HDAC介导的小胶质细胞极化在脑白质损伤中作用及机制研究

项目名称： HDAC介导的小胶质细胞极化在脑白质损伤中作用及机制研究

项目编号： No.81471257

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王国华

作者单位： 南通大学

项目金额： 70万元

中文摘要： 创伤性脑损伤（TBI）常引起严重的白质损伤（WMI），造成患者长期感觉运动和认知功能障碍。炎症反应是WMI病理生理过程的重要环节，使得脑损伤周边区域少突胶质细胞急性死亡或退行性变，造成脱髓鞘、轴突退化。本课题组前期研究发现，小胶质细胞作为神经系统炎症主要参与者，伴有时间依从性极化现象，由短暂性M2型（抗炎型）之后转化为更持久的M1型（促炎型），而M1型与WMI程度呈正相关；体外研究也表明M1型小胶质细胞加剧少突胶质细胞死亡，反之M2型则能保护。使用组蛋白去乙酰化酶（HDAC）抑制剂能纠正TBI后乙酰化平衡紊乱，发挥多重神经保护作用，同时可能潜在性介导小胶质细胞极化。为此，本研究拟验证HDAC抑制剂能否调控小胶质细胞极化，使其炎症因子释放减少，增强其吞噬功能，进而阻止少突胶质细胞免受继发性损伤，最终逆转WMI；同时探讨调控小胶质细胞极化的细胞分子机制,为脑保护药物开发提供新的思路和作用靶点。

中文关键词： 创伤性脑损伤；白质损伤；组蛋白去乙酰化酶；小胶质细胞；神经炎症

英文摘要： Extensive white matter injury (WMI) has been documented in patients with traumatic brain injury. This WMI correlates with the long-term deficits in motor and cognitive function. Neuroinflammation, including the activation of resident microglia, is thought to have an important role in pathophysiological process of WMI and finally leads to demyelination and axonal degeneration. Our latest findings showed that microglia responded dynamically to mechanical trauma, switching from a transient M2 phenotype to a sustained M1 phenotype. Notably, the severity of WMI was strongly correlated with activation of the M1 phenotype. In vitro experiments further revealed that M1 microglia-conditioned media exacerbated oxygen glucose deprivation (OGD)-induced oligodendrocyte death. The epigenetic influence of HDAC inhibitors on gene expression make them a novel class of pharmacological agents that may ameliorate disease conditions and enhance neuronal plasticity and survival. HDAC inhibitors may also be a potential candidate for anti-inflammation drug. We thus tested the hypothesis that whether HDAC inhibition can prevent WMI by adjusting microglia polarization towards a more specific titration of the inflammatory response away from the destructive M1 phenotype. Importantly, cellular and molecular mechanisms involved in HDAC-mediated polarization of microglia will be investigated, may provide new ideas and targets for drug development of cerebral protection.

英文关键词： Traumatic brain injury;White matter injury;Histone deacetylase;Microglia;Neuroinflammation