基于亮氨酸代谢重编程探讨白头翁汤调控BCKDH/mTORC1信号通路治疗溃疡性结肠炎的作用机制

亮氨酸是重要的蛋白质合成原料，研究表明亮氨酸代谢可以激活mTORC1信号通路，与肠癌等多种疾病密切相关。课题组前期临床蛋白质组与代谢组学发现溃疡性结肠炎（UC）患者血清中亮氨酸水平显著升高，mTORC1信号通路下游CRKL等相关蛋白表达显著上调。白头翁汤在UC防治上具有充分的理论和临床依据，但其作用机制尚不明确。预实验发现白头翁汤可以上调UC小鼠体内中亮氨酸代谢限速酶BCKDH降低亮氨酸的水平，并抑制mTORC1信号通路，推测亮氨酸代谢重编程调控BCKDH/mTORC1信号通路可能是白头翁汤治疗UC的潜在机制。本项目拟采用靶向代谢组学等多组学方法以及免疫荧光、免疫共沉淀等分子生物学技术，通过体内外实验研究白头翁汤抑制亮氨酸代谢对mTORC1信号通路的调控作用，进而达到减轻肠黏膜炎症、修复肠黏膜屏障的疗效，为经典名方白头翁汤功效机制的现代阐释提供参考，为中医药治疗UC研究提供新思路。

Leucine is an important raw material for protein synthesis, studies have shown that the mTORC1 signaling pathway could be stimulated by leucine metabolism which is closely related to colon cancer as well as other diseases. Previous clinical studies of proteomics and metabolomics showed that the level of leucine in serum of patients with ulcerative colitis was significantly increased, and related proteins such as CRKL downstream of mTORC1 signaling pathway were upregulated accordingly. Baitouweng Decoction is a classic prescription that has sufficient theoretical and clinical basis for the prevention and treatment of UC with an exception of unclear mechanism. Further studies showed that Baitouweng Decoction could upregulate leucine Acid-limiting enzyme BCKDH in UC mice to reduce the level of leucine and inhibit mTORC1 signaling pathway. It was speculated that leucine metabolic reprogramming to regulate BCKDH/mTORC1 signaling pathway may be the potential mechanism of Baitouweng Decoction in treatment of UC. For the validation of Baitouweng Decoction of reducing intestinal mucosal inflammation and repairing intestinal mucosa barrier, this project studies the regulation of mTORC1 signaling pathway by inhibiting leucine metabolism with Baitouweng Decoction through in vivo and in vitro experiments by Multi-omics methods such as targeted metabolomics and molecular biology techniques such as immunofluorescence and immunoprecipitation. This project provides a reference for the modern interpretation of the efficacy mechanism of the classic prescription- Baitouweng Decoction and new ideas for the research of anti-UC drugs.