妊娠期高血糖通过抑制AMPK活性导致胚胎神经元突起发育受损的作用和机制研究

Gestational diabetes do harms the health of mother and fetus which was widespread happened in China. Clinical retrospective analysis showed that offspring of gestational diabetes had an increased risk in cognitive impairment. Early neurodevelopmental abnormalities may be one of the important factors, but the pathological mechanism is still unclear.We have found that blood glucose of newborn mice were lower, which was an important factor in activing AMPK in developmental brain. In the gestational hyperglycemia mice model, maternal hyperglycemia inhibited AMPK activity in the embryonic brain which leading to cognitive impairment in offsprings. Meanwhile, glucose toxicity also restrained neurite development by inhibiting AMPK in primary neurons. We propose to demonstrate that maternal hyperglycemia restrained neurite development by inhibiting AMPK signaling pathway in embryonic neurons, which leaded to cognitive impairment in adult offsprings. This program can expand the role of AMPK signaling pathway in neurodevelopmental process, and elucidate a new pathological mechanism of the neurodevelopmental disorder in offsprings of the gestational diabetes mellitus, which can provide a theoretical guidance of maintaining gestational blood glucose in clinical.

有研究表明妊娠性糖尿病子代认知损伤隐患增高，而胚胎时期的神经元早期发育异常可能是重要病理机制，但仍缺少证据。AMPK作为细胞内代谢平衡调控核心，是代谢紊乱相关疾病的重要发病机制。我们初步发现，出生前后小鼠脑内的AMPK活性被低血糖水平持续激活，是维持正常神经元早期发育的重要因素。而在妊娠期高血糖模型中，异常的母体高血糖抑制胚胎大脑AMPK活性并引起子代认知功能受损。同时高浓度葡萄糖处理原代神经元也会抑制AMPK活性，进而导致神经突起发育阻滞。基于此，我们拟利用化学和基因操纵手段以及结合转基因小鼠，在整体动物和细胞水平上论证，妊娠期高血糖通过抑制胚胎神经元的AMPK活性进而导致神经突起发育受损的作用和机制，并最终影响成年后子代认知功能。拓展AMPK通路在神经发育过程中的重要调控作用，阐明妊娠性糖尿病子代神经发育障碍的病理新机制，为改善妊娠性糖尿病子代认知功能提供新的研究思路。

AMPK作为细胞内代谢平衡调控核心，是代谢紊乱相关疾病的重要发病机制。我们发现出生前后小鼠脑内的AMPK活性被低血糖水平持续激活，是维持正常神经元早期发育的重要因素。而在妊娠期高血糖模型中，异常的母体高血糖抑制胚胎大脑AMPK活性并引起子代认知功能受损。同时高浓度葡萄糖处理原代神经元也会抑制AMPK活性，进而导致神经突起发育阻滞。基于此，我们拟利用化学和基因操纵手段以及结合转基因小鼠，在整体动物和细胞水平上论证，妊娠期高血糖通过抑制胚胎神经元的AMPK活性进而导致神经突起发育受损的作用和机制，并最终影响成年后子代认知功能。此外我们还发现，高血糖会引起成年小鼠表现出典型的焦虑样行为，并可能通过引起神经炎症的诱发该表型。上述发现拓展AMPK通路在神经发育过程中的重要调控作用，阐明妊娠性糖尿病子代神经发育障碍的病理新机制，为改善妊娠性糖尿病子代认知功能提供新的研究思路。投稿Journal of Neurochemistry文章一篇，返修中。拟投稿IF>10分文章一篇，培养博士研究生一名（2024年毕业）。