人miR-141-3p致胎儿生长受限的分子机制研究

Fetal growth restriction (FGR) is a serious pregnancy complication, with unknown pathogenesis. miR-141-3p is a miRNA selected by chip technology, highly expressed in placental tissue of patients with FGR. Bioinformatics analysis and experiment showed that PLAG1 is the target of miR-141-3p. Literature reported that PLAG1 can activate the expression of IGF2, which can regulate the proliferation of trophoblast cells, and IGF2 participates in the fetal growth restriction by regulating cell proliferation and apoptosis. Overexpression of miR-141-3p could significantly down regulate the expression of PLAG1 and IGF2, suggesting that miR-141-3p may inhibit IGF2 by PLAG1 regulating, which mediates the occurrence of fetal growth restriction. This study intends to investigate the clinical relevance between miR-141-3p, PLAG1, IGF2 expression, trophoblast cell proliferation, apoptosis level and fetal growth restriction.n Further study will carried out using overexpression and knock down strategy to demonstrate the participation of miR-141-3p in the pathogenesis of fetal growth restriction. In-vitro assays would systematicly confirm that miR-141-3p regulate trophoblast cell proliferation and apoptosis involved in fetal growth restriction effect. There is not any report about miR-141-3p in fetal growth restriction, and this study may provide a new target for the prevention and control of fetal growth restriction.

胎儿生长受限（FGR）发病机制至今不明。miR-141-3p是我们采用芯片技术筛选出的、高表达于FGR患者胎盘组织中的差异miRNA。生物信息学分析和实验发现PLAG1为其作用靶标，文献报道PLAG1能够活化IGF2表达，而IGF2可调节胎盘滋养细胞增殖、凋亡，参与胎儿生长受限。实验证实miR-141-3p过表达可显著下调PLAG1、IGF2表达，提示miR-141-3p可能通过调控PLAG1、抑制IGF2表达介导FGR。本研究拟通过：①分析miR-141-3p、PLAG1、IGF2表达，滋养细胞增殖、凋亡水平与胎儿生长受限的临床相关性；②采用过表达、沉默和挽救实验策略，系统论证miR-141-3p参与胎儿生长受限发生的机制与作用；③在体评估miR-141-3p调控滋养细胞增殖与凋亡参与胎儿生长受限的作用。目前未见miR-141-3p参与胎儿生长受限的报道，研究将为FGR的防治提供新线索。

胎儿生长受限（FGR）是妊娠期重要并发症之一，是导致围生儿发病和死亡的重要原因，它不仅直接影响胎儿及新生儿的健康，也会增加其成年后对多种疾病的易感性。近年来研究发现胎盘组织microRNA的异常表达与FGR的发生密切相关，项目组通过miRNA表达谱芯片（TLDA）对FGR胎盘组织中异常表达的miRNA进行高通量筛检，发现miR-141在FGR胎盘组织中表达上调达4倍，而其潜在靶基因PLAG1 mRNA和蛋白均表达下调，本项目从病例-对照研究结果出发，研究胎盘组织中miR-141及其潜在靶基因PLAG1的表达，从DNA甲基化角度分析mir-141异常高表达的机制。通过体外细胞模型研究miR-141异常高表达的机制及其对靶基因PLAG1的调控作用，揭示了miR-141在FGR发生过程中的作用通路及细胞生物学功能，阐明其在FGR发生中的作用和分子机制。为FGR的病因学及其机制研究提供参考，为FGR的早期预防和治疗提供理论和实践依据。