干预wip1/NF-κB通路预防活体肝脏移植术后小肝综合症的机制研究

Small-for-size syndrome is one of the complications of living donor liver transplantation. There are lack of target protein for treatment of small-for-size syndrome.The trancript factor NF-κB plays key role in liver regeneration. Wip1 can inhibit the transcription activity of NF-κB through dephosphration. We have found that inhibiting wip1 with SPI-001 could prompt primary hepatocytes proliferation which were seperated from mice liver; wip1 expression was upregulated during liver regeneration after partial hepatectomy. And liver regeneration was accelerated in wip1 knock out mice. The expression of NF-κB and cyclin D protein was upregulated in wip1 knock out mice during liver regeneration. We also found that wip1 expression was also upregulated in liver tissues of living donor liver transplantation recipients. The results of our study implicited that wip1 might be a target protein for treating small-for-size syndrome. In this project, we will elucidate the roles and mechanisms of wip1/NF-κB signal in regulating hepatocytes proliferation and liver regeneration. And we will explore the role of SPI-001, which is wip1 inhibitor, in preventing small-for-size syndrome in rat liver transplantation and investigate its mechanisms. The objective is to clarify the mechanisms and therapeutic significance of interfering wip1/NF-κB in small-for-size syndrome,thus provide new target for small-for-size syndrome therapy.

小肝综合症严重限制了活体肝脏移植的开展，目前尚缺乏有效预防和治疗的靶蛋白。NF-κB是肝脏再生的关键转录因子，wip1是其负反馈抑制蛋白。本课题组研究发现：抑制wip1活性能促进小鼠原代肝脏细胞增殖；小鼠肝脏再生过程中wip1蛋白表达升高； wip1基因敲除小鼠肝脏再生增快，且肝脏组织中NF-κB及其下游cyclin D蛋白表达升高；活体肝脏移植受体肝组织wip1蛋白表达升高。上述结果提示wip1可能成为预防小肝综合症的靶蛋白。在前期工作基础上，本项目拟在体内、外研究wip1/NF-κB通路在肝脏细胞增殖中的作用和机制，并利用小体积大鼠肝脏移植模型研究wip1抑制剂SPI-001干预wip1/NF-κB通路预防小肝综合症的作用和机制。项目预期目标将阐明干预wip1/NF-κB通路在防治小肝综合症中的作用和机制，为临床防治小肝综合症提供新的靶蛋白。

小肝综合征是影响活体肝脏移植术后患者预后的重要因素。本项目利用小鼠2/3肝切除模型，探索肝脏wip1在肝脏再生过程中的调控机制。研究结果显示：.1、wip1在肝脏再生过程中起到重要调控作用，利用wip1抑制剂下调肝脏再生过程中wip1表达水平，能够通过上调NF-kB及其下游蛋白表达，促进肝脏再生。.2、高脂饮食会诱导肝脏脂肪变性，抑制wip1表达能够通过上调mTOR通路活性预防肝脏脂肪变性。