阻断肽适配子对AD治疗作用的研究

项目名称： 阻断肽适配子对AD治疗作用的研究

项目编号： No.30872721

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 金属学与金属工艺

项目作者： 吴江

作者单位： 吉林大学

项目金额： 29万元

中文摘要： 目前认为AD患者脑细胞内存在过量的Aβ，Aβ与Aβ30456;关乙醇脱氢酶（ABAD）结合，干扰了细胞内正常氧化还原过程，导致线粒体肿胀、神经元死亡。阻断肽ABAD-DP能竞争性抑制Aβ与ABAD结合，拮抗Aβ的毒性作用。但由于单独表达的阻断肽在体内易被内肽酶快速降解，同时不能保证在细胞内的正确折叠，从而影响它与Aβ结合，因此临床难以应用。本课题采用肽适配子原理，首先将ABAD-DP用绞架蛋白TRX以特定的构象表达在细胞内，确保阻断肽能够高效特异地同细胞内Aβ结合；进一步在我们以往的研究基础上，构建TRX1-ABAD-DP-TRX2表达盒，包装能够分泌表达肽适配子ABAD-DP的重组腺伴随病毒；进而验证了重组病毒对高表达Aβ的AD细胞模型和mAPP转基因小鼠的神经保护作用，为应用阻断肽适配子治疗AD提供新策略。

中文关键词： 阿尔茨海默病；Aβ30456;关乙醇脱氢酶；肽适配子；分子克隆

英文摘要： Aβ has been assigned a central role in the pathogenesis of Alzheimer disease. Aβ binds with Aβinding alcohol dehydrogenase(ABAD), rusulting in mitochondrial dysfunction and neuronal death. ABAD-DP, as a specific inhibitor between ABAD and Aβhas been demonstrated to effectively inhibit Aβnduced toxicity. However, a major conundrum with regard to its use is how to avert its rapid degradation by peptidases. Peptide aptamers are short peptides, usually embedded in scaffold proteins, which specifically bind to a given target protein under intracellular conditions. TRX1-ABAD-DP-TRX2 aptamer, a novel peptide aptamer, was constructed via inserting ABAD-DP into the modified human TRX and it was introduced into cells using an adeno-associated viral system which allowed its stable expression.Then the protective effects of TRX1-ABAD-DP-TRX2 were proved in the mAPP transgenic mice, holding promise for the prevention and treatment of Alzheimer disease.

英文关键词： Alzheimer disease;Aβinding alcohol dehydrogenase;Peptide aptamer;Molecular cloning