PCOS女性中甾体激素核受体选择性剪接介导的自发性早产胎盘源性病因学解析

During gestation, women with polycystic ovary syndrome (PCOS) exhibit a double risk of preterm labor without a clear pathogenic mechanism, especially spontaneous preterm labor on the etiology of which has been paid very little attention in the world. Placental insufficiency is the main cause of moderate to late spontaneous preterm labor; corticotropin-releasing hormone (CRH) is closely associated with spontaneous preterm labor. Our pilot work showed that in women during gestation and with moderate to late spontaneous preterm labor, PCOS group has significant high levels of CRH and androgen and altered placental gene expression profile; in addition, alternative splicing of androgen receptor which belongs to steroid hormone nuclear receptor superfamily, not only plays an important role in hyperandrogenism of PCOS through affecting ovarian function, but also is associated with CRH excess in placenta from spontaneous preterm labor of women with PCOS. Our hypothesis is that altered splicing of steroid hormone nuclear receptor mediates placental insufficiency resulting in the high prevalence of spontaneous preterm labor of women with PCOS. With clinical and experimental methods, firstly we will further investigate the endocrine profile of CRH and androgen and the preterm offspring outcomes in women with PCOS; furthermore, we will deeply identify the alternative splicing pattern of steroid hormone nuclear receptor in placenta from preterm labor in women with PCOS; finally, we will precisely explain the molecular biological event through which the disrupted alternative splicing of nuclear steroid hormone receptors in villous trophoblasts changes placental CRH transcription in preterm labor of women with PCOS.

多囊卵巢综合征（PCOS）人群妊娠期早产的发病风险翻倍，但分子学机制不清，尤其是自发性早产，国内外研究极少。胎盘功能障碍是中晚期自发性早产的主要病因；促肾上腺皮质激素释放激素（CRH）与自发性早产密切相关。本课题组前期工作提示，在妊娠期和中晚期自发性早产人群中，PCOS组女性呈高CRH和高雄状态、胎盘基因表达谱异常；另外，甾体激素核受体的选择性剪接，不仅影响卵巢功能而加重PCOS高雄症，且与PCOS女性自发性早产胎盘中CRH高表达相关。因此，我们假设，甾体激素核受体剪接异常介导CRH相关胎盘功能障导致PCOS女性中自发性早产高发。拟借助临床评价指标与生物实验手段，首先，拓展调查PCOS女性CRH与雄激素的内分泌状态及其早产子代健康风险的叠加效应；其次，深入鉴定PCOS自发性早产胎盘中存在的甾体激素核受体选择性剪接模式；再次，精准定位该剪接紊乱致绒毛滋养细胞CRH转录表达失衡的具体分子环节。

多囊卵巢综合征（PCOS）人群妊娠期早产的发病风险翻倍，但分子学机制不清，尤其是自发性早产，国内外研究极少。胎盘功能障碍是中晚期自发性早产的主要病因。为了探索PCOS患者早产风险的胎盘源性病因学机制，项目负责人带领项目组成员们开展了以下系列研究：第一，我们对PCOS女性的胎盘组织进行了三代全长转录组分析，结果发现，PCOS组胎盘与对照组胎盘相比，全基因组水平存在不同种类RNA水平的差异。PCOS女性妊娠期胎盘组织的pre-mRNA选择剪接变异模式与对照组存在显著的差异，其中FOSB基因最为明显。且PCOS组胎盘组织中松弛素信号通路的基因转录水平发生显著改变，可能参与了早产的病因学机制。第二，利用生物信息学手段，基于早产或分娩相关的关键基因，我们将PCOS女性人群分为两种分子亚型，并提出了五个中心基因。其中，GTF2F2与MYO6基因被验证在以上两组PCOS早产风险分子亚型间确实存在差异。该研究结果为PCOS女性中针对早产风险进行分子分型的临床应用提供了理论上的支持。第三，PCOS组胎盘中无论在mRNA转录表达还是在DNA甲基化状态上均有全基因组水平的明显改变；差异基因涉及到多种与神经元、神经突触、行为认知等相关的神经内分泌功能。转录因子FOS很可能参与调控了胎盘绒毛滋养细胞中神经因子的改变，从而引起了PCOS女性子代出生后神经行为学表型改变。第四，对PCOS子代的连续性临床随访发现，PCOS胎儿不但脑部结构出现细微的变化，其宫内生长发育模式也与对照组呈现出明显差异。在出生后，PCOS患者的女儿在儿童期年龄越大越易发生超重。第五，鉴于生物钟节律与分娩、早产密切相关，项目负责人首次观察到了PCOS女性不但可能存在中央性生物节律紊乱，其卵巢颗粒细胞中周围性生物钟节律也呈现出全基因组水平的破坏。综上，项目组团队从多个维度论证了PCOS胎盘功能障碍的病理生理学机制、剖析了PCOS女性早产风险增高的病因学机制、密切关注了PCOS子代健康的评估。