氢气对新生鼠缺氧缺血性脑损伤内源性神经干细胞增殖分化的作用及机制研究

hypoxic-ischemia brain damage(HIBD) can lead to neonatal neurological developmental disorders, now, there still lacks of effective therapy in clinic.It has been proved that hydrogen is a novel selective free radical scavenger which play a prominent role in its antioxidant, anti-inflammatory and anti-allergic effects. Recently we found that hydrogen-rich saline improve the recovery of HIBD in neonatal mice, further study revealed that hydrogen involves in regulating the proliferation and differentiation of primary cultured neural stem cells (NSCs), suggesting that hydrogen might involves the recovery of neurological function influenced by HIBD in neonatal mice through regulating the proliferation and differentiation of NSCs. To test this hypothesis, we will establish HIBD model, systematically study the effect of hydrogen on the recovery of HIBD in neonatal mice, investigate the influence of hydrogen on the proliferation and differentiation of NSCs in vivo and in vitro, detect the role of ERK signaling pathway in hydrogen regulation in the differentiation and proliferation of NSCs, using immunofluorescence, western blotting, small interfering RNA transfection methods. This research will provide theoretical and experimental basis for developing new ways on prevention and treatment of neurodevelopmental damage induced by neonatal hypoxic ischemic encephalopathy.

缺氧缺血性脑损伤（HIBD）可导致新生儿神经系统发育障碍，目前缺乏有效的治疗手段。研究证明，氢气是一种新型选择性自由基清除剂，能发挥抗氧化、抗炎、抗敏作用。最近我们发现，富氢生理盐水促进新生小鼠HIBD后的脑功能恢复；进一步研究发现，氢气参与调节原代小鼠神经干细胞（NSCs）的增殖、分化。提示氢气可能通过调节NSCs增殖、分化从而参与HIBD神经系统功能的恢复。为验证该假设，拟采用新生小鼠建立HIBD模型，系统研究氢气对新生小鼠HIBD脑功能恢复的影响；利用免疫荧光、蛋白印迹等方法检测氢气对在体及离体NSCs增殖、分化的影响；利用小干扰RNA转染等方法，检测ERK信号通路在氢气调节NSCs增殖、分化中的作用。通过上述研究，可为临床预防和治疗新生儿缺氧缺血性脑病致神经发育损伤提供理论及实验依据。

缺氧缺血性脑损伤（HIBD）可致新生儿神经系统发育障碍，目前缺乏有效的治疗手段。如何充分诱导内源性神经干细胞（NSCs）活化增殖并向病灶迁移，成为新生儿缺氧缺血性脑病（HIE）治疗领域的研究焦点。课题组以前期预实验发现：H2参与调节原代小鼠NSCs的增殖、分化为线索，采用新生小鼠建立HIBD模型，系统研究了H2对HIBD后脑功能恢复的神经保护性作用及分子机制。证实H2通过ERK信号通路参与调节内源性NSCs的增殖、分化过程，抑制神经细胞凋亡，并提出“H2对HIBD神经保护性作用，部分是通过减轻内质网应激和阻止ERK1/2的急性去磷酸化作用进而增强自噬机制实现”的新观点。本项目研究成果将进一步增加对H2生物学功能的认识，探讨H2在脑损伤模型中对内源性NSCs增殖、分化的作用，揭示其在脑损伤中神经修复的可能作用机制，为深入研究新生儿HIE的发病机制和治疗方法奠定基础。