MURINE TRANSGENIC MODELS OF PRION DISEASES

描述(摘自申请者摘要)：本项目的总体目标 是利用转基因(TG)小鼠作为人类家族性Pron疾病的模型， 它们与编码该基因的点突变和插入突变有关 20号染色体上的蛋白(PrP)。我们之前已经构建了 表达PrP分子并插入九个八肽的转基因小鼠 与家族性克雅氏病相关的突变(PG14) 人类。这些TG(PG14)小鼠发展为进行性神经疾病 以共济失调为特征，小脑颗粒细胞凋亡，点状 PrP沉积和星形细胞胶质细胞增生症。此外，从出生开始， 小鼠大脑中积累了突变的PrP分子，显示出主要的 PrP的致病亚型PrPSc的生化特征。因此，Tg(PG14) 小鼠概括了几种基本的临床、神经病理学和 遗传性人类普恩病毒病的生化特征。这些老鼠提供了一种 研究家族Pron的分子和细胞基础的难得机会 活体环境中的疾病，并建立合理的基础 未来开发更有效的诊断和治疗方式。 本申请的目的是进一步研究 转基因小鼠的PG14突变，以期了解突变 PrP分子导致家族性PrP疾病的病理，以及什么 PrPSc异构体在这一过程中发挥作用。我们计划：(1)创建新的线路 其中突变型PrP的表达受神经元特异性和 可诱导启动子；(2)研究突变PrP是否被 泛素蛋白酶体在甘油三酯(PG14)神经病理中的作用 小鼠；以及(3)比较病毒的分子、致病和传播特性。 两种形式的突变PrP，它们的蛋白水解度显著不同 抵抗。

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.