SUMO2介导的BACH2类泛素化修饰调控Treg细胞功能并影响肾移植排斥反应的机制研究

Transplant rejection is one of the major causes of kidney graft failure. In addition to hereditary factors, there is considerable evidence that post-translational modifications of proteins can be involved in the process of graft rejection. Recently, it was found that the level of urine SUMO2 in patients with renal transplant rejection is significantly increased. Our prior experiments further confirmed that serum SUMO2 is also significantly elevated in the acute rejection of renal transplantation, especially in patients with T cell-mediated rejection, suggesting that SUMO2 may play a significant role in renal transplant rejection. But its mechanism is still unknown. Some other studies reported that SUMOylation can regulate Treg cell function, but the conclusions of different studies are not consistent. Therefore, we intend to use transgenic mice to construct a renal transplant rejection model to explore the specific role of SUMOylation in renal allograft rejection; to clarify SUMO2-mediated post-translational modification of the key target protein BACH2 during rejection, and to verify its mechanism in transplant rejection. Accordingly, this project is supposed to reveal the molecular mechanism of SUMO2-mediated renal transplant rejection, providing a new target for prevention and treatment of renal transplant rejection and induction of immune tolerance.

移植排斥是造成肾移植物失功重要的原因之一。除遗传性因素外，已有不少证据表明蛋白翻译后修饰同样可参与到移植物排斥过程当中。近期有团队发现肾移植排斥患者尿液SUMO2水平明显增加，我们前期研究则进一步证实SUMO2在肾移植急性排斥，特别是T细胞介导排斥患者血浆中显著升高，提示SUMO2介导的类泛素化可能在肾移植排斥过程中起重要作用，但具体机制未明。另有研究报道类泛素化过程可参与调控Treg细胞功能，但不同研究结论并不一致。因此我们拟利用转基因小鼠构建肾移植排斥模型，探索SUMO2介导的类泛素化在肾移植排斥反应中的具体作用；明确排斥过程中SUMO2介导修饰关键靶蛋白BACH2，并通过干扰BACH2基因SUMO化修饰，验证其在移植排斥中的作用机制。据此，本项目有望揭示SUMO2介导肾移植排斥的分子机制，为防治肾移植排斥与诱导免疫耐受提供新的靶点。

肾脏移植则是目前终末期肾病最佳的治疗手段。排斥反应的发生不仅可导致移植肾功能早期丧失，而且也是限制移植肾长期生存最主要的原因。因此，深入研究移植后排异的发生机制，以及致力于探索免疫耐受的诱导与建立对于延长移植肾的长期存活，提高肾移植患者的生存预后意义重大。本课题验证SUMO2介导的泛素化修饰在肾移植免疫排斥中的作用。课题组利用临床血清和体液样本明确明确SUMO2介导的类泛素化修饰与肾移植术后排斥反应之间的相关性；利用SUMO2抑制剂和BACH2 AAV敲减证明SUMO2通过CD4+ T淋巴细胞调控肾移植排斥；利用SNEP3肾近端小管条件敲除小鼠进行肾脏缺血再灌注模型证明肾小管SUMO化修饰在IR中的作用和机制。研究结果显示血清和体液SUMO2水平在肾移植急性排斥患者中显著升高；抑制SUMO2和BACH2的表达减轻小鼠移植肾排斥反应；近端小管敲除SENP3与肾脏缺血再灌注损伤明显有相关性。项目揭示了SUMO2抑制剂和BACH2的敲减能明显抑制肾脏移植后的排异程度；并且血清和尿液中的SUMO2含量可以作为肾脏移植后的排异程度分子标记物。本研究可能为肾脏移植后排异的早期诊断和治疗提供一定的研究思路。课题组在项目实施过程共发表基金标注的第一作者SCI文章，同时另有一篇接受的SCI文章。