基于p300/CBP/CREB通路研究电针调控阿尔茨海默病小胶质细胞M2/M1极化表型平衡的组蛋白乙酰化机制

小胶质细胞(MG)极化表型平衡是MG在AD炎性反应中发挥“双刃剑”作用的焦点。IL-4是MG表型极化开关，组蛋白乙酰化酶p300/CBP与CREB转录是IL-4有效调控M2/M1极化表型平衡的关键。基于“电针可调节p300/CBP/CREB乙酰化以良性调控IL-4促向M2型转化”之假说，本课题拟在前期研究基础上，进一步以SAMP8鼠为研究对象，采用CHIP-seq等多种分子生物学技术，以调控小胶质细胞M2/M1极化表型平衡为切入点，p300/CBP/CREB为关键靶点，IL-4为效应枢纽，探讨MG激活及其M2/M1型极化在AD病理中的作用；IL-4对M2/M1极化表型的诱导效应；及p300/CBP/CREB乙酰化异常在IL-4促向M2表型极化中的影响机制，为深入揭示电针促进IL-4良性调控AD小胶质细胞M2/M1极化平衡的作用机制，有力阐明电针防治AD效应机制提供新线索与科学依据。

Balance of microglia polarization phenotype is the focus of its “double-edged sword” role in the inflammatory response of AD. IL-4 is the switch of microglia polarization phenotype, and the activity of histone acetylase p300/CBP and transcription of CREB are the key factors for IL-4 to effectively regulate the equilibrium of microglia M2/M1 polarization phenotype. Based on the hypothesis that electroacupuncture may have effects on the acetylation of p300/CBP/CREB, and positively regulate the activity of IL-4, thus inducing the polarization of microglia to M2 phenotype, we will take SAMP8 mice as the research object, adopt CHIP-seq and other molecular biology techniques, and regard regulating the balance of microglia M2/M1 polarization phenotype as the breakthrough point, p300/CBP/CREB as the key target, and the promoter region of IL-4 as the effect pivot, so as to explore the role of microglia activation and M2/M1 polarization phenotype in the process of AD pathology, as well as the inductive effect of IL-4 on microglia M2/M1 polarization phenotype, and the mechanism of abnormal acetylation of p300/CBP/CREB on microglia M2 polarization phenotype induced by IL-4. And then to reveal the mechanism of electroacupuncture on the benign regulation of microglia M2/M1 polarization balance in AD, which provide clues and scientific basis for better elucidating the mechanism of electroacupuncture in the prevention and treatment of AD.