The role of survivin in liver regeneration

肝切除术后肝再生是一个涉及细胞增殖和凋亡的复杂调控过程。这两个分子过程的主要调节因子是survivin，它是凋亡抑制剂（IAP）家族的一员。Survivin直接抑制细胞死亡蛋白酶半胱天冬酶，并通过其作为染色体乘客的功能控制有丝分裂和染色体分离。目前还不知道lap对肝脏再生的影响，也不知道survivin对肝脏再生的影响。我们在切除70%肝脏的大鼠模型中进行的初步研究显示，通过实时PCR检测，在24小时后，survivin mRNA的表达显著增加（约40倍）。免疫组化和免疫印迹法检测肝细胞Survivin蛋白表达水平升高。通过增殖标志物Ki-67检测，survivin的转录诱导与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，我们能够在人再生肝脏中显示survivin免疫表达，其与肝细胞增殖相关，但与凋亡无关。为了研究survivin在肝脏再生中的作用，我们将采用三种不同的遗传小鼠模型：(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存活素KO“'”。诱导survivin的补充研究将为我们提供survivin在肝脏再生反应中的作用的新见解，并确定选择性靶向survivin的方法，以使活体供肝移植受益。

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.