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，HGF是一种在伤口愈合和修复中具有多效性功能的细胞因子。uPA-HGF轴对于在急性或慢性损伤（例如肺纤维化）的情况下保护肺泡上皮可能是相当重要的，尽管潜在的机制在很大程度上是不确定的。因此，本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性。我们的目的是：（1）解读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活化的确切机制及其对uPA受体（uPAR）的依赖性;（3）研究HGF和uPA对肺泡上皮细胞可塑性的影响（上皮-间质转化）和肺成纤维细胞（间充质-上皮转变），IV）研究HGF信号传导对于维持体内规则肺泡结构的作用（诱导型HGF和c-Met敲除小鼠的产生），和V）分析uPA或HGF在肺纤维化的非炎性触发动物模型中的治疗功效。

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.