The role of oxidative stress in the patho-aetiology of prion disorders using infected cell culture and animal models

使用受感染的细胞培养物和动物模型研究氧化应激在朊病毒疾病病理病因学中的作用

• 批准号: nhmrc : 114212
• 负责人: Prof Steven Collins
• 金额: $ 7.47万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2000
• 资助国家: 澳大利亚
• 起止时间: 2000-01-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/role-oxidative-stress-animal-models/77385
• 关键词: role; oxidative; stress; patho; aetiology

The transmissible spongiform encephalopathies (TSE; also known as prion diseases) are a biologically unique and fascinating group of invariably fatal diseases which primarily affect the brains of both humans and animals. In humans, sporadic Creutzfeldt-Jakob disease (CJD) is the most common form, while in animals it is the recent epidemic of bovine spongiform encephalopathy (mad cow disease), and its probable transmission to humans as new variant CJD, which has drawn so much attention to this group of disorders. The preponderance of scientific evidence now supports the belief that infectivity in TSEs relates predominantly (probably exclusively) to a protein (called the prion protein; PrP) which is normally found on the cell surface of a number of types of brain cells, including neurons. Transmissibility, and hence infectivity, is more correctly associated with a malfolded version of PrP into an abnormal shape which gives the mutant protein significantly different biological and biochemical properties, including relative resistance to breakdown by enzymes that metabolise proteins (proteases) and enhanced tendency to aggregate. However, the precise steps involved in this transformation to the abnormal infectious form of PrP are not known. Similarly, our understanding of how different folding and accumulation of this protein brings about disease is not clear. Nevertheless, as with other neurological diseases (eg Alzheimer's disease) which are a consequence of unexplained spontaneous premature degeneration of parts of the brain (neurodegenerative diseases), oxidative stress is increasingly believed to play a role. Oxidative stress is a generic term used to describe the enhanced production within a cell of small, very harmful, oxygen containing molecules which under normal circumstances can be successfully detoxified. This project involves a detailed study of the role of oxidative stress in the causation of prion diseases using both mouse and cell culture models.

传染性海绵状脑病（TSE;也称为朊病毒病）是一组生物学上独特而迷人的致命疾病，主要影响人类和动物的大脑。在人类中，散发性克雅氏病（CJD）是最常见的形式，而在动物中，最近流行的牛海绵状脑病（疯牛病）及其可能作为新的变异型克雅氏病传播给人类，这引起了人们对这组疾病的极大关注。现在，大量科学证据支持这样一种信念，即TSE的传染性主要（可能完全）与一种蛋白质（称为朊病毒蛋白; PrP）有关，这种蛋白质通常存在于许多类型的脑细胞（包括神经元）的细胞表面。传播性，因此感染性，更正确地与PrP的错误折叠版本到一个异常的形状，使突变蛋白质显着不同的生物学和生化特性，包括相对抵抗分解的酶代谢蛋白质（蛋白酶）和增强的趋势聚集。然而，这种转化为异常感染形式的PrP的确切步骤尚不清楚。同样，我们对这种蛋白质的不同折叠和积累如何导致疾病的理解也不清楚。然而，与其他神经系统疾病（如阿尔茨海默病）一样，这些疾病是大脑部分（神经退行性疾病）无法解释的自发性过早变性的结果，氧化应激越来越被认为起作用。氧化应激是一个通用术语，用于描述细胞内小的、非常有害的含氧分子的增强产生，这些分子在正常情况下可以被成功解毒。该项目涉及使用小鼠和细胞培养模型详细研究氧化应激在朊病毒疾病病因中的作用。