HDAC6在术后认知功能障碍中的作用及其机制研究

项目名称： HDAC6在术后认知功能障碍中的作用及其机制研究

项目编号： No.81471107

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： 童建斌

作者单位： 中南大学

项目金额： 150万元

中文摘要： 我们在前期工作中率先从多个组蛋白去乙酰化酶（HDACs)中筛选出HDAC6，并证明其表达上调与老年大鼠术后记忆损伤密切相关。通过生物信息学方法,我们对HDAC6的转录因子及其结合序列进行了预测，结合pubmed文献检索结果、已经报道的术后认知功能障碍 (POCD)的发病机理，我们推测在POCD病理条件下转录因子STAT1对HDAC6的表达起关键的调控作用。我们预实验也证明术后STAT1活化显著增加。因此，本项目提出手术通过活化STAT1,上调 HDAC6的表达, 后者损伤了神经元的突触可塑性,进而导致POCD的科学假设。围绕假说,我们将检测：①HDAC6在POCD中的作用及其对突触可塑性的影响；② 转录因子STAT1对HDAC6表达的直接调节作用。这些结果将有助于一些成熟的临床新药及时引入POCD的防治，打破当前POCD防治无药可用的困境，开辟出一种针对POCD多个病理环节的治疗手段。

中文关键词： 术后认知功能障碍；突触可塑性；HDACs；HDAC6；STAT1

英文摘要： HDAC6 is picked out from many histone deacetylases(HDACs) in our primary experiments, whose increased expression is closely associated with postoperative cognitive dysfunction(POCD)of aged rats. We also have investigated the possible transfactors and their binding sequences of HDAC6 by bioinformatics analysis. And we have checked the information of these trasnfactors in Pubmed. Combining the information of transfactors with pathologic mechanism of POCD, we think that transfactor STAT1 plays important roles at modulating HDAC6 expression. Thus we further detect the action of STAT1. Increased action of STAT1 is detected at hippocampus of aged rats after surgery, corresponding to the impairment of cognitive function. Based on these above, we suppose that surgery induces POCD by activating STAT1, then increasing HDAC6 expression and impairing the synaptic plasticity of neurons. In the study, we will detect: 1) the roles of HDAC6 in POCD and the effects of HDAC6 on synaptic plasticity of neurons, 2) the direct modulation of transfactor STAT1 to HDAC6 expression. Our study will be useful for 1）taking clinical new drugs into the prevention and treatment of POCD， 2）breaking the ice of no drug for prevention and treatment of POCD, and 3) forming a new method of prevention and treatment of POCD targeting at multiple pathological aspects.

英文关键词： postoperative cognitive dysfunction;synaptic plasiticity;HDACs;HDAC6;STAT1