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发生的调节参与肺部炎症和肿瘤的发病机制。在急性肺损伤（All）患者中，upa介导的纤维蛋白溶解活性降低可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mRNA稳定性的转录后水平调控uPA和uPAR。我们假设肺上皮细胞的uPA和uPAR的表达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。我们的初步数据支持这一假设，并表明磷酸甘油酸激酶（PGK）和其他新发现的uPAR和uPA mRNA结合蛋白-mRNA相互作用控制着肺上皮细胞中uPAR和uPA的表达。我们的具体目标是：1)确定PGK和另一个新

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.