间充质干细胞通过p38MAPK和PI3K/Akt信号通路对热射病中枢神经系统易损区保护作用及机制研究

热射病（HS）发病率逐年增长，死亡率60%以上。早期100%患者伴发中枢神经系统（CNS）损害，超过30%遗留长期CNS功能障碍。结合临床数据及文献综述，本研究组初步确定HS相关CNS易损区为下丘脑、小脑和海马，并发现其损伤具有时相性。早期炎症因子释放和后期BDNF分泌减少分别激活和抑制p38MAPK和PI3K/Akt信号转导通路参与神经细胞凋亡。前期工作发现间充质干细胞（MSCs）可抑制神经细胞凋亡。但目前尚无针对HS相关CNS易损区损伤机制的研究且缺乏有效干预手段。本研究拟建立HS大鼠和神经细胞热应激模型，应用MSCs干预，以揭示CNS易损区损害特点；明确两条信号通路在CNS易损区不同时相的作用机制；阐明MSCs通过调控上述信号转导通路发挥其对神经细胞的保护和修复作用。本研究探索了HS相关CNS易损区损伤机制和MSCs对其保护机制，对降低长期CNS并发症具有重要的科学价值和临床意义。

The morbidity of heat stroke (HS) increasing by years and its mortality is over 60%.In early stage, 100% of HS patients have CNS injury, while more than 30% of them developed long term CNS dysfunction as sequela. Based on clinical data and literature review, our research group preliminarily determined that the CNS areas of vulnerability associated with HS are hypothalamus, cerebellum and hippocampus, and we also found that the injury has time phases. Release of inflammatory factors in early stage and reduced BDNF secretion in late stage can separately activate and inhibit the p38MAPK and PI3K/Akt signaling pathways to participate in neuron apoptosis. Our preliminary work found that mesenchymal stem cells (MSCs) can inhibit neuron apoptosis. However, no studies on the injury mechanism of CNS areas of vulnerability associated with HS have been reported at present, and effective interventions are not available yet. This subject plans to establish heat stroke model of rats and neuron, then using MSCs intervention to reveal the injury characteristics of CNS areas of vulnerability, clear the mechanism of the two signaling pathways in CNS areas of vulnerability during different phases of injury and elucidate the protective and repairing effects of MSCs on neurons through regulating two signaling pathways mentioned above. This research will explore the mechanisms of injury and protection of MSCs for HS-associated CNS areas of vulnerability, which has important scientific value and clinical significance in reducing long term CNS complications.