喹硫平促进BAF155依赖的染色质重塑在中枢神经系统髓鞘再生中的作用和机制研究

Promoting myelin repair or remyelination is an important stratagem for treatment of CNS demyelination diseases such as multiple sclerosis (MS), for which no effective therapy is currently available. In our previous study we found a unique effect of the antipsychotic quetiapine on promoting oligodendroglial differentiation and remyelination. On the basis of this finding, considering our preliminary data and the latest regulatory mechanism regarding chromatin remodeling in oligodendroglial differentiation, we proposed the further investigations on the critical role of ATP-dependent chromatin remodeling protein BAF155 in mediating the effect of quetiapine in promoting remyelination and underlying mechanism. Firstly we will apply RNA interference technique and inducible oligodendroglial lineage conditional knock-out mice to ensure the critical role of BAF155 in the effect of quetiapine on promoting remyelinajtion. Then we will exam the effect of BAF155 on stabilizing Brg1, and synergistic with Brg1 to fulfill chromatin remodeling, thus facility combination of related transcription factors with specific DNA cis-acting element to activate myelin-related gene transcription. We hope that our results could reveal the essential role of BAF155 instructed chromatin remodeling in regulation of oligodendroglial differentiation. We are also expecting that these results can help us to uncover a novel mechanism for quetiapine's effect on promoting remyelination at chromatin level, which may provide a new target for myelin repair. Finally, we expect that our research results are able to provide theoretical evidence for clinical application of quetiapine in the treatment of CNS demyelinating diseases like multiple sclerosis.

促进髓鞘修复再生是治疗多发性硬化（MS）等中枢神经系统（CNS）脱髓鞘疾病的重要途径,但目前临床缺乏特效治疗。我们在前期发现了抗精神病药喹硫平(QUE)独特的促少突胶质细胞（OL）分化和髓鞘再生作用的基础上，结合预实验结果和最新染色质重塑在OL分化中的调控机制，深入研究ATP依赖的染色质重塑蛋白BAF155在QUE促进髓鞘再生中的作用机制。研究首先利用 RNAi技术和诱导性OL系条件基因敲除小鼠明确BAF155在QUE促髓鞘再生中的关键作用。进而探讨BAF155对Brg1稳定性的维持，以及二者协同重塑染色质，协助相关转录因子与特定DNA顺式作用元件结合而激活髓鞘相关基因转录的途径。期望揭示BAF155依赖的染色质重塑在OL分化调节中的关键作用和途径，阐明QUE在染色质水平促进髓鞘再生的新机制，为髓鞘再生药物靶点的开发提供指导，为QUE用于MS 等CNS脱髓鞘疾病的临床治疗提供理论依据。

研究少突胶质细胞（Oligodendrocyte, OL）分化的调控机制对于促进中枢神经系统髓鞘再生的药物设计有重要的科学意义。本研究我们利用二元指示髓鞘化纳米柱微阵列 （BIMA）系统及微阵列等高通量筛选技术，发现抗精神病药喹硫平（Quetiapine，QUE）是一种有效促进OPC分化和髓鞘再生的候选药物，以QUE为工具药，利用微阵列技术检测了QUE作用后，OPC分化的基因表达谱改变及基因本体学变化特点，发现并证明了ATP依赖的染色质重塑蛋白BAF155在少突胶质细胞前体细胞（Oligodendrocyte precusor cell, OPC）分化中的关键作用。同时，发现QUE可抑制Wnt信号通路，促进肿瘤干细胞向少突胶质样细胞分化而提高胶质瘤对TMZ的化疗敏感性。阐明了QUE调控小胶质细胞活化而减轻脱髓鞘损害的作用机制。此外，还发现了髓鞘形成细胞中Dicer调节的非髓鞘依赖作用途径对外周神经轴突功能的维持作用，揭示了RyR3介导的内质网钙释放在OPC分化中的重要调节作用。研究结果发表SCI论文7篇，中文核心期刊论文1篇。参加国际会议交流2次，国内学术会议交流2次，举办神经胶质细胞前沿论坛1次；获重庆市自然科学二等奖1项，1人入选重庆市科技创新领军人才；培养博士研究生3名，技术员1名。