基于转基因大肠杆菌模型从地衣内生真菌中寻找Aβ42聚集抑制剂

项目名称： 基于转基因大肠杆菌模型从地衣内生真菌中寻找Aβ42聚集抑制剂

项目编号： No.81202441

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 陈国栋

作者单位： 暨南大学

项目金额： 23万元

中文摘要： 随着阿尔茨海默病（AD）研究的不断深入，Aβ寡聚体的形成逐渐被认为是AD发病的关键，因此抑制Aβ聚集成为了研发治疗AD药物的重要靶点之一。目前已发现天然来源的Aβ42聚集抑制剂有植物来源和细菌来源的，真菌来源的尚未有报道。本课题组前期采用与AD相关的Aβ42聚集大肠杆菌模型对地衣内生真菌发酵提取物及馏分进行了筛选，发现5株地衣内生真菌发酵提取物的馏分具有明显抑制Aβ42聚集的活性。本项目基于前期工作基础，拟对具有抑制Aβ42聚集活性的菌株发酵提取物进行活性成分研究。在活性指导下运用多种色谱分离手段追踪分离活性化合物，阐明抑制Aβ42聚集的物质基础；拟通过改变菌株发酵条件扩充与活性化合物具有相似结构代谢产物的数量和多样性，在此基础上，进行构效关系研究，并利用ThT和哺乳动物细胞模型确定化合物活性，以期发现1-2个地衣内生真菌来源的Aβ42聚集抑制剂，为抗AD药物的研究提供新的来源。

中文关键词： 地衣内生真菌；阿尔茨海默病；Aβ42聚集抑制剂；；

英文摘要： More and more research indicated that the formation of Aβ oligomers is one of principal cause of synaptotoxicity associated with Alzheimer's disease, so inhibiting appearance of Aβ oligomers has been seen as one of promising therapeutic targets for treatment Alzheimer's disease. Aβ42 aggregation inhibitors have been reported from artificial synthesis, plants and bacteriums. However, no inhibitor has been found from fungus. During investigation on bioactive constituents from endolichenic fungus, eight fractions from five ethyl acetate extracts of endolichenic fungus displayed inhibition of Aβ42 aggregation in engineered Escherichia coli assays. In order to obtain the bioactive constituents, the chemical investigation of the extracts of endolichenic fungus with inhibition of Aβ42 aggregation will be carry out with different chromatographic separation technology. For enhancing diversity and quantity of the bioactive compound analogues produced by endolichenic fungus, optimization of fungal fermentative condition will be executed. The inhibition of Aβ42 aggregation of all compounds will be carried out using engineered Escherichia coli assays, and then quantitative structure-activity relationship (QSAR) of bioactive compounds will be analysed by CoMFA. In addition, the inhibition will be confirmed on standard thiofla

英文关键词： endolichenic fungi；Alzheimer’s disease；Aβ42 aggregation inhibitors；；