孕期高糖母体来源exosome诱导Kcnma1高甲基化参与胎儿血管功能调节障碍的机制研究

孕期营养失衡和胎源性心血管疾病的发生密切相关，但其调控机制并不明确。我们前期研究证明孕期高糖饮食导致胎鼠胸主动脉收缩显著增强。表观遗传修饰改变是调控胎源性心血管疾病的关键，甲基化测序提示高糖组胎鼠血管中Kcnma1基因甲基化升高；进一步研究发现母体血浆外泌体（exosome）可通过胎盘屏障进入胎儿血管平滑肌细胞，且exosome中miRNAs深度测序富集miRNA-465-3p；TargetScan软件预测miRNA-465-3p可抑制甲基转移酶METTL21B的翻译，后者促进Kcnma1基因的甲基化修饰，因此本项目将利用转基因鼠、RNA干扰、CRISPR-cas9基因敲除等技术探讨“母-胎”间exosome转导miRNA-465-3p调控Kcnma1的甲基化修饰导致胎儿血管功能异常的机制。本研究将有助于理解孕期营养失衡与胎儿血管发育的重要联系，为相关靶点应用于临床转化医学提供新颖的信息。

Prenatal nutrition imbalance correlates with developmental origin of cardiovascular diseases, however related mechanism in that field is limited. Our previous study demonstrated that maternal high-sugar (HS) diets during pregnancy could increase vascular contraction in fetal thoracic aorta. Epigenetic modification is crucial to cardiovascular disease regulation in prenatal orgin. Kcnma1 hypermethylation was observed in HS fetal vessels via DNA methylation sequencing. Further study indicated exosome from maternal serum could reach fetal vascular cells by crossing the placental barrier. And miRNA-465-3p is abundant in exosome from maternal plasma. Prediction with TargetScan software indicated that miRNA-465-3p could inhibit the translation of methyltransferase METTL21B, which contributes to Kcnma1 hypermethylation. The mechanisms programming fetal vascular dysfunction with maternal exosome-miRNA-465-3p regulating kcnma1 methylation will be determined by transgenic rat, RNA interference, crispr-cas9 knockout. The data gained would provide new sight into prenatal nutrition imbalance linking fetal vascular development, and offer new information on relevant targets for clinical translational medicine.