泛素连接酶ZFP91在调节性T细胞介导的结肠炎癌转变中的机制研究

Regulatory T (Treg) cells have immunosuppressive functions and play an important role in gut immune homeostasis. Treg cell dysfunction may result in the development of inflammatory bowel disease (IBD) and colorectal cancer (CRC). Colitis-carcinoma transformation is an essential pathological step in the development of CRC. However, the role of Treg cells in colitis-carcinoma transformation is still unclear. The applicant has been focusing on Treg cell stability and function, and has defined the molecular mechanisms that regulate Treg cell-mediated immune homeostasis and tumor immunosuppression. Our recent work found that Treg cell-conditional E3 ubiquitin ligase ZFP91 knockout mice were exquisitely sensitive to DSS-induced colitis and AOM/DSS-induced colitis-related colorectal cancer. Therefore, we assume that ZFP91 plays a critical role in T cell-mediated colitis-carcinoma transformation. In this application, we will adopt the RNA-sequencing technology, transgenic mice and different animal models to investigate the regulatory role of ZFP91 in Treg cell function and the mechanism of Treg cell-mediated colitis-carcinoma transformation. Our study may provide novel drug target for the treatment of IBD and CRC.

调节性T细胞具有免疫抑制功能，在维持肠道免疫稳态中发挥关键作用，一旦其功能紊乱将导致炎症性肠病的发生，进而诱发结肠癌。炎癌转变是结肠癌发生的重要因素，然而调节性T细胞在结肠炎癌转变中的作用机制尚不清楚。申请人长期研究控制调节性T细胞稳定与功能的分子机制，揭示了调节性T细胞介导免疫稳态维持与肿瘤免疫逃逸的分子机理。申请人近期工作发现调节性T细胞条件性敲除泛素连接酶ZFP91的小鼠更容易被诱导产生炎症性肠病和结肠癌。鉴于此，申请人推测ZFP91在调节性T细胞介导的结肠炎癌转变中发挥重要作用。本项目拟采用RNA测序技术、基因工程小鼠及不同的动物模型等，研究ZFP91控制调节性T细胞功能发挥的分子机制，解析调节性T细胞控制结肠炎癌转变的作用机制，期望为炎症性肠病和结肠癌的药物开发提供新的靶点。

炎症性肠病是导致结肠癌的重要因素，研究结肠炎癌转变机制具有重要的科学价值和临床转化意义。调节性T细胞（Treg）具有免疫抑制功能，维持肠道免疫稳态，一旦其功能异常将导致炎症性肠病及结肠癌的发生。项目负责人长期致力于Treg细胞功能的研究，前期工作发现泛素连接酶ZFP91在Treg细胞中发挥重要的调节作用，Treg细胞条件性敲除ZFP91的小鼠更容易被诱导产生炎症性肠病和结肠癌，鉴于此，项目负责人推测ZFP91参与了结肠炎癌转变过程，为深入理解ZFP91介导Treg细胞功能发挥的作用机制，项目负责人应用RNA测序、基因工程小鼠以及不同动物模型等技术手段，解析Treg细胞控制结肠炎癌转变的作用模式，发现ZFP91促进TCR信号介导的自噬体形成，从而维持Treg细胞的代谢、稳态与功能。本项目的研究成果期望为炎症性肠病和结肠癌的诊断治疗提供新的思路和靶点。项目实施期间发表一篇相关论文（JEM，2021），培养研究生一名。