中药野拔子基于α7 nAChR/RAGE调控促进AD神经血管单元修复的机制研究

项目名称： 中药野拔子基于α7 nAChR/RAGE调控促进AD神经血管单元修复的机制研究

项目编号： No.81473374

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： 刘睿

作者单位： 中国医学科学院医药生物技术研究所

项目金额： 73万元

中文摘要： 阿尔茨海默病（AD）发病机制复杂，缺乏有效防治药物。本课题前期证明α7nAChR、RAGE等形成AD神经血管单元(NVU)病理网络，α7nAChR经CaMK、MAPK、AKT特异干扰RAGE通路，缓解NVU损伤。近期又发现，中药野拔子活性单体可防治AD，既能选择性激动α7nAChR，又能适度抑制RAGE，有多途径的NVU保护作用，但其促进NVU修复的机制仍需深入研究。 本课题以α7nAChR作为RAGE调节蛋白进行确证研究，以NVU修复作为功能单位，对α7nAChR等分子的网点式通路进行探索研究，对野拔子单体开展抗AD机制研究，借助基因敲除、功能通路芯片等技术，在基因调控、信号转导等方面，探讨α7nAChR调节RAGE的关联通路及在NVU的有效调控网络，阐释野拔子基于α7nAChR/RAGE调控促进NVU修复的机制。为研究α7nAChR病理作用提供理论依据，为开发防治AD新药提供有效方法。

中文关键词： 野拔子；阿尔茨海默病；α7；烟碱型乙酰胆碱受体；晚期糖基化终末产物受体；神经血管单元

英文摘要： Alzheimer's disease (AD) is a progressive neurodegenerative disorder with multiple pathological mechanisms which are fallen within the neurovascular unit (NVU) pathological changes. Up to now, there are no effective drugs in the treatment of this disease. Under the support of previous project of National Natural Science Foundation of China, we found that several potential molecules form the pathological network involved in the mechanisms of injury of the NVU, such as α7 nAChR and RAGE. We also have evidenced that α7 nAChR specifically interferes RAGE expression and its signal transduction and alleviates NVU inflammation through CaMK, CREB, and AKT pathways. Recently, we found that several natural active compounds isolated from Elsholtzia Rugulosa (Labiatae) showed the effects on the prevention and treatment of AD. These compounds can specifically activate α7nAChR, and can inhibit RAGE expression as well. They exhibit the ability to protect the NVU through multiple pathways. But the role and mechanism that they act with α7 nAChR/RAGE regulation in the NVU still need to be investigated. This project aims to investigate and verify whether α7 nAChR acts as a RAGE-regulation protein, explore the disease-networks in the NVU possibly formed by α7 nAChR by using NVU as a local unit of the brain, and discover the mechanisms of natural active compounds isolated from Elsholtzia Rugulosa (Labiatae) in the treatment of AD through targeting α7 nAChR and RAGE molecules. This project will use the knockout and functional pathway protein chip technologies. And finally, we will illustrate the key molecular mechanisms of α7 nAChR in AD both in pathological signal network and the mechanisms of drug effects by α7 nAChR/RAGE regulation in the NVU. Thus, we will offer a theoretical basis to investigate the pathological role of α7 nAChR, and also provide an effective method for drug discovery of AD.

英文关键词： Elsholtzia Rugulosa;Alzheimer's disease;alpha7 nicotinic acetycholine receptor;the receptor for advanced glycation end products;the neurovascular unit