核糖体蛋白的O-GlcNAc糖基化修饰在肝细胞癌发生发展中的功能和机制研究

肝脏是人体内核糖体丰度最高以及蛋白质合成最旺盛的器官。正常状态下，蛋白质翻译是受到精密调控并且严格限速的过程；而核糖体的异常组装和过度蛋白质翻译往往伴随肿瘤的发生。因此，蛋白质合成失控在肝细胞癌发生发展过程中发挥了重要作用。然而，肝细胞癌中蛋白质翻译过度活化的机制并不清楚。在本项目中，我们首次对核糖体蛋白的O-GlcNAc糖基化修饰在肝细胞癌发生发展中的功能和机制进行研究。我们拟鉴定肝细胞癌中核糖体蛋白的O-GlcNAc 糖基化修饰，研究O-GlcNAc 修饰对核糖体组装和蛋白质翻译的功能调控和分子机制，以期阐明肝细胞癌中O-GlcNAc 糖基化修饰在核糖体蛋白促进肿瘤过程的重要作用；同时将OGT与核糖体的结合作为潜在的药物靶点设计开发小分子化合物，为肝细胞癌的临床治疗提供新的线索。

Liver is the second-largest organ in human body with the most abundant content of ribosome and the highest efficiency of de novo protein synthesis. Under normal circumstances, ribosome biogenesis and translation initiation are tightly regulated, whereas excessive ribosome biogenesis and protein translation often leads to tumor transformation. Therefore, loss of control in protein synthesis plays a critical role in the tumorigenesis and progression of hepatocellular carcinoma (HCC). However, the underlying mechanism for the aberrant activation of protein translation is little defined. In this study, we examine the role of O-GlcNAc modification of ribosomal proteins in the tumorigenesis and development of HCC for the first time. We will identify the O-GlcNAcylation of ribosomal protein. We also will examine the effect of O-GlcNAcylation on ribosome biogenesis and protein translation and uncover the underlying mechanism, thus elucidating the role of O-GlcNAc modification in ribosomal protein-mediated HCC progression; meanwhile, we will design and develop small molecular compounds that target the association between OGT and ribosome, providing new clues for clinical treatment of HCC.