Gαq在胎盘发育过程中的作用机制研究

Placenta is a temporary organ formed during pregnancy, which plays an important role for the survival and development of the fetus. Any disturbance to the placenta development would lead to pregnancy-related diseases, even the failure of the pregnancy. Like most organs, the development of the placenta is tightly regulated by lots of signals. Galphaq, the alpha subunit of Gq protein, is highly conserved in evolution and plays an important regulatory role in multiple tissues and organs development. However, until now, fewer study about the function of Gαq in placental development. We found that, obvious absorption sites are observed in the late pregnant uteri and the percentage of homozygous mutant mice clearly not fitted to Mendelian ratio of 25% which generated from Gnaq+/- hemizygous matings. In the present research, employing Gnaq gene knockout mouse model and in vitro cultured trophoblast stem cell and allantois, we will investigate the cellular events occurring during the placental development. It is hoped that a better understanding on developmental aspects of pregnancy will provide theoretical basis and shed light on new therapy.

胎盘是妊娠过程中形成的临时性器官，其发育异常会导致妊娠相关疾病的发生，严重时可导致胎儿死亡。像其他器官一样，胎盘的发生和发育过程受到严格的调控。Gαq是由Gnaq编码的Gq蛋白α亚单位，Gαq在进化上高度保守，在多个组织器官中发挥重要调节作用。然而，Gαq 在胎盘发育过程中的功能知之甚少。我们的研究发现，雌性Gnaq+/-和雄性Gnaq+/-交配所得纯合子的比例明显低于孟德尔比例，同时妊娠中晚期子宫内有明显且占一定比例的吸收位点，提示部分纯合敲除的胚胎在发育中死亡。因此本项目拟利用Gnaq+/-妊娠小鼠模型，结合滋养层细胞和尿囊体外培养等模型，系统研究Gαq在胎盘发育中的生理作用及调控机制。以期从发育生物学角度进一步认识成功妊娠的分子基础，为预防和治疗胎盘发育异常相关妊娠疾病提供理论基础。

蜕膜化是指子宫内膜基质细胞转化为特定的蜕膜细胞，是人类胚胎成功着床和妊娠的先决条件。本研究过程中，我们发现，蜕膜化过程中特异性地敲除GANQ促进了蜕膜化的进程，同时增强蜕膜细胞内炎性细胞因子的表达。此外，我们发现蜕膜细胞内Gaq的缺乏导致NFκBIA表达减少和NF-κB信号的激活，用NFκB信号通路的特异性抑制剂能显著降低因Gaq缺乏导致的促炎细胞因子的上调和IGFBP-1和PRL表达增强。进一步对机制的探讨发现，蜕膜细胞中Gaq的缺失导致PKD/PKCμ磷酸化降低，同时HDAC5磷酸化水平降低。以上分子磷酸化水平的改变，最终减少了蜕膜细胞内HDAC5的核输出，减弱的HDAC5核输出延迟蜕膜化过程中NFκBIA乙酰化，最终抑制NFκBIA的表达。此外，蜕膜化过程中激活PKD/PKCμ信号通路或抑制HDAC5，可显著降低蜕膜化炎症状态，使蜕膜过程回归到正常状态。最后，我们发现，与正常妊娠相比，复发性妊娠丢失妇女植入窗中Gαq的表达显著降低。综上所述，Gαq在平衡蜕膜化过程以及蜕膜细胞中促炎细胞因子的表达发挥重要作用。这些发现将为女性不孕症的诊断和治疗提供一个新的理论基础。