Dexras1通过Olgs死亡及Opcs分化障碍介导的髓鞘脱失参与SAH后白质损伤的作用机制

White matter injury is an important cause of neurological dysfunction in SAH patients. Demyelination, mainly caused by Olgs death and remyelinaion disorder, is the key mechanism of white matter injury. Our previous studies showed that SAH causes iron metabolism disorders of the cells, which further induces apoptosis and ferroptosis in neurons. According to the literatures, Dexras1 can induce iron metabolism disorders of the brains. Besides Olgs are the main cells iron located in, therefore, we have reasons to believe that Dexras1 may finally cause apoptosis and ferroptosis of Olgs through inducing iron metabolism disorders. On the other hand, our previous study showed that Dexras1 is closely related to neuroinflammation after SAH. Previous research revealed that inflammation can induce the high expression of ET-1 in astrocytes, which then inhibit the differentiation of oligodendrocyte precursors (Opcs). It means that Dexras1 not only causes death of the Olgs, but also results in differentiation disorders of the Opcs, finally lead to the disorder of remyelinaion. We tend to clarify functions and mechanisms of the "Dexras1- DMT1 - Olgs apoptosis and ferroptosis" and the "Dexras1 - p54nrb - ET-1 - Opcs differentiation disorder" signaling pathways in the demyelination after SAH , trying to provide a new experimental basis for the treatment of SAH.

白质损伤是引起SAH后神经功能障碍的重要原因，而少突胶质细胞（Olgs）死亡及髓鞘再生障碍介导的髓鞘脱失是白质损伤的重要病理变化。我们前期发现，SAH可导致细胞内铁代谢紊乱，引起神经元的凋亡和铁死亡。报道称，Dexras1可诱导脑铁代谢紊乱。Olgs是铁在脑内的主要定位细胞，因此有理由相信，Dexras1可通过诱导铁代谢紊乱最终导致Olgs的凋亡和铁死亡。另外，我们前期研究表明，Dexras1还与SAH后炎症反应相关。据报导，炎症反应可诱导ET-1在星型胶质细胞内高表达，抑制少突胶质细胞前体细胞（Opcs）的分化，即Dexras1不仅可引起Olgs死亡，还可致Opcs的分化障碍，进而导致髓鞘的脱失病变。本课题拟验证“Dexras1-DMT1-Olgs凋亡和铁死亡”及“Dexras1-p54nrb-ET-1-Opcs分化障碍”在SAH髓鞘脱失中的作用及其机制，为SAH的治疗提供新的实验基础。

白质损伤是引起蛛网膜下腔出血（SAH）后神经功能障碍的重要原因，而少突胶质细胞（Olgs）死亡及髓鞘再生障碍介导的髓鞘脱失是白质损伤的重要病理变化。课题组前期发现，SAH可导致细胞内铁代谢紊乱，引起神经元的凋亡和铁死亡。报道称，Dexras1可诱导脑铁代谢紊乱，而Olgs是铁在脑内的主要定位细胞，因此我们设计相关实验，运用多种实验技术深入探究并验证 “Dexras1可通过UCP2/NCOA4通路诱导Olgs铁死亡最终导致白质损伤”假说。另外，我们前期研究表明，Dexras1还与SAH后炎症反应相关。据报导，炎症反应可诱导ET-1在星型胶质细胞内高表达，抑制少突胶质细胞前体细胞（Opcs）的分化，因此我们设计相关实验，运用多种实验技术深入探究并验证“Dexras1可通过cAMP/CREB/ET-1通路诱导Opcs分化障碍最终导致白质损伤”假说。最终明确，Dexras1不仅可以引起Olgs铁死亡，同时可致Opcs分化障碍，二者共同导致髓鞘脱失，最终导致白质损伤。本项目为SAH的治疗提供新的实验基础，为改善SAH患者的预后提供了新的方向。