PLP1调控脊髓损伤后OPC铁死亡与再髓鞘化的机制研究

少突胶质前体细胞（OPC）的死亡及分化的抑制是阻碍脊髓损伤后再髓鞘化的主要因素，但其调控机制仍不清楚。课题组前期研究表明，铁死亡（Ferroptosis）是脊髓损伤后神经细胞大量死亡的重要途径。蛋白脂蛋白1（PLP1）是再髓鞘化过程中髓鞘的主要成分之一，其可通过调控铁代谢干预OPC存活及分化，且脊髓损伤后PLP1表达持续降低。课题组提出科学假说：PLP1是调控脊髓损伤后OPC铁死亡与再髓鞘化的关键因素。本课题拟通过谱系示踪技术明确脊髓损伤后OPC铁死亡特征及时空变化规律；体外构建OPC铁死亡模型，通过敲除及过表达OPC中PLP1，探讨PLP1通过IRP2/NCOA4/FTH1介导的铁自噬调控OPC铁死亡的机制；体内过表达PLP1，探讨调控OPC铁死亡对脊髓损伤再髓鞘化的促进作用。本研究将揭示铁死亡在脊髓损伤再髓鞘化过程中的作用机制，为促进再髓鞘化修复脊髓损伤提供新的靶点与策略。

The death of oligodendrocyte progenitor cells (OPC) and the inhibition of their differentiation and maturation are the main factors hindering the remyelination after spinal cord injury, but their regulation mechanism remains unclear. Our previous work studies have shown that Ferroptosis was one of the main cell death pathways in the acute and subacute phases of spinal cord injury. Prolipid protein 1 (PLP1), one of the main components of myelin, can regulate the OPC survival, differentiation, and maturation by targeting iron metabolism, and PLP1 expression was decreased after spinal cord injury. Accordingly, we proposed a hypothesis: PLP1 is a key factor in regulating ferroptosis of OPC and remyelination after spinal cord injury. This project intends to use cell lineage tracing to investigate the characteristics of ferroptotic OPC after spinal cord injury; construct an OPC ferroptotic model with knockout or overexpression of PLP1 in vitro to explore the regulation mechanism of PLP1 in OPC ferroptosis mediated by ferritinophagy pathway IRP2/NCOA4/FTH1; overexpress PLP1 in vivo and to clarify the role of PLP1 in promoting remyelination through the regulation of ferroptosis after spinal cord injury. This study will reveal the regulation mechanism of ferroptosis in the process of remyelination after spinal cord injury, and provide new target and strategy to repair spinal cord injury for promoting remyelination.