通过调控巨核细胞甲基化促进ITP患者血小板生成的实验研究

ITP患者细胞存在DNA甲基化异常，调控DNA甲基化有望开辟ITP治疗的新领域。目前DNA去甲基化已成为MDS治疗的重要手段，在升高血小板方面疗效尤其显著。研究发现：DNA去甲基化能通过促进巨核细胞成熟和血小板释放来提升血小板数目。DNA去甲基化在ITP治疗中的作用国内外尚无报道。我们前期分别观察了ITP患者CD8+T细胞及血浆对体外巨核细胞生成的影响，发现二者均能引起巨核细胞凋亡受抑，并伴有成熟障碍及血小板生成减少。进一步研究发现在ITP患者血浆的作用下，巨核细胞内Bcl-xL表达升高，TRAIL表达降低，且对巨核细胞的抑制作用与自身抗血小板抗体无关。本项目将以脐血CD34+细胞来源的巨核细胞体外培养和ITP小鼠模型为对象，探讨DNA去甲基化对巨核细胞及血小板生成的影响，明确其在ITP中的治疗作用及具体机制，寻求ITP治疗的新靶点。

It has been discovered that ITP patients have impaired DNA methylation.Treatment against DNA methylation may provide new therapeutic strategies for this disease. DNA-hypomethylation has been reported to have a clinically significant, often long lasting effect on the platelet count in myelodysplastic syndromes(MDS). Recently, one study reported that DNA-hypomethylation could increase platelet counts by enhancing megakaryocyte maturation and platelet release. However, the effects of DNA-hypomethylation in ITP remain poorly understood. Our previous study showed that both CD8+T cells and the plasma from ITP patients inhibited in vitro megakaryocyte apoptosis, resulting in less polyploidy cells and platelet release. In these megakaryocyte, we also observed a lower expression of tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) and a higher expression of Bcl-xL. In this project, we will use in vitro megakaryocyte culture and chronic ITP mouse model as targets, trying to find the effects of DNA-hypomethylation on megakaryocyte maturation and platelet production in ITP and its possible mechanisms.