母体免疫激活诱发小鼠胎盘迷路层rpS6磷酸化活性异常增高致子代神经发育异常的机制研究

孕期母体免疫激活（MIA）是母体免疫系统对体内外不良刺激产生的病理生理反应，可导致胎儿出生后患神经精神疾病的风险增高，但其具体机制不清楚。利用小鼠模型，研究证实MIA引起胎盘血液灌流减少和组织结构紊乱，造成胎脑发育受损，诱发子代小鼠神经行为异常。通过合作研究，我们首次发现了MIA引起小鼠胎盘和胎脑损伤的同时，胎盘迷路层rpS6的磷酸化水平敏感且持续性增高；而rpS6可参与促炎因子的转录后翻译。因此，我们推测MIA引起迷路层rpS6磷酸化活性持续增高后，可能促进了胎盘炎症反应，导致胎盘功能异常，继而影响了胎脑的发育。本课题拟在前期基础上，分析胎盘迷路层rpS6磷酸化活性与MIA小鼠胎盘、胎脑损伤的预警关系；阐明rpS6磷酸化活性增高致MIA胎盘损伤的机制；探究抑制rpS6磷酸化对MIA胎盘与胎脑损伤的治疗意义。本项目的开展将为MIA导致子代神经精神障碍确定潜在的早期预警分子和新的防治靶点。

Maternal immune activation (MIA) during gestation is a pathophysiological reaction caused by maternal immune system in responding to adverse internal and external stimuli, which can lead to high risks of neuropsychiatric disorders in fetuses after birth, but the specific mechanisms responsible for it remain unclear. By utilizing a mouse model, studies have verified that MIA limits placental blood perfusion, leads to abnormal placental structure, induces fetal brain injury and neurobehavioral dysfunction in MIA offspring. Through collaborative research, we for the first time find that the level of rpS6 phosphorylation in placental labyrinth layer is sensitively and stably increased in MIA mouse meanwhile MIA leads to the damage of placenta and fetal brain; and rpS6 phosphorylation can be involved in the protein translation of inflammatory factors following transcription. Therefore, we speculate that continuous increase of rpS6 phosphorylation level in placental labyrinth layer may promote inflammatory response in MIA mouse, then lead to placental insufficiency and impact development of fetal brain. Based on our previous study, in this project, we plan to analyze the early-warning connection between rpS6 phosphorylation level of placental labyrinth zone and placental/fetal brain injuries in mouse MIA model, to clarify the mechanism responsible for the placental injury caused by increased rpS6 phosphorylation level, and to investigate the therapeutic value of placental/fetal brain injuries by inhibiting the activity of rpS6 phosphorylation in placenta. This research project will determine the early potential early-warning molecules and provide new therapeutic targets for MIA-induced neuropsychiatric disorders in offspring.