Control of Fibrinolytic Pathways in Lung Disease

描述(申请人提供)：尿激酶型(UPA)-尿激酶型受体(UPAR)系统通过蛋白水解性重塑、调节细胞迁移和有丝分裂，参与肺部炎症和修复的发病机制。急性呼吸窘迫综合征或间质性肺疾病患者肺部uPA表达降低可加重纤维性肺泡炎。我们在这笔赠款的初始资金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uPA和uPAR的表达受到新的转录后通路的调节，这些通路影响上皮细胞在肺部炎症或修复中的反应。我们的初步数据支持这一假说，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uPAR和uPA的表达。目前对这些途径的了解还很少，这是我们对肺损伤和修复机制的理解的一个重要空白。我们的具体目标是：1)确定PGK和另一个新发现的uPAR基因编码区结合蛋白如何调节肺上皮细胞uPAR的表达。2)阐明新发现的3‘-非翻译区(3’-UTR)与uPAR mRNA结合蛋白相互作用对uPAR表达的影响。3)探讨PGK和HNRNPC调节细胞因子介导的肺上皮细胞uPAR表达的机制(S)。4)鉴定uPA mRNABp，并研究其对肺上皮细胞uPA表达的调节作用。这些研究建立在本项目第一个资助周期中完成的工作的基础上，以扩大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的新疗法的开发。

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.