蛋白磷酸酶2Ac通过影响血管内皮细胞转分化参与特发性纤维化发病机制的探讨

Several recent studies have revealed that endothelial-to-mesenchymal transition (EndMT) is implicated in the pathogenesis of pulmonary fibrosis in mice model. protein phosphatase 2A (PP2A) plays an important role in the progress of EndMT in vitro and most of the function of PP2A is depend on its catalytic subunit PP2Ac. However, there is no reports about the effect of PP2Ac on pulmonary fibrosis. We completed some reseaches in which we used the Y127WT as a specific inhibitor of PP2Ac and found that in vivo fluorescence imaging, Y127WT was increasing in the lung at 30min after intraperitoneal injection and Y127WT could attenuate the lung inflammation and fibrosis in the model of pulmonary fibrosis by compared with bleomycin group or bleomycin + Y127Scr group. Based on these knowledge，firstly, we plan to investigate the expression of PP2Ac with EndMT and the role of EndMT on clinical symptoms by detecting the lung sctions of idopathic pulmonary fibrosis patients. Secondly, some interfering studies will be carried out in vivo and vitro by Y127WT or PP2Acα plasmid，in order to reveal the role of PP2Ac on the pathogensis of pulmonary fibrosis. This study may augment the knowledge of IPF pathogenesis and potentially find a new promising target for IPF therapy.

目前研究表明，内皮细胞转分化促进小鼠肺纤维化模型中纤维化的发生。在研究中发现蛋白磷酸酶2A（PP2A）在内皮细胞转分化中发挥着重要作用，PP2A的功能是通过催化亚基PP2Ac实现的，但其在肺纤维化中作用尚无研究。在预实验中，我们采用干预序列(Y127WT)特异性的抑制磷酸酶2Ac的活性。通过活体动物成像，发现注射后30min，干预序列在肺组织内明显增加；通过对比各组，发现干预序列能明显减轻小鼠肺纤维化模型中肺部炎症及纤维化。本研究拟通过观察特发性肺纤维化患者肺组织中PP2Ac的表达与内皮细胞转分化及内皮细胞转分化与临床症状的关系，分析探讨PP2Ac对于特发性肺纤维化的影响；并进一步以干预序列(Y127WT)为研究工具，通过动物模型及体外实验，研究PP2Ac对内皮细胞转分化和肺纤维化的影响及其分子机制。本研究的实施将进一步扩展我们对于特发性肺纤维化发病机制的认识，并可能发现新的潜在治疗靶点。