滋养细胞AMPK经GLUT3调控葡萄糖摄取的机制及对妊娠期糖尿病宫内高血糖环境的影响及机制研究

Excessive glucose transport from mother to fetus caused by GDM intrauterine hyperglycemia environment is the main cause of adverse fetal outcome, and the glucose metabolism of the placenta plays an important role in changing the glucose flux from mother to fetus. Our team had identified that GLUT3 is a very important glucose transport, while GLUT3existed significantly reduced location in membrane of GDM placenta tissue with reduced AMPK phosphorylation level, and also we found the protein-protein interaction between AMPK and GLUT3. Based on those above, we hypothesize that AMPK in trophoblasts interact with GLUT3, and promote GLUT3 transport to membrane for glucose uptake, but the activity of AMPK is inhibited in the intrauterine hyperglycemia of GDM, resulting in abnormal GLUT3 position and weakened glucose metabolismof the placenta, this abnormal situation increase the glucoes flowing to the fetus causing the complications such as macrosomia. Based on preliminary founds ,this project mainly research on GLUT3`s transplation in trophblasts, we will fully validate the hypothesis from part to whole by the application of molecular biology and genetic engineering methods in tissue, cell and mouse model level, in order to clarify the mechanism of AMPK - GLUT3 impacts trophblaste`s glucose uptake and metabolism, aims to provide new research ideas and therapeutic targets for reduce the adverse fetal development programming caused by intrauterine hyperglycemia of GDM.

GDM产生的宫内高血糖环境导致母胎间过度葡萄糖转运进而使胎儿出现不良结局，而胎盘自身的葡萄糖代谢水平对改变母胎界面葡萄糖通量具有重要作用。课题组前期发现GLUT3是滋养细胞重要的葡萄糖转运蛋白，在GDM胎盘组织的胞膜定位显著下调伴随AMPK磷酸化水平降低，并且AMPK与GLUT3之间存在相互作用，继而推测滋养细胞AMPK通过与GLUT3相互作用，促进GLUT3转位并摄取葡萄糖，而GDM高糖环境抑制AMPK活性，导致GLUT3异常定位进而减弱胎盘自身糖代谢水平，增加流向胎儿的葡萄糖净运输从而导致巨大儿等并发症。本课题以前期工作为基础，在组织、细胞及小鼠模型水平上应用分子生物学及基因工程等方法，研究滋养细胞GLUT3转位，以期阐明调控滋养细胞AMPK-GLUT3信号轴影响胎盘葡萄糖摄取和代谢的机制，为减轻GDM高糖环境引起的胎儿不良发育编程提供新的研究思路和治疗靶点。

GDM宫内高血糖环境引起母胎间过度葡萄糖转运是导致胎儿不良结局的主要原因，而胎盘自身的葡萄糖代谢水平对改变母胎间葡萄糖通量具有重要作用。课题组前期已发现GLUT3是滋养细胞重要的葡萄糖转运蛋白，在GDM胎盘组织的质膜定位显著下调伴随AMPK磷酸化水平降低，并且AMPK与GLUT3之间存在相互作用。本课题进一步深入探索，在组织、细胞及小鼠模型水平上应用分子生物学及药理学等方法，研究发现GDM与糖酵解、AMPK活性、GLUT3胞膜易位和胎盘细胞活力受损有关，并且激活AMPK能缓解滋养细胞在高血糖环境下的受损变化。高血糖db/ +和HFD诱导的GDM小鼠模型胎盘内AMPK-GLUT3轴受损，胎盘细胞活力受到抑制，胎鼠生长过度，但经二甲双胍激动后可得到部分缓解。综上所述，本课题研究确定了滋养细胞内AMPK-GLUT3信号轴调控葡萄糖摄取的细胞学机制，有助于为减轻GDM高糖环境引起的胎儿不良发育编程提供新的治疗靶点。