XBP1/O-GlcNAcylation轴对心脏骤停复苏后脑损伤的影响

Cardiac arrest (CA) is a serious medical emergency. The high incidence of post-CA mortality and neurologic deficits are primarily caused by hypoxic-ischemic brain injury. However, except therapeutic hypothermia, no neuroprotective intervention has proven to improve neurologic outcome in CA patients. Recent data has demonstrated that O-GlcNAcylation is activated in young but not aged brains after CA/CPR. Thus, we hypothesized that boosting this axis confers neuroprotective effects and improves CA outcome in mice. To test this hypothesis, genetically-modified XBP1 mice and pharmacologic intervention approach will be used to systematically determine the significance of XBP1/O-GlcNAc axis in CA-induced brain injury, especially in aged mice. The work proposed is expected to define the role of XBP1/O-GlcNAcylation axis in CA-in mice. Such findings may provide an important theoretical basis for the future of novel therapeutic interventions that improve quality-of-life for CA patients.

目前心脏骤停(CA)引起的脑损伤的治疗方案极其有限。我们最新研究发现心脏骤停复苏(CA/CPR)后老年鼠比年轻鼠脑损伤更重且蛋白O-GlcNAcylation降低。因此我们推测激活促存活XBP1/O-GlcNAcylation轴有可能改善小鼠心脏骤停后的脑损伤。本课题拟运用神经元特异性XBP1修饰小鼠，分析XBP1对小鼠CA/CPR后脑损伤的影响；进一步Glucosamine增强O-GlcNAcylation检测其对XBP1敲除和野生型小鼠CA/CPR后脑损伤的影响；最后分析Glucosamine对老年鼠CA/CPR后脑损伤的影响。通过以上实验阐明XBP1/O-GlcNAcylation轴激活对小鼠尤其是老年鼠心脏骤停复苏后神经功能的保护作用，为临床治疗心脏骤停复苏后的脑损伤提供重要的实验基础和和治疗策略。

心脏骤停（CA）复苏后，包括大脑在内的各种器官中的未折叠蛋白反应（UPR）被激活。然而，UPR在CA结果中的作用仍然不太清楚。剪接的X盒结合蛋白1（XBP1s）是一个UPR分支。值得注意的是，XBP1s可以上调与葡萄糖代谢相关的特定酶的表达，并随后促进O-乙酰氨基葡萄糖修饰（O-GlcNAcylation）。本课题研究了XBP1 UPR分支及其下游O-GlcNAcylation对CA预后的影响。使用功能丧失和功能获得的小鼠遗传工具，我们证明CA后大脑中XBP1 UPR分支的激活具有神经保护作用，即神经元特异性Xbp1敲除小鼠的CA预后更差，而大脑中神经元特异性表达Xbp1的小鼠的CA预后更好。以往研究表明XBP1s信号通路在缺血条件下的保护作用是通过增加O-GlcNAcylation介导的，我们随后用葡糖胺治疗年轻小鼠，并发现功能缺陷在CA后第3天得到缓解。最后，我们用葡萄糖胺处理老年CA小鼠，发现葡萄糖胺处理的老年小鼠在行为测试中表现明显更好。总之，我们的数据表明XBP1s/O-GlcNAc通路是CA治疗的一个潜在靶点。