放射性脊髓损伤中p38MAPK信号通路调控内源性神经干细胞向少突胶质前体细胞分化的机制研究

Radiation induced spinal cord injury (RISC) is a serious complication of radiotherapy, which affects the quality of life of patients. Endogenous neural stem cells (eNSC) are the major source of differentiation of oligodendrocyte precursor cells (OPC). After radiotherapy, eNSC was significantly damaged, resulting in a significant reduction in its ability to differentiate into OPC, and its specific mechanism has not been elucidated. Previous studies have shown that MAPK signaling pathway is the key factor to regulate the differentiation of eNSC into OPC. Does the MAPK signaling pathway mediate abnormal eNSC differentiation after radiotherapy? In our previous experiments, we found that the activation of p38MAPK pathway in eNSC with radiation injury was significantly inhibited, resulting in a significant reduction in the secretion of NGF. We hypothesized that the inhibition of p38MAPK pathway in RISC leads to the abnormal function of eNSC to OPC, and then affects the process of RISC re-myelination. This research uses the tamoxifen dependent Nestin promoter CreER transgenic mouse and other tools, aim to clarify the key role of p38MAPK signaling pathway in the differentiation of eNSC and regulation mechanism after radiation injury. This study will provide new ideas for the prevention and treatment of radiation induced spinal cord injury.

放射性脊髓损伤(RISC) 是肿瘤放疗严重并发症，影响患者生存质量。内源性神经干细胞（eNSC）是体内少突胶质前体细胞（OPC）主要分化来源，放疗后eNSC受到明显损伤，导致其向OPC分化能力显著降低，其具体机制尚未阐明。已有研究证实MAPK信号通路是调控eNSC向OPC分化的关键因素。那么MAPK信号通路是否介导放疗后eNSC分化异常？我们前期实验中发现：放射损伤后的eNSC中p38MAPK通路激活受到明显抑制，导致分泌NGF显著减少。据此我们推测：RISC中p38MAPK通路抑制导致eNSC向OPC分化功能异常，进而影响RISC再髓鞘化过程。本项目采用他莫昔芬依赖的Nestin启动子控制的CreER 转基因小鼠等工具，阐明放射损伤后p38MAPK信号通路在eNSC分化功能中的关键作用及调控机制，为防治放射性脊髓损伤提供新思路。

放射性脊髓损伤(RISC)是肿瘤放疗严重并发症，影响患者生存质量。内源性神经干细胞(eNSC)是体内少突胶质前体细胞(OPC)主要分化来源，放疗后eNSC受到明显损伤，导致其向OPC分化能力显著降低，其具体机制尚未阐明。我们前期实验中发现：放射损伤后的eNSC中p38MAPK通路激活受到明显抑制，导致分泌NGF显著减少。据此，我们推测放射损伤的eNSC通过下调OPC分化形成少突胶质细胞的能力，导致脊髓再髓鞘化受阻，最终形成脱髓鞘病变。故本项目拟探讨放射性脊髓损伤中p38MAPK信号通路调控内源性神经干细胞向少突胶质前体细胞分化的机制研究。在本项目中，我们先后证实：①通过蛋白分泌水平、基因表达水平验证不同放射剂量下p38信号通路激活水平；②构建放射损伤的 NSC 与 OPC 的Transwell非接触培养系统，检测 NSC 对 OPC 的增殖、凋亡与分化的调控，并通过特异性的 p38 拮抗剂验证p38信号通路在其中的作用；③以他莫昔芬依赖的Nestin启动子控制的CreER转基因小鼠为主要研究平台，进一步验证放疗后eNSCs激活、分化及迁移的路径，探讨eNSCs在放射性脊髓损伤后再髓鞘作用的影响。综合以上结果，我们阐明放射损伤后p38MAPK信号通路在eNSC分化功能中的关键作用及调控机制，为防治放射性脊髓损伤提供新思路。同时探讨eNSCs在体内再髓鞘化过程的分化、迁移路径及调控作用，为脱髓鞘病变的研究提供体内实验基础。在本项目的资助下，我们共发表SCI论著1篇，IF达4.691。在此基础上，我们进一步对放射性脊髓损伤发病机制进行探索，为本项目成果进一步延续和深入研究提供了保障。