脑缺血过程中TNF-α介导TNFR1/TNFR2调控少突胶质细胞前体细胞功能的机制研究

少突胶质细胞（OL）大量坏死所致的脱髓鞘损伤是缺血性脑卒中神经功能受损的重要原因。靶向提高OL再生效率是修复脑损伤的重要途径。少突胶质细胞前体细胞（OPCs）是脑内OL的直接来源，但脑缺血后OPCs向OL分化进程受阻，其具体机制尚不清楚。我们前期研究发现：脑缺血后，OPCs向缺血区域聚集数量不足，而到达缺血区的OPCs却大量凋亡，这些过程与肿瘤坏死因子（TNF-α）的调控密切相关。因此提出假设：脑缺血早期跨模型TNF-α（tmTNF）介导TNFR2抑制OPCs向内皮细胞分化，使其无法及时参与缺损血管修复，血管结构的不完整阻碍了OPCs向缺血区域的聚集；缺血晚期分泌型TNF-α（solTNF）介导TNFR1促进OPCs凋亡，抑制其向OL分化，最终降低髓鞘再生的效率。本课题拟以OPCs为主要研究对象，系统阐明TNF-α阻碍OPCs向OL分化的具体机制，为脑缺血后神经功能修复提供精准的调控靶点。

Demyelination injury caused by the massive necrosis of oligodendrocytes (OL) is an important cause of neurological damage in ischemic stroke. Targeted improvement of OL regeneration efficiency is an important way to repair cerebral ischemia injury. OPCs are the direct source of OL in the brain. The process of OPCs differentiation to OL is blocked after cerebral ischemia, but the specific mechanism is unknown. Our previous studies found that the migration ability of OPCs to the ischemic area was impaired after cerebral ischemia, but a few OPCs reached the ischemic area were apoptotic. These processes are related to the expression of TNFR1 and TNFR2, suggesting that TNF-α may regulate the differentiation of OPCs to OL. Therefore, we hypothesize that tmTNF mediates TNFR2 to inhibit the migration of OPCs in the early stage of cerebral ischemia, solTNF mediates TNFR1 to promote the apoptosis of OPCs in the late stage of cerebral ischemia, inhibiting the differentiation of OPCs to OL, and ultimately reduce the efficiency of myelin regeneration. In this study, OPCs will be used as the main research object to elucidate the specific mechanism of TNF-α mediated TNFR1/TNFR2 regulating the differentiation of OPCs to OL in vivo and in vitro. This study will provide a precise regulatory target for the repairment of neural function after cerebral ischemia.