78kD葡萄糖结合蛋白(GRP78)在核糖糖化中的作用及细胞死亡机制

项目名称： 78kD葡萄糖结合蛋白(GRP78)在核糖糖化中的作用及细胞死亡机制

项目编号： No.31270868

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 赫荣乔

作者单位： 中国科学院生物物理研究所

项目金额： 90万元

中文摘要： 蛋白质的非酶糖基化（简称蛋白糖化）不但使蛋白质丧失生物学功能，同时可以产生具有细胞毒性的糖基化蛋白终末产物，导致细胞功能紊乱，乃至死亡。非酶糖基化蛋白的升高，常见于糖尿病等代谢性疾病，并与糖尿病的并发症的发生发展密切相关。然而，在过去的几十年里，大量的报道集中在葡萄糖代谢及其相关途径方面，但对于核糖导致的蛋白质非酶糖基化的研究非常少。由于核糖的特殊结构，使其具有很强的蛋白非酶糖基化性质。申请者的实验室前期工作表明：核糖糖基化性质远比葡萄糖活泼，能够迅速与蛋白质发生反应，形成具有明显细胞毒性的产物。本项目拟建立核糖非酶糖基化的细胞模型、核糖导致的认知功能障碍动物模型（鼠模型），研究78 kD葡萄糖调节蛋白（GRP78）、Tau、突触核蛋白等的核糖非酶糖基化及其功能变化，糖化后的细胞毒性；核糖非酶糖基化在细胞内的发生以及相关代谢途径，阐明核糖非酶糖基化导致动物的认知功能障碍的分子机制。

中文关键词： 核糖；葡萄糖结合蛋白；核糖糖基化；糖尿病；阿尔茨海默病

英文摘要： Glycation not only resultes in dysfunction of a protein but also produces cytotoxic advanced glycation end products, which lead to cellular metabolic problems and even cell death. Increase in glycated protein is commonly observed in metabolic disorders especially in diabetes. The increase in concentrations of glycated protein is closely related with the complications of diabetes. However, for several decades, D-glucsoe and the related pathways have been paid great attentions to the glycations and diabetic complications. Very few groups have investigated the relationship between D-ribose and glycation, and the resultant advanced glycation end products. In fact, D-ribose is very active in glycation because of its special chemical characteristics. As shown by our previous work, ribosylation is much more active than glycosylation, rapidly reacting with protein and formation of cytotoxic products. Here, the applicants attempt to establish the D-ribose-glycated cell models as well as D-ribosed-glycated cognitive impairment animal models (mouse and rat), in order to study ribosylated 78 kD glucose regulated protein (GRP78), Tau, alpha-synuclein and changes in functions and the resultant cytotoxic products. Occurence and development of ribosylation in vivo and the related pathological pathways would clarify the mechanis

英文关键词： D-ribose；glucose-regulated protein 78 kD (GRP78)；ribosylation；diabetes；Alzheimer’s disease