免疫检查点分子CD22介导小胶质细胞异常吞噬在老年术后认知功能障碍中的作用及机制研究

术后认知功能障碍(POCD)高发于老年麻醉手术患者，文献及我们前期研究发现小胶质细胞功能异常是重要诱发机制，但吞噬功能改变在其中的作用尚不清楚。免疫检查点分子CD22是新发现的脑内特异表达于小胶质细胞的吞噬负向调控因子，可作为神经退行疾病免疫治疗靶点。预实验提示麻醉手术导致小胶质细胞吞噬受抑和极化紊乱，同时伴CD22过表达及下游SHP1磷酸化水平升高。鉴于小胶质细胞极化稳态与吞噬密切相关，我们推测：麻醉手术激活CD22-SHP1通路诱导小胶质细胞M1/M2极化失衡致吞噬受损进而诱发POCD。本项目拟构建POCD体内外模型，利用认知行为学、脑片电生理和基因干预等技术：明确POCD中小胶质细胞吞噬功能下降；揭示CD22过表达在POCD小胶质细胞吞噬功能下降中的作用；探索CD22介导小胶质细胞吞噬下降促进POCD的分子机制。本项目将揭示POCD发病新机制，为POCD的免疫治疗新策略提供依据和靶点

Postoperative cognitive dysfunction (POCD) is a highly prevalent condition in elderly patients undergoing anesthesia and surgery. Based on our previous studies and other research findings, we suggest that the dysfunction of microglia is deeply involved in the pathogenesis of POCD. However, it remains unclear whether the microglial phagocytosis plays a critical role in POCD. Recently, studies have shown that the disorder in microglial phagocytosis is closely related with neurodegenerative diseases. Immune checkpoint CD22, a newly identified negative regulator of microglial phagocytosis, may be a potential target of immunotherapy in neurodegenerative diseases, which is expressed exclusively by microglia in the central nervous system. In our preliminary experiments, we observed that anesthesia and surgery induced POCD and a significant polarization imbalance in microglial M1/M2 phenotype with overexpression of CD22 and phosphorylated SHP1 protein in microglia. Moreover, it has been demonstrated that microglial polarization stability is associated with its phagocytosis. Therefore, we hypothesize that the activation of microglial CD22-SHP1 signaling pathway induced by anesthesia and surgery and the resulting M1/M2 polarization imbalance may contribute to deleterious microglial phagocytosis, which consequently leads to POCD. For validating the hypotheses, utilizing cells and animal models, we will use cognition behavior tests, electrophysiology, gene interference and other techniques to investigate the effect of abnormal phagocytosis of microglia in POCD and show the critical role of CD22 in microglial phagocytosis. Furthermore, we will explore the molecular mechanism underlying CD22-mediated microglial phagocytosis in POCD. The study will reveal the new mechanisms underlying POCD. Our findings will provide reliable experimental basis and a new target for immunotherapy strategies in POCD.