谷氨酰胺调控BCAT2的分子机制及其功能研究

胰腺导管癌诊断极其困难，恶性程度高，病程进展快，有“癌中之王”之称。KRAS突变是PDAC发生的早期事件，驱动“谷氨酰胺成瘾”成为PDAC代谢重塑的重要特征之一。我们的研究已发现支链氨基酸转氨酶2（BCAT2）介导的支链氨基酸（BCAA）代谢在胰腺癌的发生发展中起着重要作用。我们前期的预实验结果发现谷氨酰胺缺乏诱导BCAT2蛋白水平的下调，并影响其泛素化水平和乙酰化水平。基于此，我们推测谷氨酰胺可以调控BCAT2的稳定性，进而影响胰腺癌细胞生长。该项目将进一步深入研究谷氨酰胺调控BCAT2的表达调控的分子机制及其功能，阐明谷氨酰胺和支链氨基酸代谢通路之间的串话，为胰腺癌治疗提供新的治疗思路和靶点。通过联合靶向谷氨酰胺和BCAA代谢可能为胰腺癌提供新的治疗措施。

Pancreatic ductal adenocarcinoma is extremely difficult to diagnose. It’s malignancy is extremely high and progress is aggressive, so it is known as "the king of cancer". KRAS mutation is an early event of PDAC. Driven by KRAS mutation, "glutamine addiction" is one of the important features of metabolic remodeling of PDAC. Our previous studies have found that BCAT2-mediated branch chain amino acid metabolism plays an important role in the development of pancreatic cancer. Our previous results showed that glutamine deficiency induced the down-regulation of the protein level of BCAT2 and affected its ubiquitination and acetylation levels. Based on this, we hypothesize that glutamine can regulate the protein stability of BCAT2 and further affect the growth of pancreatic ductal adenocarcinoma cells. This project will futher study the molecular mechanism and function of glutamine metabolism in regulating the expression of BCAT2, clarify the intrinsic relationship between glutamine metabolism and branched-chain amino acids may provide a new therapeutic thoughts and target for the treatment of pancreatic ductal adenocarcinoma. Combination of targeting glutamine and BCAA metabolism may provide a new therapeutic approach for pancreatic ductal adenocarcinoma.