Nrf2调控颅脑创伤后炎症信号通路作用研究

Nrf2 signaling pathway is intracellular protective signaling pathway in mediating a series of cytoprotective proteins, which have been reported to reduce oxidative stress, inflammatory damage, apoptosis and calcium overload. Our previous studies have demonstrated that Nrf2 signaling pathway would play an important protective role in limiting the cerebral inflammatory response and secondary brain injury after TBI. The purpose of this study is therefore to take a further research on the regulation of inflammatory signaling pathway mediated by Nrf2 after traumatic brain injury: (1) to investigate the temporal change of the activation of inflammatory signaling pathways JAK-STAT, MAPK and NF-κB mediated by Nrf2 after TBI. (2) to investigate the activation of inflammatory signaling pathways when Nrf2 knockout and upregulation. (3) to investigate the mechanism underlying the activation of inflammatory signaling pathways mediated by Nrf2 after TBI: Nrf2 signaling pathway would affect the intracellular redox equilibrium, and thereby mediate the activation of inflammatory signaling pathways. The results of our study will perfect the precise mechanism underlying Nrf2 signaling pathway network and provide new therapeutic target and time window for the treatment of TBI.

NNrf2信号通路是细胞内在的保护性信号通路，研究表明该通路表达的下游分子具有抗氧化应激、调节炎症损伤、拮抗细胞凋亡、缓解钙离子超载等多种细胞保护作用。我们的前期研究证实了Nrf2信号通路可以调节颅脑创伤后继发性炎症反应，从而改善颅脑创伤预后。本项目拟进一步深入研究Nrf2调控颅脑创伤后炎症信号通路的作用及机制，探讨：（1）TBI后不同时间窗，Nrf2调控炎症信号通路JAK-STAT信号途径、MAPK信号途径及NF-κB信号途径；（（2）Nrf2敲除状态（反向调控）及使用特异性激动剂上调Nrf2状态（正向调控）下TBI后炎症信号通路的激活情况；（3）Nrf2调控TBI后炎症信号通路的可能机制：Nrf2通路调节细胞内氧化还原平衡，进而调控炎症信号途径。研究结果不仅完善了颅脑创伤后Nrf2信号通路细胞信号转导分子网络关系，而且为临床颅脑创伤后脑保护治疗时间窗的选择以及新治疗靶点的研究提供理论依

Nrf2信号通路是细胞内在的保护性信号通路，该通路表达的下游分子具有抗氧化应激、调节炎症损伤、拮抗细胞凋亡、缓解钙离子超载等多种细胞保护作用。我们的前期研究证实了Nrf2信号通路可以调节颅脑创伤后继发性炎症反应，从而改善颅脑创伤预后。本项目进一步深入研究Nrf2调控颅脑创伤后炎症信号通路的作用及机制，探讨：（1）TBI后不同时间窗，Nrf2调控炎症信号通路JAK-STAT信号途径、MAPK信号途径及NF-κB信号途径；（2）Nrf2敲除状态（反向调控）及使用特异性激动剂上调Nrf2状态（正向调控）下TBI后炎症信号通路的激活情况；（3）Nrf2调控TBI后炎症信号通路的可能机制。研究结果证实了创伤后24小时Nrf2通路激活达最高峰，其激活同脑组织炎症反应及脑损伤存在相关性，Nrf2可显著抑制TBI后炎症信号通路JAK-STAT信号途径、MAPK信号途径及NF-κB信号途径的活化，以Nrf2为靶点的治疗具有脑保护作用。并且进一步证实了Nrf2通路调节细胞内氧化还原平衡，进而调控炎症信号途径。本项目结果将为临床颅脑创伤后脑保护治疗时间窗的选择以及新治疗靶点的研究提供理论依据和实验基础。