CONSTRUCTION OF TET REGULATED PSI TRANSGENICS

TET 调节的 PSI 转基因的构建

• 批准号: 6071990
• 负责人: Karen Duff
• 金额: $ 7.38万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6071990
• 关键词: Alzheimer's disease; amyloid proteins; disease /disorder etiology; disease /disorder model; gene expression; genetically modified animals; laboratory mouse; model design /development; neuritic plaques; presenilin; protein metabolism; tetracyclines

Alzheimer's disease (AD) is characterized by the presence of amyloid plaques and intracellular tau tangles in the brain. Amyloid plaques are composed of a core of beta amyloid (Abeta) which is derived by the proteolytic processing of the amyloid precursor protein (APP). Mutations found in APP that affect the processing the precursor protein into Abeta are associated with the development of familial AD. This circumstantial evidence strongly suggests that Abeta accumulation and/or deposition causes AD (at least in patients with APP mutations) and that modulation of Abeta levels or deposited Abeta may allow therapeutic intervention against the disease. The best animal model in which to study the deposition of amyloid is a transgenic mouse that over-expresses both mutant presenilin-l (PSl) and APP. This line of animal form amyloid deposits by 12 weeks of age. Since mutant PSl elevates Abeta levels in the APP mouse, switching off PSl expression would be expected to reduce Abeta levels. Our overall aim is to investigate whether reducing Abeta levels by switching off Psl after deposits have formed can lead to resolution of the plaques in doubly transgenic tet-PS1/APP mouse model. To do this, we wish to generate a transgenic mouse that constitutively expresses mutant PSl which can be switched off after administration of the tetracycline analogue, doxycycline. Having achieved this, we will seek further funding to cross tet-PSl with APP mice for the study of amyloid stability.

阿尔茨海默病（AD）的特征在于脑中存在淀粉样蛋白斑块和细胞内tau缠结。淀粉样蛋白斑块由β淀粉样蛋白（Abeta）核心组成，其通过淀粉样蛋白前体蛋白（APP）的蛋白水解加工而衍生。在APP中发现的影响前体蛋白加工成Abeta的突变与家族性AD的发展相关。这种间接证据强烈表明，A β积累和/或沉积导致AD（至少在APP突变的患者中），并且A β水平或沉积A β的调节可能允许针对该疾病的治疗干预。研究淀粉样蛋白沉积的最佳动物模型是过表达突变型早老素-1（PS1）和APP的转基因小鼠。由于突变型PS1升高APP小鼠中的Abeta水平，因此关闭PS1表达将预期降低Abeta水平。我们的总体目标是研究在沉积物形成后通过关闭Psl来降低Abeta水平是否可以导致双转基因tet-PS1/APP小鼠模型中斑块的消退。为此，我们希望产生组成型表达突变体PS1的转基因小鼠，所述突变体PS1可以在施用四环素类似物多西环素后关闭。在实现这一点之后，我们将寻求进一步的资金来将tet-PSl与APP小鼠杂交以研究淀粉样蛋白的稳定性。