母胎界面滋养细胞tRF-Gly-TCC-044靶向作用CXCL14诱导蜕膜巨噬细胞代谢重编程调控其表型转换在子痫前期发病中的作用机制研究

蜕膜巨噬细胞(DMs)表型失衡与子痫前期(PE)的发病密切相关。作为新的研究热点，转运RNA衍生的小RNA(tsRNA)未见与PE的相关报道。我们采用高通量测序筛选PE和正常胎盘差异tsRNA，发现tRF-Gly-TCC-044显著高表达于PE胎盘且定位于绒毛外滋养细胞，推测它可能参与PE母胎界面滋养细胞-免疫细胞异常对话。我们进一步发现tRF-Gly-TCC-044可靶向作用趋化因子CXCL14，后者能够诱导THP-1来源巨噬细胞向M2型转化并伴有能量代谢表型改变。本项目拟通过体外研究和动物模型，证明母胎界面滋养细胞表达上调的tRF-Gly-TCC-044，通过靶向结合CXCL14 mRNA抑制其表达和分泌，进而阻断DMs受体CXCR4及下游PI3K/AKT信号通路，诱导糖代谢重编程，DMs发生M2向M1表型转换，导致PE免疫失衡。这将为母胎免疫耐受研究和PE免疫治疗提供新思路。

The phenotype imbalance of decidual macrophages (DMs) is closely related to the pathogenesis of preeclampsia (PE). As a new research hotspot, there is no report on the relationship between transport RNA derived small RNA (tsRNA) and PE. We used high-throughput sequencing to screen the difference tsRNA between PE and normal placenta. We found that tRF-Gly-TCC-044 was highly expressed in PE placenta and located in extravillous trophoblast, which suggested that tRF-Gly-TCC-044 might be involved in the abnormal trophoblast-immune cell dialogue at the maternal fetal interface of PE. We further found that tRF-Gly-TCC-044 can target chemokine CXCL14, which can induce THP-1-derived macrophages to transform into M2 type with energy metabolism phenotype changes. Using in vitro and animal model, this project will prove that tRF-Gly-TCC-044, which is upregulated in trophoblast cells at the maternal-fetal interface, inhibits CXCL14 expression and secretion by targeting CXCL14 mRNA, blocks receptor CXCR4 on DMs and downstream PI3K / Akt signaling pathway, induces glucose metabolism reprogramming and M2 to M1 phenotype transition in DMs, resulting in PE immune imbalance. This will provide new ideas for the study of maternal fetal immune tolerance and PE immunotherapy.