ppp2r2b基因介导DRP1蛋白磷酸化在未成熟脑缺氧缺血性损伤中的作用及分子机制研究

围产期缺氧缺血性脑病（HIE）是导致新生儿死亡或严重的终身性残疾的主要原因之一，且仍无特效疗法。寻找潜在治疗靶点及筛选可靠药物是HIE研究中面临的重大问题。我们前期研究显示，缺氧缺血（HI）可引起磷酸酶相关基因ppp2r2b表达量上升和p-Drp1含量下降，并导致线粒体过度分裂。关于脑特异性高表达基因ppp2r2b调控Drp1磷酸化在HI脑损伤中的作用仍未知。综合前期研究结果及文献证据，推测降低未成熟脑HI损伤后ppp2r2b基因表达量，可通过调控Drp1磷酸化、减少细胞凋亡和改善线粒体生命循环及功能等方面来发挥神经保护作用。因此，本课题拟采用Cre-loxP系统构建ppp2r2b条件性敲除小鼠，并制作HI脑损伤模型，探讨ppp2r2b基因敲除对未成熟脑HI损伤的保护作用，并从细胞凋亡、线粒体生命循环和线粒体形态与功能等多角度对其潜在分子机制进行探索，为HIE的防治提供新的角度和作用靶点。

Perinatal hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of neonatal death or severe lifelong disability, and there is still no specific treatment. Finding potential therapeutic targets and screening effective therapeutic drugs are major issues in HIE research. Our previous studies have shown that hypoxia-ischemia (HI) can increase the expression of phosphatase-related gene ppp2r2b and decrease the content of p-Drp1, and lead to excessive mitochondrial fission. Although ppp2r2b, a brain-specific highly expressed gene, regulates the phosphorylation of Drp1, its role in HI injury of the immature brain is still unknown. Based on previous research results and literature evidence, it is speculated that reducing the expression of ppp2r2b gene after HI injury in the immature brain can play a neuroprotective effect by regulating Drp1 phosphorylation, reducing apoptosis, and improving mitochondrial life cycle and function. Therefore, this project intends to make a HI brain injury model in the ppp2r2b cortical-specific knockout mouse which was constructed by using the Cre-loxP system, and to explore the protective effect of ppp2r2b gene knockout on HI injury in the immature brain. It also discusses its potential molecular mechanism from multiple perspectives, such as apoptosis, mitochondrial life cycle, mitochondrial morphology and function, and this will provide a new perspective and target for the prevention and treatment of HIE.