TRANSGENIC MODELS OF FAMILIAL ALZHEIMER'S DISEASE

家族性阿尔茨海默病转基因模型

• 批准号: 6299372
• 负责人: DONALD L PRICE
• 金额: $ 33.13万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-15 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6299372
• 关键词: Alzheimer's disease; amyloid proteins; disease /disorder model; gene mutation; genetic disorder; genetically modified animals; laboratory mouse; membrane proteins; model design /development; polymerase chain reaction; protein biosynthesis; protein transport

Autosomal dominant familial Alzheimer's disease (FAD) has been linked to mutations in genes that encode amyloid precursor proteins (APP) and two related proteins (PS1/PS2) with 7-9 transmembrane domains. Using a recently developed expression plasmid, we propose to create mice expressing relatively high level (less than 4 times endogenous) of wild-type (wt) and mutant PS1/PS2, and to determine the neurobiological/neuropathical phenotypes of these animals. Moreover, as part of an ongoing effort to generate models of APP-linked FAD using cDNA and yeast artificial chromosome/embryonic stem cell methods, we have produced a number of mouse lines that expressing wt and human APP; the influences of wt and mutant Ps1/PS2 on the biology of APP can be examined in mice harboring both transgenes. Several lines of evidence strongly encourage us in this effort: the expression plasmid vector drives the expression of APP and PS1 in a relatively copy-dependent manner; and using these approaches, we have already generated founders harboring PS1-wt and PS1-A246E cDNA transgenes and PS1 nucleic acid probes, and antibodies have demonstrated that our transgene construct expresses wt and mutant PS1 at relatively high levels (about 5 fold over endogenous). We anticipate that mice expressing high levels of mutant PS1/PS2 will develop behavioral/brain abnormalities that share features with FAD. Moreover, through breeding paradigms, lines of APP transgenic or null mice can be used to explore the interactions of PS1/PS2 and APP in the pathogenesis of disease. We are confident that these efforts will lead to development of transgenic models of FAD, the study of which will clarify the mechanisms of disease. Moreover because we plan to make these animals widely available so that they can be used by other investigators to test novel therapies for AD.

常染色体显性遗传家族性阿尔茨海默病（FAD）与以下疾病有关： 编码淀粉样前体蛋白（APP）的基因突变， 相关蛋白（PS1/PS2），具有7-9个跨膜结构域。 使用 最近开发的表达质粒，我们建议建立小鼠表达 相对高水平（小于内源性的4倍）的野生型（wt）和 突变体PS1/PS2，并确定神经生物学/神经病理学 这些动物的特征。 此外，作为目前努力的一部分， 用cDNA和酵母人工合成的APP连接的FAD模型 染色体/胚胎干细胞的方法，我们已经产生了一些小鼠 表达野生型和人APP的细胞系;野生型和突变型的影响 Ps1/PS2对APP生物学的影响可以在同时携带 转基因 有几条证据有力地鼓励我们这样做。 努力：表达质粒载体驱动APP和PS1的表达 以相对依赖于复制的方式;使用这些方法，我们 已经产生了携带PS1-wt和PS1-A246 E cDNA转基因的创始人 和PS1核酸探针，以及抗体已经证明，我们的 转基因构建体以相对高的水平表达野生型和突变型PS1 （约为内源性的5倍）。 我们预期高表达的小鼠 水平的突变PS1/PS2将发展行为/大脑异常， 与FAD共享功能。 此外，通过育种模式， APP转基因或无效小鼠可用于探索 PS1/PS2和APP在疾病发病机制中的作用。 我们有信心 这些努力将导致FAD的转基因模型的发展， 对它的研究将阐明疾病的机制。 而且由于 我们计划广泛提供这些动物， 其他研究人员来测试AD的新疗法。