已经证明低温是临床有效的脑保护措施，在缺血缺氧性脑病（HIE）的治疗中作为I级推荐。但低温的短时间窗、有限的疗效及复温后脑水肿反弹限制了其治疗效果。近年来发现Sur1-Trpm4通道阻滞剂格列本脲对缺血性脑损伤具有显著的保护作用，但在成人HIE中的作用尚未见研究。我们前期利用体外糖氧剥夺神经细胞及大脑局灶性缺血大鼠研究发现格列本脲对神经元和内皮细胞均具有保护作用，且可显著增强低温的治疗作用。本课题拟在成熟的HIE体内、体外模型上，采用siRNA 及CRISPR/Cas9等技术进一步研究格列本脲是否能通过干预Sur1-Trpm4通道而达到提高低温治疗HIE的治疗效果、延长低温治疗的时间窗及预防或减轻复温后脑水肿反弹，并通过Sur1-Trpm4上下游基因调控和表达的研究等明确低温和格列本脲的协同脑保护机制，旨在为临床在低温治疗成人HIE时联合使用Sur1-Trpm4阻滞剂获得实验依据。

Hypothermia is one of the few effective clinical treatment in hypoxic-ischemic encephalopathy (HIE) and has been the first recommendation for the treatment of HIE. However, the short therapy time window, incomplete therapeutic effects and rebounded cerebral edema during rewarming stage have greatly limited its clinical application. Recently, Glibenclamide, the specific inhibitor of sulfonylurea receptor 1 - transient receptor potential M4 (Sur1-Trpm4) channel has been attracted a lot attentions because its protection role in treatment of ischemic brain injury. Glibenclamide has also been proven to have a good effect on protection of neurons and the integrity of the endothelial cells. Our preliminary studies showed that Glibenclamide enhanced the neuroprotective effect of hypothermia in oxygen-glucose deprivation nerve cells model and transient middle cerebral artery occlusion (tMCAO) rats. In this study, Sur1 and trpm4 proteins will be silenced or knockdown by siRNA or CRISPR/Cas9 technology in vitro or in vivo HIE models. Then we will further investigate whether Glibenclamide will enhance the efficacy of hypothermia, extend hypothermia therapeutic time window and reduce rebound cerebral edema during rewarming in HIE model.