从蛋白质降解途径新视角探讨补肝养髓中药楮实子防治阿尔茨海默病的分子机制

项目名称： 从蛋白质降解途径新视角探讨补肝养髓中药楮实子防治阿尔茨海默病的分子机制

项目编号： No.81473742

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： 李映红

作者单位： 深圳大学

项目金额： 72万元

中文摘要： 构象病的概念是近年提出的分子医学新概念，被西方学者誉为人类在疾病认识史上的又一次飞跃，为阿尔茨海默病（AD）等 重大疑难疾病的防治开辟了新方向；基于蛋白质构象病分子机制的治疗措施不再是新的姑息疗法，而可能具有根治性的意义。AD为典型的神经变性构象病，目前现代医学治疗乏术。本项目立足多年研究基础，结合近年关于AD内质网应激（ERS）和蛋白质降解障碍的病理病机研究最新进展，拟采用补肝养髓天然中药楮实子，以离体实验（ERS细胞模型和AD细胞模型）与在体实验(快速老化小鼠)相结合，运用Realtime-PCR、Western blot、激光共聚焦成像等技术, 检测细胞内重要蛋白质降解途径（自噬溶酶体途径和泛素蛋白酶体系统）关键功能蛋白及神经细胞凋亡的变化；旨在从蛋白质降解新视角，在基因、分子和细胞水平探讨楮实子的神经元保护作用、作用靶点及其分子机制，为中医药防治AD等重大疑难疾病的研究拓展新思路。

中文关键词： 楮实子；阿尔茨海默病；构象病；自噬溶酶体途径；泛素蛋白酶体系统

英文摘要： Conformational disease is a new concept of molecular medicine proposed in recent years, which has been hailed by western scholars as another leap forward in the history of the understanding of human diseases. It has opened up a new direction for the prevention of Alzheimer's disease (AD) and other major incurable diseases. The treatment measures based on the molecular mechanisms of protein conformational disease is no longer a new palliative therapy, which may have a radical significance. Alzheimer's disease (AD) is a typical neurodegenerative protein conformational disease with high incidence rate in the global. At present，there is no ideal treatment method of modern medicine for it，however, Chinese medicine has accumulated rich experiences. This project is based on the basis of many years of research on AD, combining with the latest research progress of AD about the pathology and pathogenesis on endoplasmic reticulum stress (ERS) and protein degradation in disorder. In our study, AD cases will treated with Bugan Yangsui therapy method in according of the TCM principle from the liver. The natural Chinese herbal drug Fructus Broussonetae has the efficacy of reinforcing the liver and nursing the brain. So we will use it as our research drug to detect the key molecules in ERS signaling pathway, the key functional proteins in two important cell protein degradation pathways-autophagy lysosome pathway(ALP) and the ubiquitin proteasome system(UPS), as well as the changes in neuronal apoptosis, by applying Real time quantified PCR, Western blot, Flow cytometry(FCM), Confocal laser scanning microscopy(CLSM), Transmission electron microscopy, and other techniques, combining the experiment in vitro (ERS cell model induced by tunicamycin and AD cell model induced by Aβ) with the experiment in vivo (senescence- accelerated mouse-prone 8,SAM/P8). The results of this project will explore the neuronal protective effect of Fructus Broussonetae and the targets, interpret the molecular mechanism in the genetic, molecular and cellular levels, from the angle of ERS and its associated protein degradation pathway. It can expand a new idea for the research of TCM for the prevention and treatment of AD and other major diseases following important academic and social significance.

英文关键词： Fructus Broussonetae;Alzheimer's disease;C;autophagy lysosome pathway;ubiquitin proteasome system