Control of Fibrinolytic Pathways in Lung Disease

University Of Texas Hlth Ctr At Tyler, Tyler TX

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Abstract

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.