SCI后铁超载及其致Ferroptosis在白质继发损伤中的作用研究

项目名称： SCI后铁超载及其致Ferroptosis在白质继发损伤中的作用研究

项目编号： No.81471261

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 胡胜利

作者单位： 中国人民解放军第三军医大学

项目金额： 70万元

中文摘要： 脊髓损伤(SCI)致残率高，后果严重，但损伤机制不完全清楚，白质继发损伤可能在其中起重要作用。本研究所前期研究及文献报道发现SCI后灰白质交界处存在广泛灶性出血，其中血液分解时间规律与SCI后白质细胞死亡规律高度一致，给予Fe螯合剂可减轻Fe蓄积/超载，促进神经功能恢复。最近研究显示Ferroptosis是Fe高度依赖的细胞死亡新方式。据此并结合文献我们推测SCI后可能由于局部血液分解，Fe长期蓄积，铁调节及转运蛋白异常，致少突胶质细胞Fe超载，持续产生活性氧族（ROS），引起细胞长时程Ferroptosis死亡，轴突脱髓鞘甚至变性。本项目在既往研究工作基础上，拟采用离体和在体实验，结合形态学、分子细胞生物学、电生理、7.0T micro MRI和行为学等方法，探讨SCI后Fe超载机制及其在白质继发损伤中的作用和机制，为SCI治疗提供新靶点，为铁螯合剂的临床转化应用奠定基础。

中文关键词： 脊髓损伤；少突胶质细胞；铁超载；Ferroptosis；白质继发损伤

英文摘要： There is an increasing tendency in the incidence of spinal cord injury(SCI) which always induces parslysis of patients. However, the effective threpies are absent and the mechanism of secondary damage following SCI remains to be elucidated. Our previous study and recent evidences have shown that white matter damage may be more important than grey matter injury after SCI. Past studies have reported that there is a wide range of focal hemorrhage between gray and white matter following SCI and the time law of blood decomposition is highly consistent with oligodendrocytes death. Furthermore, iron chelator deferoxamine can reduce iron overload, alleviate white matter injury, and improve neurological function. Therefore, we hypothesized that SCI may lead to the local increase in the iron content and abnormalities of iron transport, metabolism and regulation proteins, which would cause iron overload of oligodendrocytes, then cell ferroptosis, axon demyelination and Wallerian degeneration. On the basis of our previous research work, this programme will use methods of in vitro and in vivo experiments, combined with morphology, molecular and cell biology, neurophysiology, imaging and ethology, to explore iron generation, distribution and overloading and its role in the white matter secondary injury after SCI. The purpose of this study is to demonstrate that iron overload would result in white matter secondary injury in SCI and provide new targets for SCI treatment and promote the clinical application of the iron chelator.

英文关键词： traumatic spinal cord injury;oligodendrocytes;iron overload;Ferroptosis;white matter secondary injury