Disordered fibrin turnover and extravascular fibrin deposition have been implicated in the pathogenesis of lung injury and repair and lung cancer. Lung epithelial cells contribute to remodeling of extravascular fibrin by elaboration of urokinase (uPA), the urokinase receptor (uPAR) and plasminogen activator inhibitor-1 (PAl-1). Abnormal expression of these molecules in lung injury and neoplasia disrupts local fibrin turnover, potentiates local inflammation, and promotes organization of transitional fibrin with eventual fibrosis. We recently found that uPA induces expression of uPAR by lung epithelial cells. We now demonstrate that exogenous uPA also induces uPA and PAI-1 expression by these cells. These studies clearly show that lung epithelial cells regulate the uPA-uPAR-PAI-1 system by novel pathways about which little is currently understood. Our preliminary data show that posttranscriptional regulation contributes to uPA-mediated autoinduction as well as that of uPAR and PAI-1. Our central hypothesis is that novel pathways by which uPA regulates its own expression as well as that of uPAR and PAI-1 by lung epithelial cells are crucial in the pathogenesis of acute lung injury, its repair and lung cancer. Our objective is to elucidate the regulatory mechanisms by which uPA induces expression of these molecules. We will accomplish the objective in four specific aims.
In Aim 1, we will determine if uPA induces epithelial cell uPAR at both transcriptional or posttranscriptional levels and define the responsible mechanisms.
In Aim 2, we will determine the mechanism by which a-thrombin blocks uPA-mediated uPAR induction.
In Aims 3 and 4, we will determine the mechanisms by which uPA induces its own expression as well as that of PAl-1, respectively, in lung epithelial cells. We will use a wide range of molecular, immunohistochemical, protein purification, and cell culture techniques with which we are experienced to complete the proposed work. These studies will increase our understanding of novel mechanisms by which the lung epithelium regulates the uPA-uPAR-PAI-1 system. This information could hasten the development of new, mechanism-based interventions for lung disorders, including acute lung injury or lung neoplasia.
|Shetty, Sreerama; Velusamy, Thirunavukkarasu; Shetty, Rashmi S et al. (2010) Post-transcriptional regulation of plasminogen activator inhibitor type-1 expression in human pleural mesothelial cells. Am J Respir Cell Mol Biol 43:358-67|
|Shetty, Praveenkumar; Velusamy, Thirunavukkarasu; Bhandary, Yashodhar P et al. (2010) Urokinase receptor expression involves tyrosine phosphorylation of phosphoglycerate kinase. Mol Cell Biochem 335:235-47|
|Bhandary, Yashodhar P; Velusamy, Thirunavukkarasu; Shetty, Praveenkumar et al. (2009) Post-transcriptional regulation of urokinase-type plasminogen activator receptor expression in lipopolysaccharide-induced acute lung injury. Am J Respir Crit Care Med 179:288-98|
|Velusamy, Thirunavukkarasu; Shetty, Praveenkumar; Bhandary, Yashodhar P et al. (2008) Posttranscriptional regulation of urokinase receptor expression by heterogeneous nuclear ribonuclear protein C. Biochemistry 47:6508-17|
|Shetty, Praveenkumar; Velusamy, Thirunavukkarasu; Bhandary, Yashodhar P et al. (2008) Urokinase expression by tumor suppressor protein p53: a novel role in mRNA turnover. Am J Respir Cell Mol Biol 39:364-72|
|Shetty, Sreerama; Shetty, Praveenkumar; Idell, Steven et al. (2008) Regulation of plasminogen activator inhibitor-1 expression by tumor suppressor protein p53. J Biol Chem 283:19570-80|
|Shetty, Sreerama; Velusamy, Thirunavukkarasu; Idell, Steven et al. (2007) Regulation of urokinase receptor expression by p53: novel role in stabilization of uPAR mRNA. Mol Cell Biol 27:5607-18|
|Shetty, Sreerama; Velusamy, Thirunavukkarasu; Idell, Steven et al. (2007) Regulation of urokinase receptor expression by protein tyrosine phosphatases. Am J Physiol Lung Cell Mol Physiol 292:L414-21|
|Shetty, Sreerama; Rao, Gadiparthi N; Cines, Douglas B et al. (2006) Urokinase induces activation of STAT3 in lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 291:L772-80|
|Shetty, Sreerama (2005) Regulation of urokinase receptor mRNA stability by hnRNP C in lung epithelial cells. Mol Cell Biochem 272:107-18|
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