Control of Fibrinolytic Pathways in Lung Disease

描述（由申请人提供）：尿激酶(uPA)-尿激酶受体（uPAR）系统与肺部炎症的发病机制和通过蛋白水解重塑、细胞迁移和有丝分裂发生的修复有关。急性呼吸窘迫综合征（ARDS）或肺间质性疾病患者肺部uPA表达的降低会加剧纤维化肺泡炎。我们在该基金的初始资助周期中发表的工作表明，肺上皮细胞在转录后水平调节uPA和uPAR。我们假设肺上皮细胞的uPA和uPAR的表达受到新的转录后通路的调节，这些通路影响肺炎症或修复中的上皮细胞反应。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uPAR和uPA在肺上皮细胞中的表达。目前对这些途径的了解甚少，这代表了我们对肺损伤和修复的发病机制的理解上的一个重要空白。我们的具体目的是：1)确定PGK和另一种新发现的uPAR mRNA编码区结合蛋白如何调节肺上皮细胞中uPAR的表达。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和另一种被认为是调节蛋白hnRNPC在肺上皮细胞中调节细胞因子介导的uPAR表达的机制。4)对uPA mRNABp进行表征，确定其在肺上皮细胞中调控uPA表达的机制。这些研究建立在本项目第一个资助周期完成的工作基础上，以扩展我们对肺上皮细胞调节uPAR和uPA表达的机制的理解，并将加速急性肺损伤或肺纤维化新疗法的开发。

DESCRIPTION (provided by applicant): The urokinase (uPA)-urokinase receptor (uPAR) system is implicated in the pathogenesis of pulmonary inflammation and repair via proteolytic remodeling, regulation of cell migration and mitogenesis. Depressed uPA expression in the lungs of patients with ARDS or interstitial lung diseases potentiates fibrosing alveolitis. Work we published in the initial funding cycle of this grant shows that lung epithelial cells regulate both uPA and uPAR at the posttranscriptional level. We hypothesize that expression of uPA and uPAR by lung epithelial cells is regulated by novel posttranscriptional pathways and that these pathways influence epithelial cell responses in lung inflammation or repair. Our preliminary data support the hypothesis and show that phosphoglycerate kinase (PGK) and other newly recognized uPAR and uPA mRNA binding protein-mRNA interactions control uPAR and uPA expression by lung epithelial cells. These pathways are poorly understood at this time, representing an important gap in our understanding of the pathogenesis of lung injury and repair. 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 the mechanism(s) by which PGK and hnRNPC, another putative regulatory protein, regulate cytokine-mediated expression of uPAR in lung epithelial cells. 4) To characterize the uPA mRNABp and determine how it regulates uPA expression in lung epithelial cells. These studies build on work accomplished in the first funding cycle of this project to extend our understanding of mechanisms by which lung epithelial cells regulate uPAR and uPA expression and will hasten development of novel therapeutics for acute lung injury or pulmonary fibrosis.