间充质干细胞通过外泌体传递的LncRNA-HBRR调控Brg1/Sirt1/FoxO3a通路对移植肝细胞程序性坏死的作用及机制研究

移植肝功能障碍严重影响受体预后，肝缺血再灌注损伤（HIRI）是主要原因，缺少有效防治方法仍是热点问题；间充质干细胞（MSCs）展现良好治疗前景，明确主要机制是提高其疗效关键所在。我们发现有炎症放大特性的程序性坏死在移植肝HIRI中十分明显；通过芯片分析首次发现并命名MSCs的LncRNA-HBRR经外泌体传递，调控Brg1对移植肝产生保护作用；并在国自然项目支持下证实Brg1调控Sirt1/FoxO3a介导Fas、Trail作用，Fas、Trail是调控程序性坏死的重要因子。据此我们推测MSCs的LncRNA-HBRR经外泌体传递调控Brg1/Sirt1/FoxO3a减轻移植肝程序性坏死。本项目拟从分子、细胞和整体水平，利用小鼠肝移植模型，借助基因修饰鼠、相关分子干预手段等验证这一假说，探讨MSCs减轻移植肝HIRI的新机制，从LncRNA-HBRR和外泌体新视点为其临床转化提供新思路。

Liver transplantation dysfunction seriously affects the prognosis of the recipient. Hepatic ischemia reperfusion injury (HIRI) is the main cause of liver transplantation dysfunction. Stem cell therapy shows a good prospect for liver transplantation dysfunction. It is expected to significantly improve the therapeutic effect of stem cells to clarify the main mechanism of concurrent intervention. We found that necroptosis with inflammatory magnification was evident in transplanted liver subjected with HIRI. Through gene chip analysis, we first discovered and named LncRNA-HBRR derived from mesenchymal stem cells (MSCs), which was transmitted to liver cells through exosomes, and regulated Brg1 to have a protective effect on liver transplantation injury. Bioinformatics combined with preliminary experimental results showed that Brg1 can regulate the activity of Sirt1/FoxO3a signaling pathway, and the role of Sirt1/FoxO3a signaling pathway in the regulation of Fas and Trail has been confirmed by the previous national natural science foundation of the applicant. Fas and Trail are important factors in the regulation of programmed necrosis related complexes, so it is speculated that MSCs regulates the Brg1/Sirt1/FoxO3a pathway through the release of LncRNA-HBRR by exosomes to have a protective effect on the necroptosis of the transplanted liver. This project intends to explore the new mechanism of the protective effect of MSCs on the injury of transplanted liver from the perspective of molecules, cells and the overall level, using the mouse liver transplantation and hypoxic reoxygenated cell model, with the help of gene knockout mice and molecular intervention means, through in vivo and in vitro experiments, to provide a new theoretical basis for its clinical transformation and application.