Dissecting the Mechanism of Prion Formation with a Permissive Host

项目摘要 Pron病是一种由诱导性 宿主编码的糖蛋白PrPC的构象变化为致病 整形器，PrPSc。目前，还没有针对这些疾病的疫苗或疗法。 总是致命的疾病，主要是因为我们不了解 PrPSc队形。 有趣的是，在宿主对Pron感染的易感性上， 不同的动物物种。例如，兔子似乎对所有的Pron菌株都有抵抗力， 而银行田鼠似乎是一种普遍的宿主。这种变化依赖于 PRP序列为我们提供了一个独特的机会来确定PrPSc中的关键步骤 形成了所有物种共有的队形。使用我们开发的严格的生化工具 实验室中，我们将利用这些自然产生的宿主易感性差异 剖析了Pron复制的机制。具体地说，这个强大的比较 生物化学方法将用于实现以下目标： 1.直接检验普恩病毒感染性的纯蛋白质假说。 2.鉴定和鉴定PrPC结构域，该结构域控制对PrP转换的敏感性。 3.确定辅因子分子和翻译后修饰是否限制 普恩病毒感染的宿主范围。 该项目的结果将极大地促进我们对Prion复制的理解 机制。它们还将影响我们对相关的、类病毒的疾病的理解， 比如阿尔茨海默氏症和帕金森氏症。

Project Summary Prion diseases are infectious neurodegenerative diseases caused by the induced conformational change of a host-encoded glycoprotein, PrPC, into a pathogenic conformer, PrPSc. Currently, there are no vaccines or therapies available for these invariably fatal diseases, primarily because we do not understand the mechanism of PrPSc formation. Interestingly, there are large differences in host susceptibility to prion infection between different animal species. For instance, rabbits appear to be resistant to all prion strains, while bank voles appear to be a universal host. This variation, which is dependent on PrP sequence, provides us with a unique opportunity to identify the key steps in PrPSc formation shared by all species. Using rigorous biochemical tools developed in our laboratory, we will exploit these naturally occurring differences in host susceptibility to dissect the mechanism of prion replication. Specifically, this powerful comparative biochemistry approach will be used to accomplish the following aims: 1. Directly test the protein-only hypothesis of prion infectivity. 2. Identify and characterize PrPC domains that control susceptibility to prion conversion. 3. Determine whether cofactor molecules and post-translational modifications restrict the host range of prion infection. The results of this project will greatly advance our understanding of the prion replication mechanism. They will also impact our understanding of related, prion-like diseases, such as Alzheimer's and Parkinson's disease.