SRC-1介导Wnt/β-catenin信号通路在恐惧记忆再巩固中的作用及机制研究

项目名称： SRC-1介导Wnt/β-catenin信号通路在恐惧记忆再巩固中的作用及机制研究

项目编号： No.31500896

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 神经、认识与心理学

项目作者： 边晨

作者单位： 中国人民解放军第三军医大学

项目金额： 20万元

中文摘要： 恐惧记忆激活后的再巩固（reconsolidation）是创伤后应激障碍（PTSD）症状不易消退的重要原因，干预恐惧记忆再巩固的关键分子是治疗PTSD的主要途径。研究发现，Wnt/β-catenin信号通路在恐惧记忆再巩固中发挥重要作用，SRC-1是该通路调节靶基因转录必要的辅助活化因子。我们的近期研究表明抑制SRC-1会阻断恐惧记忆的再巩固且靶基因BDNF的水平显著降低，提示SRC-1在恐惧记忆再巩固中可能发挥重要作用，但具体机制未明。我们推测SRC-1可能通过与β-catenin结合，调节BDNF启动子Ⅰ/Ⅳ区组蛋白H3K9/K14的乙酰化水平，促进BDNF的表达并增强恐惧记忆再巩固。本项目拟在已有研究的基础上利用病毒转染、电生理记录、染色质免疫共沉淀等方法，探讨SRC-1介导Wnt/β-catenin信号通路对靶基因BDNF的表观遗传学调节机制，为治疗PTSD症状探索新的药物靶点。

中文关键词： 创伤后应激障碍；恐惧记忆；再巩固；BDNF；乙酰化

英文摘要： Reconsolidation after retrieval of fear memory is one of the important reasons to maintain the core symptoms in post-traumatic stress disorder (PTSD) of not easy to extinction. Intervening the key molecules in reconsolidation of fear memory is the effective way for the treatment of PTSD. It is reported that Wnt/β-catenin signaling pathway play an important role in reconsolidation of fear memories, and SRC-1 is a key coactivator of Wnt/β-catenin signaling pathways regulating target gene transcription. Our recent studies have found that inhibition of SRC-1 would block the fear memory reconsolidation and the level of the target gene BDNF significantly reduced, implying SRC-1 may play an important role in reconsolidation of fear memory. However, the specific mechanism is unclear. We speculate that SRC-1, as acetyltransferase, could combine with β-catenin, regulating acetylation of BDNF at H3K9/K14 site, promoting its expression and enhance reconsolidation of fear memory. The project is proposed on the basis of our earlier researches, using some experimental methods, such as virus transfection, electrophysiological recording, chromatin immune coprecipitation, exploring the epigenetic regulation mechanism of SRC-1 mediated Wnt/β-catenin signaling pathway to BDNF, the target genes, in reconsolidation of fear memory, providing a new therapy target for treatment of PTSD.

英文关键词： PTSD;fear memory;reconsolidation;BDNF;acetylation