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

尿激酶和肝细胞生长因子在介导肺纤维化上皮细胞保护作用中的相对作用和相互依赖性

• 批准号: 173756413
• 负责人: Dr. Clemens Ruppert, Ph.D.
• 金额: --
• 依托单位: Biomedizinisches Forschungszentrum Seltersberg (BFS)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/173756413?language=en
• 关键词: Relative; role; interdependence; urokinase; hepatocyte

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.

最近的实验结果暗示了尿激酶纤溶酶原激活剂（UPA）系统与肝细胞生长因子（HGF）之间的联系，这是一种在伤口愈合和修复中具有多效性功能的细胞因子。在急性或慢性损伤的条件下，肺纤维化的条件下，UPA-HGF轴对于保护肺泡上皮可能非常重要，尽管基本的机制在很大程度上尚未确定。因此，该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。 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成纤维细胞（间质 - 上皮过渡），iv）研究HGF信号在体内维持常规肺泡结构（可诱导型HGF和C-MET敲除小鼠的产生）中的作用，以及V）在分析非传染性动物模型中的upa或HGF治疗效应中的治疗功效。