细胞外分泌蛋白SPP2在肝纤维化发展中的作用及其分子机制研究

In human tissues, secreted phosphoprotein 2 is mainly expressed in liver, howerver, its role in the liver remain unknown. Our preliminary results showed that the expression level of SPP2 in the hepatic fibrosis tissues significantly decreased, and closely related to the prognosis of liver cirrhosis. By liver fibrosis model in the SPP2 KO mouse an wild type mouse, we found SPP2 deletion can promote the liver fibrosis development. In addition, we discovered that SPP2 is maily expressed in hepatic stellate cells, and its expression level was stikingly decresed when the hepatic stellate cells were activated. The overexpression of SPP2 in the hepatic stellate cells can markedly inhibite the cells' proliferation. Based on these fingdings, we will go further to study the role of SPP2 in the liver fibrosis and the underlying mechanisms, and hopefully to provide new therapeutic methods for liver fibrosis.

分泌磷蛋白SPP2在人体中主要表达于肝脏组织，但其在肝脏中所发挥的作用完全未知。我们前期结果表明在肝纤维化/肝硬化病变中SPP2的表达量显著降低，而且其表达量与肝硬化预后好坏密切相关。通过SPP2基因敲除小鼠和野生小鼠的肝纤维化造模，我们确定SPP2基因的敲除能够显著促进肝纤维化的发展。此外，我们还发现SPP2在肝脏中主要表达于肝星状细胞，而且在肝星状细胞激活过程中SPP2的表达显著下降。在肝星状细胞系中过表达SPP2能够明显抑制HSCs的增殖。我们拟进一步从动物水平和细胞水平深入揭示SPP2调节肝纤维化发展的具体分子机制。从而进一步揭示肝纤维化发展的机理，为肝纤维化的减缓甚至逆转提供新的治疗方法。

分泌磷蛋白SPP2在人体中主要表达于肝脏组织，但其在肝脏中所发挥的作用完全未知。通过本项目的研究，我们发现在小鼠肝纤维化/肝硬化病变中SPP2的表达量显著降低，而且其表达量与肝硬化预后好坏密切相关。通过SPP2基因敲除小鼠和野生小鼠的肝纤维化造模，我们确定SPP2基因的敲除能够显著促进肝纤维化的发展。此外，我们还发现SPP2在肝脏中高表达于肝星状细胞，而且在肝星状细胞激活过程中SPP2的表达显著下降。在肝星状细胞系LX-2中过表达SPP2能够明显抑制HSCs的增殖。SPP2的活性结构域多肽TRH1能够抑制肝纤维化的发展。而且研究表明SPP2和TRH1多肽主要是通过抑制TGF-β通路的激活来发挥抑制肝纤维化作用。我们的研究还发现RARα调控SPP2在肝纤维化过程中的表达下调。本项目研究进一步揭示了肝纤维化发展的机理，为肝纤维化的减缓甚至逆转提供新的治疗方法。