ASK1-K716R基因突变抑制缺血性脑损伤的炎症反应并促进白质修复的机制研究

缺血性脑损伤后白质损伤得不到修复则导致感觉运动功能障碍和认知功能缺陷。凋亡信号调节激酶1(ASK1) 可以被与缺血损伤有关的不同类型的细胞毒性应激作用所激活。ASK1活性调节的结构基础仍然不清楚。激酶结构域中Lys-716位点的磷酸化对ASK1的活化的作用尚未见报道。我们前期的研究证明了ASK1/JNK通路加重神经元凋亡，而ASK1/p38通路 并未直接参与神经元的死亡。而ASK1/p38介导小胶质细胞中神经炎症反应是否参与了ASK1-介导的缺血性脑损伤尤其是对白质损伤？本项目拟采用ASK1-K716R突变转基因小鼠（ASK1m）以及小胶质细胞特异性ASK1敲除小鼠（ASK1-cKO）从基因水平上验证ASK1激酶结构域中716位点赖氨酸残基磷酸化对ASK1激活的重要作用，同时验证小胶质细胞中ASK1对调节小胶质细胞极化和炎症反应的调节作用，并进一步揭示ASK1在白质损伤修复中的作用。

White matter injury may disrupt motor and sensory function and cause neurobehavioral syndromes and cognitive impairment after ischemic brain injury. Apoptosis signal regulated kinase 1 (ASK1) is activated in cells by various forms of cytotoxic stress that are relevant to ischemic injury. Relatively little is known about the structural basis of ASK1 regulation, the role of lys-716 phosphorylation in the activation of ASK1 has not been reported. Our previous studies have shown that ASK1/JNK pathway aggravates neuronal apoptosis, while ASK1/p38 pathway is not directly involved in neuronal death. Therefore, whether ASK1/p38 pathway mediates neuroinflammatory response in microglia and participates in ASK1 mediated ischemic brain injury, especially white matter injury? This project is to verify the important role of phosphorylation of L-lysine residues at 716 site in the activation of ASK1 in ischemic brain injury via using ASK1-K716R mutant transgenic mice (ASK1m) and microglia specific ASK1 knockout mice (ASK1-cKO). Futhermore, this project is to verify the important role of ASK1 in microglia in regulating microglial polarization and inflammation, and the effect of ASK1 in white matter injury & repair.