BCAA激活mTOR信号通路在慢加急性肝衰竭肝脏再生中的作用机制研究
结题报告
批准号:
82000601
项目类别:
青年科学基金项目
资助金额:
24.0 万元
负责人:
吴大先
依托单位:
学科分类:
肝保护和人工肝
结题年份:
2023
批准年份:
2020
项目状态:
已结题
项目参与者:
吴大先
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中文摘要
慢加急性肝衰竭(ACLF)给我国带来沉重的卫生健康负担,而肝细胞再生程度决定了患者的最终结局。已有研究表明,支链氨基酸(BCAA)通过激活哺乳类雷帕霉素靶蛋白(mTOR)信号通路参与机体多种病理生理的调节。同时,mTOR对肝切除术后的再生调控也成为近年来的研究热点。但BCAA以及mTOR对ACLF肝脏再生的调控尚未见报导。我们前期研究发现:①BCAA降解下调是ACLF肝组织最主要变化的通路,这是机体主动适应性改变;②ACLF肝组织存在明显的mTOR激活和肝细胞再生。由此,我们提出假设:BCAA通过激活mTOR信号通路促进ACLF的肝脏再生。本研究拟先通过患者及大鼠模型,观察ACLF肝组织中BCAA水平、mTOR活性、及肝脏再生水平的变化,然后在动物及细胞水平上验证BCAA-mTOR-肝脏再生这一信号通路。本研究旨在通过对ACLF肝脏再生机制的研究,为ACLF的防治提供新的循证医学证据。
英文摘要
The acute-on-chronic liver failure (ACLF) brings a heavy health burden to China, and the outcomes of ACLF patients are determined by the degree of hepatocyte regeneration. It has been shown that branched chain amino acid (BCAA) participated in the regulation of various pathophysiological processes by activating mTOR signaling pathway. Additionally, the regulation of mTOR on liver regeneration after hepatectomy has become a research hotspot in recent years. However, the regulation of BCAA and mTOR on liver regeneration of ACLF has not been reported. The results of our previous experiments showed that: (1) the most important pathway enriched in ACLF was the decreased BCAA degradation and it is an active adaptive response; (2) significant mTOR activation and liver regeneration was observed in liver tissue of ACLF patients. Hence, a scientific hypothesis is speculated: BCAA promotes liver regeneration of ACLF by activating mTOR signaling pathway. In this study, the alterations of BCAA level, mTOR activity and liver regeneration level in liver tissue would be firstly observed by ACLF patients and rats; Then, the signaling pathway of BCAA-mTOR-liver regeneration would be verified with animal and cell models respectively. Present study aims to provide new evidence-based stools for ACLF management by clarifying the mechanism of liver regeneration during ACLF occurrence.
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DOI:10.3389/fmed.2021.655863
发表时间:2021
期刊:Frontiers in medicine
影响因子:3.9
作者:Wu D;Zhang L;Ma S;Zhao Y;Chen R;Zhang F;Liu Q;Xu X;Xie Z
通讯作者:Xie Z
DOI:10.1111/hepr.13970
发表时间:2023-10-17
期刊:HEPATOLOGY RESEARCH
影响因子:4.2
作者:Tu,Yasi;Ji,Feiyang;Wu,Daxian
通讯作者:Wu,Daxian
DOI:10.3350/cmh.2022.0121
发表时间:2022-10
期刊:CLINICAL AND MOLECULAR HEPATOLOGY
影响因子:8.9
作者:Wu, Daxian;Rao, Qunfang;Xie, Zhongyang;Zhu, Xiaoqing;Che, Yuanmei;Wu, Jian;Gao, Hainv;Zhang, Jingyu;Hou, Zhouhua;Cheng, Xiaoyu;Sun, Zeyu
通讯作者:Sun, Zeyu
国内基金
海外基金