lncRNA CTD-2012K14.6诱导胎盘IGF-2分泌导致胎儿巨大的作用机制研究

LncRNA CTD-2012K14.6 is highly conserved and significantly upregulated in placenta from GDM groups identified by RNA sequence technology. Our further studies revealed CTD-2012K14.6 regualted IGF-2 secretion of trophocytes and correlated with fetus weight. Bioinformatic analysis and experiments suggested CTCF was its candidate target gene. It has been reported that CTCF could lead to fetal macrosomia in GDM by increasing IGF-2 secretion from placenta, suggesting the role of CTD-2012K14.6 in GDM. In this research, we intend to assess the relation between CTD-2012K14.6 and macrosomia outcomes in clinical samples. Adopting overexpression and knock down strategies in vitro and in vivo , we explicit the function and mechanism of CTD-2012K14.6 in IGF-2 secretion and weight of offspring mice weight.. So far there is no report of CTD-2012K14.6 in gstational diabetes pathogenesis, and it may provide new intervention targets for prevention of GDM.

CTD-2012K14.6是我们借助测序技术发现的、人鼠高度同源、显著高表达于妊娠糖尿病合并巨大儿患者胎盘组织的lncRNA。前期发现，胎盘CTD-2012K14.6表达水平与胎儿体重正相关；其过表达可调控滋养细胞分泌IGF-2；软件分析和实验提示CTCF为其调控靶点；而文献报道CTCF可增加胎盘组织IGF-2分泌致巨大儿发生，提示CTD-2012K14.6可能通过调控CTCF表达、影响IGF-2分泌、在巨大儿发生中发挥作用。研究拟：借助临床样本进一步评估CTD-2012K14.6表达与巨大儿发生的关系，探索其表达影响因素；应用靶向过表达和沉默策略，在体评估CTD-2012K14.6对IGF-2分泌及子鼠体重的影响；以CTCF为线索，运用挽救策略，评估CTD-2012K14.6影响IGF-2分泌的机制。CTD-2012K14.6的功能与机制未见报道，有望为巨大儿发生的防治提供潜在新靶点。

临床上妊娠期糖尿病（GDM）患者子代巨大儿的发生率要显著高于正常产妇，但其具体机制尚不清楚。借助测序技术我们发现一条人鼠高度同源的lncRNA CTD-2012K14.6，其显著高表达于妊娠糖尿病合并巨大儿患者胎盘组织中。临床样本检测发现，胎盘CTD-2012K14.6表达水平与胎儿体重呈正相关，且生物信息分析CTCF可能为CTD-2012K14.6的调控靶点。体外实验中，在高糖、高脂、炎症条件分别刺激下，人滋养细胞HTR-8/Svneo中CTD-2012K14.6表达水平的改变与CTCF、IGF-2表达水平改变具有相关性。体内实验中，胎盘靶向过表达CTD-2012K14.6后，CTCF水平降低，IGF-2水平升高；而胎盘靶向沉默CTD-2012K14.6后，CTCF水平升高，IGF-2水平降低。机制方面，在lncRNACTD-2012K14.6 过表达（沉默）基础上过表达（沉默）CTCF可挽救lncRNACTD-2012K14.6 过表达（沉默）引起的表型改变，表明CTCF为CTD-2012K14.6的调控靶点。在本研究中，我们发现了与妊娠糖尿病合并巨大儿密切相关的lncRNA CTD-2012K14.6，通过调控CTCF影响下游IGF-2的表达，影响巨大儿的发生。本研究为有助于阐明妊娠糖尿病合并巨大儿的发病机理并为其防治提供潜在的新靶点。