靶向调节小胶质细胞NLRP3炎症小体活化通路对多发性硬化模型鼠认知的影响及机制研究

认知障碍是多发性硬化(MS)患者的重要临床特征，但其损害机制尚不清楚，缺乏有效的治疗措施。小胶质细胞与NLRP3炎症小体及相关的IL-1β/IL-1R信号在MS的免疫紊乱及脱髓鞘病理机制中发挥作用，但在认知损害中的作用不清楚。本研究在前期发现抑制小胶质细胞NLRP3炎症小体激活可以改善EAE小鼠在病程恢复期出现的学习记忆能力下降以及海马神经元衰老，拟进一步研究小胶质细胞NLRP3炎症小体活化通路是否通过IL-1β/IL-1R信号传导，进而激活海马神经元的MyD88/p38以及MyD88/NFκB信号通路，诱导衰老及相关分泌表型形成，导致EAE小鼠认知障碍。本课题的研究结果对阐明MS认知障碍的机制具有重要的科学意义。

Cognitive impairment is a recognized feature in multiple sclerosis. However, the mechanism is still unknown and the treatment is proved to be ineffective. Recent studies show that microglia and inflammasome activation as well as its related IL-1β-IL-1R pathway play important role in the immune disorder of multiple sclerosis. But their contribution to the cognitive impairment of multiple sclerosis and underlying mechanism are not yet clear. In our previous study, we have found that inhibition of microglia NLRP3 inflammasome activation can improve learning and memory capability of EAE mice in its chronic phase, and this effect may via the reduction of hippocampal neuronal senescence. The overall goal of this proposal is to test the hypothesis that NLRP3 inflammasome activation in microglia, releasing IL-1β that acts in its IL-1R pathway in hippocampal neuron, subsequently activating its downstream pathway such as MyD88/p38 and MyD88/NFκB pathway, Thereby promoting the formation of senescence-associated secretory phnotype in neuron, which leading to the hippocampal neuronal senescence that makes the cognitive impairment in multiple sclerosis mouse model. Overall, this proposal will help define NRLP3 as a new regulator of cognitive function in multiple sclerosis, and may have important scientific significance for cognitive impairment in multiple sclerosis.