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

最近的实验结果表明，尿激酶型纤溶酶原激活物(UPA)系统和肝细胞生长因子(HGF)之间存在联系，肝细胞生长因子是一种在伤口愈合和修复中具有多效性功能的细胞因子。在肺纤维化等急性或慢性损伤条件下，uPA-HGF轴可能对肺泡上皮细胞的保护具有相当重要的作用，尽管其潜在的机制在很大程度上尚不清楚。因此，这个项目的主要目标是破译uPA和HGF信号之间的相互作用和相互依赖。我们的目标是：1)破译uPA或HGF处理后培养的上皮细胞和成纤维细胞中的下游信号事件；2)研究uPA诱导HGF激活的确切机制及其对uPA受体(UPAR)的依赖；3)研究HGF和uPA对肺泡上皮细胞(上皮-间充质转化)和肺成纤维细胞(间质-上皮转化)细胞可塑性的影响；4)研究HGF信号在维持体内正常肺泡结构(产生可诱导的HGF和c-Met基因敲除小鼠)中的作用；以及5)分析uPA或HGF在非炎症性肺纤维化动物模型中的治疗作用。

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.