细胞外基质蛋白Tenascin-C介导异种肝移植术后早期移植肝损伤的作用与机制研究

供体短缺是阻碍器官移植发展的最大难题，以猪为供体的异种移植是重要的解决方法之一。但猪与灵长类动物的种间差异大，术后出现严重移植肝损伤，导致移植失败。申请者在国内最早成功开展GTKO猪为供体的异种肝移植大动物实验，并分析手术前后移植肝差异基因谱，发现细胞外基质蛋白Tenascin-C（TNC）术后明显上调。进而发现TNC转录激活可能发挥以下作用：直接效应—介导肝细胞凋亡，加重缺血再灌注损伤；间接效应—诱导Th17细胞活化，介导急性免疫排斥损伤，但机制不清。为此本项目拟以猪-猴肝移植模型为对象，以凋亡线粒体途径、死亡受体途径为代表，研究TNC转录激活促进肝细胞凋亡的机制；以TNC-IL-6/TLR4-IL-17轴为代表，探索TNC调控Th17细胞转化对急性免疫排斥损伤的影响。本研究将有望揭示移植肝损伤机制并提供潜在干预靶点，以降低移植肝早期失功发生率，实现受体长期存活并推动异种肝移植走向临床。

Shortage of donor organs greatly limits the development of organ transplantation. Xenotransplantation is one of the pathways to solve this problem. Among different xenotransplantation organ sources, pig organ has been mostly studied. However, owing to considerable genetic differences between pigs and primates, there will be severe liver graft injuries after xenogeneic liver transplantation, leading to dysfunction of liver grafts at early postoperative period or even recipient death. Applicant successfully carried out the first liver xenotransplantation between α-1,3-Gal knockout (GTKO) pig donor and primate recipient. Then the gene expression changes of liver grafts before and after xenotransplantation was analyzed using gene chip. One of extracellular matrix proteins, Tenascin-C (TNC), was considerably upregulated. It’s proved that TNC plays a crucial role in liver graft injuries through in vitro and in vivo studies. The two main working pathways of TNC: direct effect—inducing hepatocyte apoptosis and worsening liver graft IRI; indirect effect—activating Th17 and aggravating acute immune rejection injuries with unclear mechanism. Therefore, using GTKO pig - Tibetan macaque as transplantation model, we propose to investigate: the mechanism of TNC inducing hepatocyte apoptosis through potential mitochondrial apoptosis pathways and death receptor pathways; TNC regulating Th17 cells and the effect on acute rejection injuries through TNC-IL-6/TLR4-IL17 axis. Through the research of this project, we have a good chance to know the cellular and molecular mechanism of TNC regulating Th17 on acute rejection injuries and then get potential therapeutic targets to relieve early stage liver graft IRI and acute rejection injuries, reduce the risk of liver graft dysfunction, achieve long-term survival of recipients and finally promote clinical practice of liver xenotransplantation.