MURINE TRANSGENIC MODELS OF PRION DISEASES

朊病毒疾病的小鼠转基因模型

• 批准号: 6886647
• 负责人: DAVID A HARRIS
• 金额: $ 3.06万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-15 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6886647
• 关键词: disease /disorder model; gene induction /repression; genetic promoter element; genetically modified animals; laboratory mouse; model design /development; point mutation; prions; spongiform encephalopathy; tetracyclines; transposon /insertion element; ubiquitin

DESCRIPTION (From the Applicant's Abstract): The overall goal of this project is to utilize transgenic (Tg) mice as models for human familial prion diseases, which are linked to point and insertional mutations in the gene encoding the prion protein (PrP) on chromosome 20. We have previously constructed lines of transgenic mice that express a PrP molecule with a nine-octapeptide insertional mutation (PG14) associated with a familial form of Creutzfeldt-Jakob disease in humans. These Tg(PG14) mice develop a progressive neurological disorder characterized by ataxia, apoptosis of cerebellar granule cells, punctate deposition of PrP, and astrocytic gliosis. In addition, beginning at birth the mice accumulate mutant PrP molecules in their brains that display the major biochemical hallmarks of PrPSc, the pathogenic isoform of PrP. Thus, Tg(PG14) mice recapitulate several of the essential clinical, neuropathological, and biochemical features of inherited human prion diseases. These mice offer a unique opportunity to study the molecular and cellular basis of familial prion diseases in an in vivo setting, and to establish a rational basis for the future development of more effective diagnostic and therapeutic modalities. The purpose of the present application is to carry out further studies of the PG14 mutation in transgenic mice, with a view toward understanding how mutant PrP molecules cause the pathology seen in familial prion diseases, and what role the PrPSc isoform plays in this process. We plan to: (1) create new lines of Tg in which expression of mutant PrP is controlled by neuron-specific and inducible promoters; (2) investigate whether degradation of mutant PrP by theubiquitin-proteasome plays a role in the neuropathology observed in Tg(PG14) mice; and (3) compare the molecular, pathogenic, and transmission properties of two forms of mutant PrP that differ significantly in their degree of protease resistance.

描述（来自申请人的摘要）：该项目的总体目标 是利用转基因（Tg）小鼠作为人类家族性朊病毒疾病的模型， 这与编码基因中的点突变和插入突变有关 20号染色体上的朊病毒蛋白（PrP）。我们之前构建了 表达带有九个八肽插入物的 PrP 分子的转基因小鼠 与家族性克雅氏病相关的突变（PG14） 人类。这些 Tg(PG14) 小鼠出现进行性神经系统疾病 特征为共济失调、小脑颗粒细胞凋亡、点状 PrP 沉积和星形胶质细胞增生。此外，从出生开始 小鼠大脑中积累了突变的 PrP 分子，这些分子显示出主要的 PrPSc（PrP 的致病亚型）的生化特征。因此，Tg(PG14) 小鼠概括了一些基本的临床、神经病理学和 遗传性人类朊病毒疾病的生化特征。这些小鼠提供了 研究家族性朊病毒分子和细胞基础的独特机会 体内疾病，并为该疾病建立合理的基础 未来开发更有效的诊断和治疗方式。 本申请的目的是对该问题进行进一步的研究 转基因小鼠PG14突变，以期了解突变是如何发生的 PrP 分子引起家族性朊病毒病的病理学，以及什么 PrPSc 同种型在此过程中发挥的作用。我们计划：（1）创建新线路 Tg，其中突变型 PrP 的表达受神经元特异性和 诱导型启动子； (2)研究突变体PrP是否​​被降解 泛素蛋白酶体在 Tg(PG14) 中观察到的神经病理学中发挥作用 老鼠； (3) 比较病毒的分子、致病性和传播特性 两种形式的突变型 PrP 的蛋白酶程度显着不同 反抗。