Control of Fibrinolysis by the Lung Epithelium

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。在急性肺损伤患者中（All），uPA介导的纤溶活性降低促进肺泡纤维蛋白沉积，有利于加速纤维化修复。我们最近发现，肺上皮细胞调节uPA和uPAR在转录后水平的mRNA稳定性。我们推测肺上皮细胞表达uPA和uPAR是通过这些新发现的转录后途径来调节的，从而影响上皮细胞对All及其修复的反应。我们的目标是阐明这些途径。目前对这些途径的了解还很有限，这是我们对ALL发病机制理解的一个重要空白。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相互作用控制肺上皮细胞的uPAR和uPA表达。我们的具体目标是：1）确定PGK和另一个新的 识别型uPAR mRNA编码区结合蛋白调节肺上皮uPAR表达 细胞2)阐明新发现的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)探讨PGK和另一种可能的调节蛋白hnRNPC对细胞因子介导的肺上皮细胞uPAR表达的调节机制。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。这些研究将扩展我们对肺上皮细胞调节uPAR和uPA表达的机制的理解，并加速开发新的治疗ALI及其修复的方法。

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.