Relative role and interdependence of urokinase and hepatocyte growth factor in mediating epithelial cell-protective effects in lung fibrosis

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Recent experimental results implicate a link between the urokinase plasminogen activator (uPA) system and hepatocyte growth factor (HGF), a cytokine with pleiotropic functions in wound healing and repair. The uPA-HGF axis may be of considerable importance for protection of the alveolar epithelium under conditions of acute or chronic injury, such as lung fibrosis, although the underlying mechanisms are largely unsettled. Major goals of this project are therefore to decipher the mutual interaction and interdependence between uPA and HGF signaling. We aim to I) decipher the downstream signaling events in cultured epithelial cells and fibroblasts upon treatment with uPA or HGF, II) study the precise mechanism of uPA-induced HGF activation and its dependence on the uPA receptor (uPAR), III) investigate the influence of HGF and uPA on cellular plasticity of alveolar epithelial cells (epithelial-mesenchymal transition) and lung fibroblasts (mesenchymal-epithelial transition), IV) study the role of HGF signaling for the maintenance of a regular alveolar structure in vivo (generation of inducible HGF and c-Met knockout mice), and V) to analyze the therapeutic efficacy of uPA or HGF in non-inflammatory triggered animal models of pulmonary fibrosis.