靶向抑制HDAC3调控阿尔茨海默病记忆-神经环路重塑的机制研究

项目名称： 靶向抑制HDAC3调控阿尔茨海默病记忆-神经环路重塑的机制研究

项目编号： No.81200839

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 神经系统疾病、精神疾病

项目作者： 朱晓蕾

作者单位： 南京大学

项目金额： 23万元

中文摘要： 内嗅皮层-海马神经环路与Alzheimer's disease（AD）的记忆功能密切相关。前期研究发现，APP/PS1小鼠海马区H3和H4组蛋白乙酰化水平低于正常组，而特异性干扰HDAC3可提高组蛋白乙酰化水平，改善APP/PS1小鼠的学习和记忆功能，提示组蛋白乙酰化可调控AD记忆-神经环路的重塑。本课题利用行为学、病理学、分子生物学等技术进行以下体内外研究：1）靶向抑制HDAC3具有神经保护作用，进一步探讨受其调控的AD记忆-神经环路的特异性基因群；2）特定基因群的乙酰化对AD记忆-神经环路重塑的影响。本项目首次将AD的记忆-神经环路乙酰化稳态与环路的重塑相联系，阐明AD记忆-神经环路重塑的分子调控机制；对AD记忆-神经环路重塑的基础研究具有一定贡献，同时对临床早期诊断和治疗提供新的靶点。

中文关键词： 阿尔茨海默病；组蛋白去乙酰化酶3；神经环路重塑；；

英文摘要： Entorhinal cortex-hippocampal neural circuits are closely related to the memory function in Alzheimer's disease (AD). Preliminary studies demonstrated that H3 and H4 histone acetylation levels in hippocampus of APP/PS1 mice were lower than that of wide-type group. Knocking-down histone deacetylase 3 (HDAC3) could increase histone acetylation levels and improve learning and memory function of the APP/PS1 mice, suggesting that histone acetylation could regulate the remodeling of the memory-neural circuits. This study will mainly focus on the following two parts: 1) to confirm that inhibition of HDAC3 exerts neuroprotective effects and to explore the memory-neural circuits specific genes of AD regulated by HDAC3 inhibition; and 2) to identify the effects of acetylation of specific targets to the regulation of AD memory-neuronal circuits by behavioristics, pathology and molecular biology. For the first time this project have demonstrated the relation of the acetylation homeostasis and remoding of the memory-neural circuits of AD. In addition, this study will investigate the molecular mechanisms of the remolding of memory -neural circuits of AD, which would promote the researches on the remodeling of memory neural circuits and provide new targets for early diagnosis and treatment for AD.

英文关键词： Alzheimer's disease；histone deacetylase 3；neural circuits remodeling；；