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 编码淀粉样蛋白前体蛋白 (APP) 的基因突变和两个 具有 7-9 个跨膜结构域的相关蛋白 (PS1/PS2)。 使用 最近开发的表达质粒，我们建议创建表达小鼠 野生型 (wt) 和相对较高水平（少于内源性的 4 倍） 突变体 PS1/PS2，并确定神经生物学/神经病理学 这些动物的表型。 此外，作为持续努力的一部分 使用 cDNA 和酵母人工生成 APP 连接的 FAD 模型 染色体/胚胎干细胞方法，我们生产了多只小鼠 表达wt和人类APP的系； wt和突变体的影响 Ps1/PS2 对 APP 生物学的影响可以在携带两者的小鼠中进行检查 转基因。 几条证据强烈鼓励我们这样做 努力：表达质粒载体驱动APP和PS1的表达 以相对依赖复制​​的方式；使用这些方法，我们有 已经产生了携带 PS1-wt 和 PS1-A246E cDNA 转基因的创始人 和PS1核酸探针和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体 PS1 （大约是内源性的 5 倍）。 我们预计小鼠表达高 PS1/PS2 突变水平会导致行为/大脑异常 与 FAD 共享功能。 此外，通过育种范式， APP转基因或无效小鼠可用于探索相互作用 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 转基因模型的开发 其研究将阐明疾病的机制。 而且因为 我们计划让这些动物被广泛使用，以便它们能够被利用 其他研究人员正在测试 AD 的新疗法。