Triptolide通过调控Super-enhancer抑制抗体产生改善抗体介导的移植肾排斥反应

肾移植是治疗终末期肾病的首选方法，但抗体介导的移植肾排斥反应仍是导致移植肾功能丧失的重要因素。我们前期利用小鼠肾移植和动脉移植分别构建的急、慢性排斥模型，均证实triptolide可显著抑制抗体的生成，但机制不明。现有研究发现B细胞身份基因相关的超级增强子（Super-enhancer），在抗体生成中扮演关键角色，而最新研究证实triptolid可调控Super-enhancer，另外，预实验中我们发现triptolide可调控B细胞身份基因的表达。据此，我们提出triptolide通过调控B细胞身份基因相关的Super-enhancer抑制抗体生成的科学假说。本项目拟在分子、细胞和动物组织三个层面，利用ChIP-seq技术、小鼠肾移植模型等解析Triptolide调控Super-enhancer抑制B细胞抗体产生的关键分子机制。项目研究成果有望为抗体介导移植肾排斥的防治提供新途径。

Kidney transplantation is the most ideal way to treat patients with end-stage renal disease. However, antibody-mediated rejection of the transplanted kidney is still an important factor leading to the loss of graft function. We previously used mouse kidney transplantation and arterial transplantation to construct acute and chronic rejection models and found that triptolide could significantly inhibit the production of antibodies, but the mechanism is unclear. Studies have confirmed that super-enhancers related to B cell identity genes play a key role in antibody production, and triptolid can regulate the expression of super-enhancers. In addition, in preliminary experiments, we found that triptolide can regulate the expression of B cell identity genes. Therefore, we put forward the scientific hypothesis that triptolide inhibits antibody production by regulating the super-enhancer related to B cell identity genes. This project intends to use ChIP-seq technology and mouse kidney transplantation models to analyze the key molecular mechanism of Triptolide's regulation of super-enhancer to inhibit the production of antibodies at the three levels: molecules, cells and animal tissues. The research results of the project are expected to provide a new method for the prevention and treatment of antibody-mediated renal transplant rejection.