Dissecting the Mechanism of Prion Formation with a Permissive Host

用许可的宿主剖析朊病毒形成的机制

基本信息

批准号：
9512261
负责人：
Surachai Supattapone
金额：
$ 52.11万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9512261
关键词：
Affect Alzheimer&apos s Disease American Animals Biological Assay Biology Bovine Spongiform Encephalopathy Brain Brain Diseases Canis familiaris Cattle Chemicals Chronic Wasting Disease Communicable Diseases Comparative Biochemistry Creutzfeldt-Jakob Syndrome Data Deer Disease Disease Outbreaks Epidemic Equus caballus Etiology Event Glycoproteins Human In Vitro Infection Infectious Agent Laboratories Measures Microtus Molecular Molecular Conformation Mus Neurodegenerative Disorders Oryctolagus cuniculus Parkinson Disease Pathogenicity Patients Pattern Post-Translational Protein Processing PrP PrP sequence PrPSc Proteins Predisposition Prion Diseases Prions Process Proteins Public Health Reaction Recombinants Resistance Scrapie Series Sheep System Testing Therapeutic Intervention Time Titrations Vaccines Variant Work base biochemical tools cofactor combat conformer design drug development experimental study glycosylation in vivo insight misfolded protein permissiveness prion hypothesis prion-like public health relevance recombinant PrP reconstitution targeted treatment tool

项目摘要

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.

项目概要朊病毒病是由诱发性病毒引起的传染性神经退行性疾病宿主编码的糖蛋白 PrPC 的构象变化为致病性构象异构体，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其机制 PrPSc 形成。有趣的是，宿主对朊病毒感染的易感性存在很大差异。不同的动物种类。例如，兔子似乎对所有朊病毒株都有抵抗力，而银行田鼠似乎是万能宿主。这种变化取决于 PrP 序列为我们提供了一个独特的机会来识别 PrPSc 中的关键步骤所有物种共有的形成。使用我们开发的严格生化工具实验室中，我们将利用宿主易感性中自然发生的差异剖析朊病毒复制机制。具体来说，这种强有力的比较生物化学方法将用于实现以下目标： 1. 直接检验朊病毒感染性的纯蛋白质假说。 2. 识别并表征控制朊病毒转化易感性的 PrPC 结构域。 3.确定辅因子分子和翻译后修饰是否限制朊病毒感染的宿主范围。该项目的结果将极大地增进我们对朊病毒复制的理解机制。它们还将影响我们对相关的朊病毒样疾病的理解，例如阿尔茨海默病和帕金森病。