MURINE TRANSGENIC MODELS OF PRION DISEASES

朊病毒疾病的小鼠转基因模型

• 批准号: 6823263
• 负责人: DAVID A HARRIS
• 金额: $ 55.62万
• 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 2006-08-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6823263
• 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朊病毒疾病的模型， 这些突变与编码 朊病毒蛋白（PrP）在20号染色体上。我们之前已经构建了 转基因小鼠表达带有九个八肽插入序列的PrP分子， 与家族性克雅氏病相关的突变（PG 14）， 人类这些Tg（PG 14）小鼠发展为进行性神经障碍， 以共济失调、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， 小鼠在大脑中积累突变的PrP分子， PrPSc的生化标志，PrP的致病同种型。因此，Tg（PG 14） 小鼠概括了几个基本的临床，神经病理学， 遗传性人类朊病毒病的生化特征。这些老鼠提供了 研究家族性朊病毒的分子和细胞基础的独特机会 在体内环境中的疾病，并建立一个合理的基础， 未来开发更有效的诊断和治疗方式。 本申请的目的是对本发明的化合物进行进一步的研究。 转基因小鼠中的PG 14突变，以期了解突变体如何 PrP分子导致家族性朊病毒疾病的病理学改变， PrPSc同种型在此过程中发挥的作用。我们计划：（1）创建新线路 其中突变型PrP的表达受神经元特异性和 诱导型启动子;（2）研究突变型PrP是否被 泛素-蛋白酶体在Tg（PG 14）中观察到的神经病理学中起作用 小鼠;和（3）比较的分子，致病性，和传输特性， 两种形式的突变PrP，其蛋白酶的程度显著不同， 阻力