The role of survivin in liver regeneration

肝切除后肝再生是一个涉及细胞增殖和凋亡的复杂调控过程。Survivin是这两个分子过程的主要调节者，它是细胞凋亡抑制因子(IAP)家族的成员。Survivin通过其作为染色体乘客的功能，直接抑制细胞死亡蛋白Caspase，并控制有丝分裂和染色体分离。大体而言，LAPS和Survivin对肝脏再生的影响目前都不清楚。我们在70%肝切除大鼠模型上的初步工作显示，实时荧光聚合酶链式反应(Real-time PCR)显示，24小时后Survivin mRNA显著诱导(~40倍)。免疫组织化学和Western blotting检测显示肝细胞Survivin蛋白表达水平升高。Survivin的转录诱导与增殖标记物Ki-67检测的肝细胞增殖显著相关。令人惊讶的是，没有观察到与细胞凋亡程度相关。与动物研究一致，我们能够显示Survivin在人类再生肝中的免疫表达，它与肝细胞增殖有关，但与细胞凋亡无关。为了研究Survivin在肝再生中的作用，我们将使用三种不同的基因小鼠模型：(1)杂合Survivin K0+/“；(2)肝细胞特异性Survivin KO”‘；(3)可诱导的肝细胞特异性Survivin KO“’。与诱导Survivin互补的研究将使我们对Survivin在肝脏再生反应中的作用有新的认识，并找到选择性靶向Survivin的方法，以利于活体供体肝移植。

Liver regeneration after hepatectomy is a complex regulated process involving cell proliferation and apoptosis. A major regulator of both molecular processes is survivin, a member of the inhibitor of the apoptosis (IAP) family. Survivin directly inhibits the cell death proteases of the cell, the caspases, and controls mitosis and chromosome segregation via its function as chromosomal passenger. Neither the impact of lAPs in general nor that of survivin in particular in liver regeneration is currently known. Our preliminary work in a 70% liver resection rat model has shown a dramatic induction of survivin mRNA (~40-fold) after 24 hours as measured by real-time PCR. Survivin protein expression levels in hepatocytes were also increased as detected by immunohistochemistry and western blotting. The transcriptional induction of survivin correlated significantly with the proliferation of hepatocytes detected by the proliferation marker Ki-67. Surprisingly, no correlation could be observed with the extent of apoptosis. In line with the animal study, we were able to show survivin immuno-expression in the human regeneration liver, which correlates with hepatocyte proliferation but not with apoptosis. To investigate the role of survivin in liver regeneration we will employ three different genetic mouse models: (1) a heterozygous survivin K0+/"; (2) a hepatocyte-specific survivin KO"'"; and (3) an inducible hepatocytespecific survivin KO"'". Complementary studies with inducing survivin will give us new insights of the role of survivin in the regenerative response of the liver, and identify approaches to selectively target survivin for the benefit of living donor liver transplantation.