HMGB1调控小胶质细胞极化在血管性认知障碍小鼠OPCs成熟分化中的作用及机制研究

血管性认知障碍(Vascular Cognitive Impairment，VCI)发病率高，无有效疗法，主要病理改变为脑白质髓鞘损伤。我们发现小胶质细胞M1型极化的促炎反应是导致少突胶质前体细胞(Oligodendrocyte Precursor Cells, OPCs)成熟障碍致髓鞘损伤的重要原因。高迁移率族蛋白1 (High-mobility group box 1, HMGB1)是小胶质细胞激活相关的晚期炎性因子，前期研究患者血清HMGB1与髓鞘蛋白水平相关。因此，通过调节HMGB1信号通路来抑制M1型小胶质细胞极化，促进OPCs成熟可能成为VCI的治疗靶点。本课题将分别以细胞、VCI动物及患者为研究对象，观察HMGB1信号通路与OPCs及髓鞘损伤的关系，并通过调控HMGB1通路关键蛋白减少M1型小胶质细胞极化，促进OPCs成熟，修复髓鞘，改善认知，为VCI治疗提供新思路。

Vascular cognitive impairment (VCI) has high incidence and is lack of efficient therapy.White matter lesions caused by myelin damage are the most common pathological changes of VCI. Our previous work found that the increased polarization of pro-inflammatory (M1) microglia induced inflammatory reaction was an important reason for oligodendrocyte precursors (OPCs) failed to maturate and differentiate，and eventually resulted in myelin damage. High-mobility group box 1 (HMGB1), an important late-stage brain inflammatory factor, is closely related to microglial activation and depression. It was also found in our previous study that patients with depression showed high level of HMGB1 related to myelin damage. Therefore, we hypothesize that the regulation of HMGB1-related signaling pathway to inhibit M1 microglial polarization may promote the maturation of OPCs and remyelination. It may be an important target of VCI therapy. We propose an experiment on the expression of HMGB1 and the relationship with M1 type of microglia and demyelination with the model of microglia cell line, VCI mice and VCI patients. In this study we will regulate the HMGB1-related signaling pathway to inhibit M1 micrglial polarization for the maturation of OPCs and myelin regeneration, to attenuate cognitive disorder. The hypothesis above can provide an important theoretical basis and new targets for VCI treatment.