过氧化物还原酶-2调控滋养层细胞迁移和分化的机制

Trophoblast migration plays a key role in the process of embryo implantation and vascular remodeling. Furthermore, trophoblasts express specific antigen and secrete immune regulatory factors during cell differentiation, which allow maternal immune system to accept the allogeneic fetus and its appurtenances. The reduction of trophoblast migration and differentiation is closely related with the pathogenesis of recurrent miscarriage. Previous studies of our research group have found that Peroxiredoxin-2 (Prdx2), mediated by c-Myc, plays an important role in the regulation of trophoblast proliferation and apoptosis through phosphorylated p53 and p38-MAPK/p21. Herein, we will further study the mechanism of Prdx2 in trophoblast migration and differentiation. We aim to identify the upstream and downstream signaling pathways of Prdx2 through construction of the wild-type and mutant promoter reporter, explant culture, RNA interfering and overexpression plasmid transfection. We will also study the role of Prdx2 in the recruitment and polarization of M1 and M2-type decidual macrophages with megnetic-affinity cell sorting and cell coculture techniques. Animal models and clinical samples will be used to verify in vitro experiments. The expected findings will not only help us deeply understand the mechanism of trophoblast migration and differentiation, but also further reveal the potential of Prdx2 as a new target in early diagnosis and treatment of pregnancy-related diseases.

滋养层细胞的迁移是胚胎着床、胎盘血管形成的关键环节，同时滋养层细胞表达特异性抗原并分泌免疫因子，使母体接受同种异基因胎儿及其附属物。滋养层细胞迁移能力降低和分化不足与复发性流产的发生密切相关。我们前期研究发现过氧化物还原酶-2（Prdx2）在c-Myc调控下通过磷酸化p53和p38-MAPK/p21调节胎盘滋养层细胞的增殖和凋亡。本项目将进一步研究Prdx2在细胞迁移和分化中的作用机制。我们将通过构建启动子报告基因、绒毛外植体培养、RNA干扰和质粒过表达等技术，确认Prdx2上下游信号通路及作用；采用磁珠亲和细胞分选和细胞共培养等技术，探索滋养层细胞Prdx2在M1和M2型蜕膜巨噬细胞招募、极化中的作用；同时运用小鼠模型和临床样本验证体外实验结论。这项研究不仅有助于我们深入解析滋养层细胞迁移和分化的机制，而且有助于探索Prdx2能否成为复发性流产等妊娠相关疾病早期诊断以及后续治疗的靶点。

母胎界面滋养层细胞正常的增殖、迁移和分化对维持妊娠具有重要意义。我们的前期研究结果显示，Prdx2作为抗氧化因子，在滋养细胞中受到转录因子c-Myc的调控，从而促进了滋养细胞的增殖，抑制了细胞的凋亡，基于上述结果，我们进一步对Prdx2敲减后其下游基因表达的做了芯片分析，发现Prdx2通过转录因子SPIB调控组蛋白去乙酰化酶2（HDAC2）的表达，进而影响组蛋白乙酰化修饰，影响滋养层细胞E-cadherin、Slug、Snail等基因的表达，继而调控滋养层细胞的增殖、迁移和分化。Prdx2及其相关信号通路分子为复发性流产等妊娠相关疾病临床前诊断和治疗提供了新的靶点。在对胎界面免疫细胞功能的研究中，我们阐述了母胎界面骨髓来源的抑制性细胞（MDSCs）的减少及其基因表达谱的变化与复发性流产的相关性。这项研究进一步揭示了母-胎免疫耐受的相关机制，为复发性流产等疾病的免疫治疗提供了新的科学依据。