O-GlcNAc糖基化修饰介导GRB2/STAT3通路调控小胶质细胞活化在代谢性炎症中的作用研究

糖基转移酶OGT介导的底物蛋白糖基化修饰在小胶质细胞活化和代谢性疾病中发挥重要功能。本课题组发现OGT与接头蛋白GRB2相互作用，促使其发生糖基化修饰，进而与炎症信号转导分子STAT3结合，参与高糖高脂诱导的小胶质细胞炎性活化。据此提出“营养过剩通过OGT-GRB2-STAT3正反馈轴促进小胶质细胞活化进而参与肥胖”的科研假说。课题组首先在小胶质细胞活化模型中分析OGT对GRB2糖基化修饰的调节；其次分析GRB2-STAT3结合对STAT3磷酸化和GRB2转录的影响；在此基础上干预OGT的表达，探讨OGT对GRB2-STAT3结合的影响及对小胶质细胞活化和神经元凋亡的意义；最后在食源性动物模型中靶向干预下丘脑小胶质细胞内OGT，明确OGT-GRB2-STAT3轴促进小胶质细胞活化、神经元凋亡和脑功能损伤的正反馈机制。课题研究可为蛋白质糖基化修饰参与代谢性疾病的发生和防治提供实验基础。

O-GlcNAc transferase-mediated glycosylation of substrate protein plays an important role in microglia activation and metabolism disease. Our team found that OGT interacts with adaptor protein GRB2 to promote its glycosylation, and then associates with inflammatory signal transduction molecule STAT3 to participate in high glucose and high fat-induced inflammatory activation of microglia. Based on this, we propose a hypothesis that overnutrition promotes microglia activation through the OGT-GRB2-STAT3 positive feedback axis that participates in obesity development. The research group firstly analyzed the regulation of OGT on GRB2 glycosylation modification in microglia activation model; secondly, analyzed the effect of GRB2-STAT3 complex on STAT3 phosphorylation and GRB2 transcription; based on this data, intervened the expression of OGT, and explored the effect of OGT knockdown on GRB2-STAT3 binding and its significance on microglia activation and neuronal apoptosis; finally, the OGT was targeted to intervene in hypothalamic microglia in diet-induced animal models to clarify the positive feedback mechanism of OGT-GRB2-STAT3 axis promoting microglia activation and neuron apoptosis as well as brain function injury. This study can provide an experimental basis for protein glycosylation to participate in the occurrence and prevention of metabolic diseases.