胎儿生长受限孕早期无创预测模型构建及锌指蛋白ZNF687调控胎盘生长发育的机制研究

Fetal growth restriction (FGR) refers to 2 standard deviations or tenth percentiles of fetal weight lower than the average weight of the same gestational age, or birth weight less than 2500g, which is an important cause of perinatal death. The etiology of FGR is complex and varied.Fetal, placental,matenal and genetic causes are the main reasons of FGR. It was found that the placenta of FGR fetus was small. To investigate the correlation between first trimester placental volume, placental quotient and FGR,we taking prospective to the project, and based on the NIPT data selected from the FGR gene, a classifier, combined with first trimester placental volume and placental quotient in early pregnancy taking constructing FGR noninvasive prediction model; at the same time based on our previous research , we plan to investigate zinc finger protein ZNF687 regulates growth and development in the placenta downstream regulated protein molecules, regulating network pathway and the related protein substrate, to investigate the molecular mechanism of zinc finger protein ZNF687 in the occurrence and development of FGR. Noninvasive early detection and early diagnosis of fetal growth restriction can reduce or delay the appearance of fetal growth restriction, reduce the morbidity and mortality of perinatal children, and improve the quality of population.

胎儿生长受限（FGR）是指由于病理原因造成的出生体质量低于同孕龄、同性别胎儿平均体质量的2个标准差或第10百分位数，或孕37周后胎儿出生体重<2500g。是围产儿死亡的重要原因。FGR病因复杂多样，包括母体、胎盘胎儿及遗传学因素。胎盘功能不全是最常见的病因。研究发现，FGR胎儿胎盘体积偏小。本项目旨在前瞻性探讨孕早期胎盘体积、胎盘商与FGR的相关性，以及基于NIPT数据筛选出FGR相关基因，建立分类器，联合孕早期胎盘体积、胎盘商构建孕早期FGR无创预测模型；同时在前期研究基础上，研究锌指蛋白ZNF687在胎盘组织中调控胎盘组织生长发育的下游调节蛋白分子、调节网络途径以及相关底物蛋白，探讨锌指蛋白ZNF687在FGR发生发展的分子机制。对生长受限胎儿进行无创早发现、早诊断，降低或延缓胎儿生长受限的出现，减少围产儿的患病率和死亡率，提高人口素质。

胎儿生长受限(fetal growth restriction，FGR)发病率为3%~9%，约20%~50%的死产与FGR相关。FGR病因复杂多样，其中胎盘发育不全是最主要的因素。目前诊断FGR大都通过中晚孕期胎儿超声评估胎儿体重或出生后诊断，尚未有早期预测FGR的有效方法，且胎盘发育不全导致FGR的发病机制有待研究。本项目通过三维能量多普勒超声前瞻性采集早孕期单胎妊娠孕妇的胎盘体积（PV）、胎盘商（PQ）、血管化指数(VI)、血流指数(FI)和血管血流指数(VFI)等指标，探讨了各项指标与胎儿生长受限的相关性，研究发现FGR早孕期PV、PQ、VI、FI、VFI均值显著小于正常妊娠组，ROC曲线分析结果显示VI和VFI预测FGR的AUCs高达0.870和0.873（p<0.001）；同时我们采集了早中孕期孕妇外周血和无创产前基因检测（NIPT）数据，证实母体血浆游离DNA（cfDNA）的启动子谱可以反映母血和胎盘的基因表达水平，基于FGR和对照组的差异启动子谱筛选出103个差异基因转录本，以14个差异基因组成的最佳分类器预测FGR的准确率为83.2%；随后我们基于胎盘组织RNA测序筛选出与ZNF687同属C2H2型锌指蛋白的转录因子EGR1，证实EGR1在胎儿生长受限的胎盘组织中显著低表达，EGR1下调可能通过抑制滋养细胞的增殖、迁移等生物学行为，导致FGR的发生。本研究成果可对FGR实现无创早期预测，为FGR发生的分子机制提供新观点。