HDAC6抑制剂贝利司他通过上调Sirt6改善多发性硬化神经炎症的表观遗传机制研究

多发性硬化（MS）是一种以脱髓鞘损伤为主要特征的自身免疫性疾病，神经炎症损伤在MS发病机制中扮演了重要角色，但详细机制仍不清楚。我们前期研究发现组蛋白去乙酰化酶6（HDAC6）抑制剂贝利司他可显著改善小鼠实验性自身免疫性脑脊髓炎（EAE），且与上调小胶质细胞中Sirt6有关。因此提出“贝利司他上调Sirt6改善MS神经炎症”这一假设。本项目拟在前期工作基础上，综合运用小鼠EAE模型和体外小胶质细胞活化体系，借助小胶质细胞特异性Sirt6敲除鼠以及基因转染和沉默等手段，系统考察并确证Sirt6表达水平与EAE发生发展的关联性，考察上调Sirt6策略在改善神经炎症中的关键作用，明确上调Sirt6与抑制小胶质细胞活化之间的关联，阐明贝利司他改善EAE的表观遗传机制，包括上调Sirt6进而抑制小胶质细胞活化介导的神经炎症等。本项目为基于表观遗传的MS发病机制研究和抗炎治疗提供新的策略与候选药物。

Multiple Sclerosis (MS) is an autoimmune inflammatory disease characterized by demyelination. Neuroinflammation plays an important role in the pathogenesis of MS, but the mechanism remains unclear. Our previous data showed that histone deacetylase 6 (HDAC6) inhibitor Belinostat significantly improved experimental autoimmune encephalomyelitis (EAE), and the mechanism might be due to the up-regulating effects of Belinostat on Sirt6 in microglia. Therefore, we propose that Belinostat alleviates MS neuroinflammation through up-regulating Sirt6. Based on the above work, this project intends to comprehensively use EAE model and in vitro microglia activation system, with the help of microglia-specific Sirt6 knockout mice, gene transfection and silencing techniques, to systematically investigate and confirm whether Sirt6 is involved in the pathogenesis of EAE and the key role of up-regulation of Sirt6 strategy in improving neuroinflammation. This study will determine the correlation between the up-regulation of Sirt6 and the inhibition of microglia activation, and clarify the epigenetic mechanism of Belinostat on improving EAE, including the microglial activation-mediated neuroinflammation ameliorating effects through Sirt6 up-regulation. This study will provide new strategies and ideas for the pathogenesis clarification and anti-inflammatory treatment of MS based on epigenetics.