组胺H2受体在新生儿缺氧缺血性脑病中对白质修复的作用及机制研究

Neonatal hypoxic-ischemic encephalopathy is a devastating disease, which results in life-long cognitive and neurobehavioral dysfunction. The white matter damage caused by hypoxic-ischemia is one of the major pathological changes of neonatal hypoxic-ischemic encephalopathy, especially in premature infants. Currently there are no well-established treatments; thus, it is imperative to search effective approaches to promote white matter repair. We focus on the role of histamine in the brain for a long time and found that histamine via its receptors participates in the cerebral ischemic injury during adulthood. Recently, we found that the expression of histamine H2 receptor is increased in the white matter in neonatal mice with hypoxic-ischemic encephalopathy and blocking H2 receptor alleviates the white matter damage and cognitive impairments. Additionally, the preliminary experiments also suggest that this protection is largely attributed to the promotion of oligodendrocyte differentiation after hypoxic-ischemia, whereas the in-depth mechanism is still unclear. This project will investigate the role of H2 receptor in oligodendrocyte differentiation in neonatal hypoxic-ischemic encephalopathy by conditional knockout of H2 receptor in oligodendrocytes or premature oligodendrocytes and adeno-associated virus mediated overexpression or knockdown of H2 receptor. This project is aimed to give more evidence to elucidate the pathophysiology and provide new targets for the treatment of neonatal hypoxic-ischemic encephalopathy.

新生儿缺氧缺血性脑病是由于宫内缺氧缺血造成的脑部不可逆的病变，目前临床上尚无十分有效的治疗手段。脑白质区的髓鞘损伤是其主要的病理表现，因此非常有必要寻找促进白质修复的新途径。申请人及所在课题组长期从事组胺的神经药理学研究，发现组胺通过其受体参与了成年动物的脑缺血损伤。并且，在前期工作中发现在幼年动物缺氧缺血性脑病（HIE）中白质区组胺H2受体表达升高，拮抗H2受体明显减轻髓鞘损伤并改善认知功能，还初步发现该作用可能是通过促进少突胶质细胞的分化而利于髓鞘再生，但具体机制尚不清楚。本课题将利用少突胶质细胞特异性或分化阶段少突胶质细胞特异性H2受体基因敲除小鼠，结合病毒干扰H2受体表达或过表达H2受体等手段，研究少突胶质细胞上的H2受体在HIE中通过调控其分化影响白质修复的作用机制。本研究将进一步揭示HIE中白质修复机制，并将为新生儿缺氧缺血性脑病的治疗提供非常具有临床应用价值的药物治疗新靶点。

新生儿缺氧缺血性脑病会导致终身认知和行为功能障碍，目前临床上尚无十分有效的治疗手段。脑白质区的髓鞘损伤是其主要病理表现，因此非常有必要寻找促进白质修复的新途径。本课题通过病毒介导的蛋白干扰或过表达等手段研究发现，组胺H2受体在缺血后能够抑制少突胶质细胞的分化，但对少突胶质前体细胞和成熟的少突胶质细胞并无影响。利用Cre-loxp系统选择性敲除少突胶质细胞上H2受体发现，缺失H2受体能够促进少突胶质细胞的分化，并促进髓鞘和轴突再生，从而改善神经功能。H2受体对少突胶质细胞分化的调节作用是通过与Axin2相互结合调控Wnt/β-catenin信号通路而产生的。采用药理学手段拮抗H2受体可以促进新生小鼠缺氧缺血引起的脑白质损伤的恢复，并改善运动和认知功能障碍。本研究结果进一步揭示新生儿缺氧缺血性脑病中白质损伤的病理机制，并为该病的治疗提供非常具有临床应用价值的潜在精准药物干预靶点。