去乙酰化酶抑制剂减轻氟致小胶质细胞炎性反应和脑损伤的分子机制

The application of histone deacetylase inhibitors has made a breakthrough in the treatment of neurological diseases, but its role in brain damage caused by fluorosis is rarely reported. Our previous experiments demonstrated that activation of microglia and activation of MAPK (JNK) and NF-κB signaling pathways to promote inflammatory cytokine secretion in microglia may be one of the main causes of fluorosis brain injury. We speculate that histone deacetylase inhibitors play a protective role by regulating the polarization dynamics of microglia and microglia-mediated MAPK and NF-κB signaling pathways. It is intended to elucidate the mechanism of protecting fluorosis from encephalitis damage longitudinally. At the same time, iTRAQ combined with mass spectrometry and bioinformatics methods were used to elucidate laterally the protein network of deacetylase inhibitors that regulate fluorosis brain injury and verify the related pathway effects. A preliminary exploration of the multiple mechanisms that play a role in neuroprotection after fluorosis and the significance of modulating inflammatory responses throughout the biological process. In summary, the “protein-biological pathway-response” system of fluorosis brain injury will be systematically studied from the perspective of epigenetics to provide scientific basis for the prevention and treatment of fluorosis brain injury.

组蛋白去乙酰化酶抑制剂的应用，使神经系统疾病的治疗有了突破性的进展，但其在氟中毒脑损伤中的作用鲜见报道。前期实验的结果表明氟可以活化小胶质细胞，并通过激活MAPK（JNK）和NF-κB信号通路诱导小胶质细胞炎性因子分泌，这可能是氟致脑损伤的主要机制之一。我们推测组蛋白去乙酰化酶抑制剂，通过调控小胶质细胞的极化动态以及小胶质细胞介导的MAPK和NF-κB信号通路，发挥保护作用。拟纵向阐述其保护氟中毒脑炎性损伤的机制。同时利用iTRAQ联合质谱蛋白质组学技术，生物信息学方法，横向探索去乙酰化酶抑制剂调控氟中毒脑损伤的蛋白质网络，以及调控炎症反应在整个生物学过程中的意义。综上，拟在表观遗传学视角下，通过横纵两个方向，进行氟中毒脑损伤的“蛋白质-生物通路-效应”系统研究，为氟中毒脑损伤的防治提供科学依据。

组蛋白去乙酰化酶抑制剂的应用，使神经系统疾病的治疗有了突破性的进展，但其在氟中毒脑损伤中的作用鲜见报道。本课题构建氟中毒模型，运用学习记忆行为学、透射电镜、免疫荧光、WB等实验技术，TMT质谱技术，生物信息学方法，着重研究组蛋白去乙酰化酶抑制剂在氟诱导的脑学习记忆损伤的作用机制。研究结果显示：（1）去乙酰化酶抑制剂可改善氟诱导的学习记忆能力损伤。（2）去乙酰化酶抑制剂通过调控糖代谢和能量代谢相关分子（LDHA、LDHB、PKM、ACAT1、MDH2、DLAT）进而拮抗氟诱导的神经损伤。（3）去乙酰化酶抑制剂可以调控氟诱导小胶质细胞炎症因子分泌异常发挥保护效应。（4）去乙酰化酶抑制剂可能通过调控氟中毒乙酰化和巴豆酰化修饰，发挥神经保护效应。综上，本课题组在表观遗传学视角下，通过横纵两个方向，进行氟中毒脑损伤的“蛋白质-生物通路-效应”系统研究，为氟中毒脑损伤的防治提供科学依据。