基于表观遗传修饰探析衰老大鼠高皮质酮致海马GR-学习记忆关键蛋白下调的分子机制及补肾益气方药的作用

项目名称： 基于表观遗传修饰探析衰老大鼠高皮质酮致海马GR-学习记忆关键蛋白下调的分子机制及补肾益气方药的作用

项目编号： No.81473583

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： 金国琴

作者单位： 上海中医药大学

项目金额： 73万元

中文摘要： 大脑海马区域退行性变化是衰老性学习记忆损害的重要病理机制。我们前期实验发现，老年大鼠HPA轴过度亢进导致分泌过多皮质酮，反馈作用于海马相应受体（GR）使之呈现毒性反应，以致关键蛋白表达及学习记忆能力下降。结合新近提出的表观遗传修饰机制，我们推测表观遗传修饰异常可能是大脑海马区域GR表达下调，进而影响学习记忆关键蛋白下降的重要原因，高浓度皮质酮是引起衰老相关性学习记忆损害的重要根源。本课题拟采用MSP、ChIP、mi-RNA芯片、Q-PCR、Western blot等分子生物学方法，从体内、外观察大鼠海马神经细胞表观遗传修饰酶蛋白（DNMT、HACT、HDAC、MeCP2）的退行性变化，从基因表观遗传修饰角度解析高皮质酮-海马GR-学习记忆关键蛋白（Acr、Syn1、Gara5等）下调的分子机制，及补肾、益气方药、中药有效成分对上述指标变化的干预作用，为补肾、益气健脑提供新的科学依据。

中文关键词： 抗衰老；皮质酮；表观遗传修饰；学习和记忆；补肾益气方药

英文摘要： Degenerative changes in the hippocampus region of the brain are the important pathological mechanism of learning and memory impairment of the aging body. Previous studies have founded that in aged rats HPA axis hyperfunction lead to excessive secretion of corticosterone which interaction with its receptor (GR) in hippocampus in a feedback mode to make it show toxic reaction, resulting in decrease of key proteins expression and learning and memory ability.Combining epigenetic modification progression proposed recently , we hypothesized that abnormal of epigenetic modification may down regulated the expression of GR in hippocampus and thereby be an important factor affecting key proteins releated to learning and memory , may be an important root cause of higher corticosterone induced learning and memory impairment in aging.This study intends to observe the degenerative changes of epigenetic modification enzyme protein (DNMT, HACT, HDAC, MeCP2)and RNA interference in rat hippocampal neural cells in vitro and in vivo, with MSP, ChIP, micro-RNA microarray, Q-RT-PCR, Western blot and other molecular biology techniques, and to analyze molecular mechanisms of high corticosterone →hippocampal GR→ down regulated key proteins releated tolearning and memory (arc, Syn1 and Gabra5 etc.) from the perspective of gene epigenetic modifications. This study also intends to observe the interference effect of kidney-tonifying recipe, Qi-benefiting recipe and active ingredients of traditional Chinese medicine on degenerative changes of those above indicators and provide experimental basis and new targets for reinforcing kidney and replenishing qi to nourish the brain.

英文关键词： anti-aging;cordicosterone;epigenetic modification;learning and memory;Tonifying Kidney and Yi-Qi recipe