EB病毒驱动的精氨酸代谢重编程的分子机制研究

鼻咽癌为重要致瘤病毒EBV感染致癌的代表性肿瘤。EBV（LMP1）通过多种机制诱导关键代谢通路/代谢酶/代谢产物改变，造成宿主细胞代谢模式异常，促进鼻咽癌发生发展。我们新近研究提示，EBV（LMP1）阳性细胞精氨酸内源合成途径受阻，外源摄入水平增强，胞内精氨酸含量显著升高，精氨酸分解代谢活跃。根据国内外前沿进展及前期工作基础，本项目拟以EBV（LMP1）阳性的鼻咽癌为模型，明确EBV（LMP1）驱动的精氨酸代谢重编程的特征；阐明EBV（LMP1）活化精氨酸-NO代谢途径，改变关键代谢酶巯基亚硝基化（SNO）修饰及活性，重塑细胞能量代谢的分子机制；探讨精氨酸剥夺策略用于EBV（LMP1）阳性鼻咽癌治疗的可行性，为EBV致瘤机理及其相关肿瘤治疗提供新的实验证据与理论依据。

Nasopharyngeal carcinoma (NPC) is a representative cancer driven by EBV infection. EBV (LMP1) induces changes in key metabolic pathways/metabolic enzymes/metabolites through multiple mechanisms, remodels host cell metabolic patterns, and promotes the development of NPC. Our recent studies suggest that in EBV (LMP1)-positive cells the endogenous synthesis pathway of arginine is blocked, the transport rate for arginine is enhanced, the intracellular arginine level is significantly increased, and the catabolism of arginine is active. Based on the research progress and our previous work, this project intends to clarify the characteristics of arginine metabolism driven by EBV (LMP1), to elucidate the molecular mechanism of EBV (LMP1) activating of arginine-NO metabolism pathway and remodeling cell energy metabolism, and to explore the feasibility of arginine deprivation strategy in the treatment of EBV (LMP1)-positive NPC. It will provide new molecular mechanism of carcinogenesis and treatment strategies for the EBV-related cancers.