RAGE介导Aβ经内质网应激损伤血脑屏障的机制及益智防呆方的干预研究

项目名称： RAGE介导Aβ经内质网应激损伤血脑屏障的机制及益智防呆方的干预研究

项目编号： No.81473739

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： 李亚明

作者单位： 复旦大学

项目金额： 70万元

中文摘要： Aβ可通过内质网应激（ERS）介导细胞凋亡，损伤血脑屏障（BBB），从而促进阿尔茨海默病（AD）发生发展。晚期糖基化终产物受体（RAGE）作为Aβ神经毒性的重要调节因子，在Aβ损伤BBB中发挥重要作用。有研究表明ERS具有RAGE依赖性。我们前期研究也发现Aβ可诱导BBB上RAGE表达增加。故我们推测：RAGE在Aβ介导BBB损伤中起着桥梁作用并放大该反应，而阻断该路径可有效抑制Aβ对BBB的损伤，从而缓解AD发展。本项目将采用体外BBB模型和APP/PS1转基因小鼠，分别从细胞、分子水平观察Aβ损伤BBB时RAGE表达、ERS相关蛋白等的变化及相互作用，探究RAGE介导Aβ经ERS损伤BBB的分子机制，阐释AD发病机理；同期施以临床有效组方-益智防呆方，观察其干预效应，以揭示培元填精、化痰祛瘀法治疗AD的现代医学原理，既为AD治疗提供新思路，也是中医治则治法现代化研究的丰富。

中文关键词： 阿尔茨海默病；血脑屏障；β淀粉样蛋白；内质网应激；益智防呆方

英文摘要： Aβ can induce apoptosis via endoplasmic reticulum stress (ERS), thus damage the blood brain barrier (BBB) and exacerbate the Alzheimer's disease (AD) course. The receptor for advanced glycation end products (RAGE)is an important regulatory factor of Aβneurotoxicity, and acts as a crucial role in the BBB damage induced by Aβ. Evidence shows tha ERS is RAGE-dependent, and our own studies show that Aβcan increase RAGE expression in BBB.Therefore, we speculate that RAGE has a role in the progress of the BBB damage caused by Aβvia ERS,and blocking the interaction can attenuate AD. We will take the BBB model and APP/PS1 AD model mice to study the change of ERS related proteins in vitro and in vivo, and further explore the role of RAGE, and reveal the complex relationship of Aβ-RAGE with BBB damage caused by Aβvia ERS. Meanwhile, we utilize YiZhi-FangDai Fang to interfere this progress to uncover the mechanism of this formula's therapeutic effect and the principle of replenishing primoridal jing and essense, reducing phlegmas and eliminating blood stasis. We hope this can offer a new therapeutic method for AD and rich the modernization research of traditional chinese medicinal therapeutic rules.

英文关键词： Alzheimer's disease;Blood brain barrier;β-amyloid peptide;Endoplasmic reticulum stress;YiZhi-FangDai Fang