应激颗粒核心组分G3BP1调控ULK1/LARS1/ATP信号途径对急性肝衰竭的影响及机制研究

前期研究发现急性肝衰竭(ALF)患者肝脏中G3BP1蛋白水平明显降低,促进G3BP1表达可减轻肝细胞炎症损伤。研究显示G3BP1介导组装的应激颗粒(SGs)可减轻细胞炎症反应,但G3BP1对ALF影响机制不明确。最新研究发现SGs能募集mRNA使其翻译为蛋白质;促进ULK1/LARS1/ATP途径可为细胞存活提供能量。基于此我们发现G3BP1蛋白能靶向结合并调控ULK1蛋白表达,使用SGs诱导剂、激活ULK1/LARS1/ATP途径均可减轻肝细胞炎性损伤。推测:上调G3BP1可通过促进ULK1/LARS1/ATP途径缓解ALF。本项目拟从细胞、分子及动物实验层面,明确G3BP1是否一方面介导组装SGs后募集ULK1 mRNA并促进其翻译,另一方面直接结合并促进ULK1蛋白表达,二者共同激活ULK1/LARS1/ATP途径缓解ALF。通过本项目实施为ALF药物防治及早期干预提供新策略。

Previous studies have found that the level of G3BP1 protein in the liver patients with acute liver failure (ALF) is significantly reduced. Promoting the expression of G3BP1 can reduce hepatocyte inflammatory damage. Studies have shown that G3BP1-mediated assembly of stress granules (SGs) can alleviate cellular inflammation, but the mechanism of G3BP1's influence on ALF is unclear. The latest research found that SGs can recruit mRNA to translate it into protein. Promoting ULK1/LARS1/ATP pathway can provide energy for cell survival. Based on this, we found that G3BP1 protein can target and regulate ULK1 protein expression. Using SGs inducers and activating ULK1/LARS1/ATP pathway can alleviate hepatocyte inflammatory damage. Therefore, it is speculated that G3BP1 regulates ULK1/LARS1/ATP signaling pathway and affects ALF outcome. This project intends to clarify whether G3BP1 mediates the recruitment of ULK1 mRNA and promotes its translation after the assembly of SGs on the one hand, G3BP1 directly binds to and promotes the expression of ULK1 protein on the other hand from the cell, molecular and animal experimental levels. The two ways together activate ULK1/LARS1/ATP ways to alleviate ALF. Through the implementation of this project, it will provide new strategies for ALF drug prevention and early intervention.