钙蛋白酶在肺间质纤维化上皮-间质转化过程中的作用及其信号传导机制研究

特发性肺纤维化发病机制尚不清楚，上皮-间质转化（EMT）是肺成纤维细胞重要来源。研究表明TGFβ1 可通过激活EGF-ERK/MAPK途径诱导EMT发生。我们前期研究发现：特发性肺纤维化患者肺组织中钙蛋白酶表达显著上调；TGFβ1通过上调钙蛋白酶诱导了肺泡上皮细胞来源的A549细胞发生EMT。研究发现钙蛋白酶可被EGF-ERK/MAPK途径激活，钙蛋白酶的下游信号分子CTGF也参与了肺纤维化过程。据此，我们假设EGF-ERK/MAPK-钙蛋白酶-CTGF 是TGFβ1诱导EMT的信号通路之一。本课题拟通过收集临床肺组织标本，研究钙蛋白酶及信号通路分子的表达；通过转基因小鼠及建立肺纤维化动物模型，研究钙蛋白酶在肺纤维化过程中的作用及机制；通过肺泡Ⅱ型上皮细胞培养及干预研究进一步探讨钙蛋白酶在EMT中的作用及其信号传导机制。从而丰富特发性肺纤维化发病机制，并为特发性肺纤维化提供新的治疗靶点。

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown pathogenesis. Epithelial-mesenchymal transformation (EMT), an essential source of fibroblast, has been proved to be induced by TGFβ1 through activating EGF-ERK/MAPK siganl pathway. In our previous study, we found that the expression of calpain in lungs of patients with IPF was higher than that of normal people and TGFβ1 could induce EMT in A549 cells through up-regulating the expression of calpain. It was found that calpain can be activated by EGF-ERK/MAPK siganl pathway. CTGF, a downstream signal molecular of calpain was proved to be involved in the development of pulmonary fibrosis. Thus, we hypothesized that EMT can be induced by TGFβ1 through EGF-ERK/MAPK-Calpain-CTGF siganl pathway. We plan to investigate the expression of calpain and other molecular in lung tissue specimens. We also try to explore the detailed mechanisms of calpain in pulmonary fibrosis by transgenic mice model. In addition, we will explore the role of calpain in EMT and its signal pathway by type 2 alveolar epithelial cell culture in vitro. This research will improve the mechanism of IPF from a new perspective and provide a new target for the treatment of IPF.