺上皮中uPAR的表达 细胞。 2) 阐明新识别的 3'-非翻译区 (3'UTR) uPAR mRNA 结合蛋白相互作用对 uPAR 表达的作用。 3) 确定PGK和hnRNPC（另一种假定的调节蛋白）调节肺上皮细胞中细胞因子介导的uPAR表达的机制。 4)克隆uPA mRNABp的cDNA并确定其如何调节肺上皮细胞中uPA的表达。这些研究将加深我们对肺上皮细胞调节 uPAR 和 uPA 表达机制的理解，并加速 ALI 及其修复新疗法的开发。