严重烧伤后miR-145调控Mcl-1L表达介导Treg/Th17 失衡的作用机制研究

The disequilibrium between Treg and Th17 is believed to be key reason for the development of sepsis and other complications after severe burn injuries but the underlying molecular mechanism is largely elusive. In our preliminary study, we found that the ratio of Treg/Th17 was increased in the severely burned patients accompanied by Mcl-1L(an anti-apoptosis protein) downregulation and miR-145 upregulation in Th17 suggesting that the Mcl-1L might be the molecular target of miR-145 and RORγt might have a great affinity with the promoter of miR-145 gene. We then hypothesize that in the setting of severe burn, the overexpression of miR-145 modulated by the polarization of Th17, leads to the downregulation of Mcl-1L expression and then the increased apoptosis of Th17, which in turn results in a shift of Treg/Th17 balance to the Treg dominance and then triggers the immune disequilibrium after severe burn. We want to validate the above hypothesis as follows: Firstly, we try to demonstrate that miR-145 has a direct regulatory role on Mcl-1L on the Th cell and then corroborate the intrinsic relationship between miR-145-Mcl-1L pathway and Treg/Th17 disequilibrium; Finally, we prepare to validate the role of miR-145-Mcl-1L pathway in the pathogenesis of immune dysfunction after severe burn injuries. We are confident that our study when upon completion, may shed new light on the pathology of grave complications complicated with severe burn and bring novel targets for clinical treatment.

Treg/Th17 失衡是机体免疫抑制形成的核心因素，但内在调控机制不明。我们前期研究发现严重烧伤患者免疫抑制后Treg/Th17比率增高，且Th17细胞中抗凋亡蛋白Mcl-1L表达显著降低而miR-145 表达明显上调，预实验显示Mcl-1L 是miR-145 的靶分子，生物信息学预测提示极化因子RORγt对miR-145转录具有调控作用，结合文献，我们认为"严重烧伤后增强表达的miR-145能阻遏Mcl-1L表达从而诱导Th17凋亡，促使Treg/Th17失衡，而RORγt可能是调控miR-145转录的关键信号分子"。本研究拟从Th 细胞切入，从细胞及动物水平证实miR-145直接调控Mcl-1L表达，进而明确上述分子在Treg/Th17 失衡及严重烧伤后免疫紊乱发生中的作用及其信号转导机制。研究结果将深化对严重烧伤后免疫抑制发病机制的认识，同时也为临床免疫紊乱干预提供新靶点。