供肝SUR1 A1369S突变参与他克莫司诱导的肝移植术后新发糖尿病发生及机制研究

移植后新发糖尿病(NODAT)严重影响肝移植患者长期生存，探讨其发病机制是该领域的研究前沿。前期联合DMET和EXON芯片发现KATP通道蛋白SUR1 A1369S与他克莫司（TAC）诱导的NODAT发生显著相关，且TAC代谢、耗氧量和ROS检测表明SUR1 A1369S参与ROS介导的糖和TAC代谢异常，然而供肝SUR1 A1369S如何引起NODAT的机制尚不清楚。为此我们通过免疫共沉淀发现TAC可调控激酶CDK1结合SUR1 A1369S。推断:TAC抑制CDK1磷酸化SUR1 A1369S蛋白，降低KATP通道活性，引起线粒体膜电位降低，促进ROS生成，导致ROS介导的TAC代谢和糖脂代谢异常。本项目将进一步利用小鼠肝移植新发糖尿病模型、电镜和ROS检测等手段明确供肝SUR1 A1369S突变调控TAC诱导的NODAT发生的分子机制,为寻找新的NODAT预后指标和治疗手段奠定基础。

New-onset diabetes after transplantation (NODAT) severely affects the long-term survival of liver transplant patients, and exploring its pathogenesis is the forefront of research in this field. Early combination of DMET and EXON chips found that the KATP channel protein SUR1 A1369S was significantly related to NODAT induced by tacrolimus (TAC). Further TAC metabolism, OCR and ROS detection showed that SUR1 A1369S can participate in ROS-mediated abnormalities in glucose and TAC However, the mechanism of how donor liver SUR1 A1369S causes NODAT is unclear. For this reason, we found that TAC can regulate kinase CDK1 binding to SUR1 A1369S through co-immunoprecipitation. It is concluded that TAC inhibits CDK1 phosphorylation of SUR1 A1369S protein, reduces KATP channel activity, reduces mitochondrial membrane potential and promotes ROS generation, leading to ROS-mediated TAC metabolism and glucolipid metabolism abnormalities. This project will further use the mouse liver transplantation new-onset diabetes model,electron microscopy and ROS detection to clarify the molecular mechanism by which the donor liver SUR1 A1369S mutation regulates the occurrence of NODAT induced by TAC.