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

• 批准号: 9910466
• 负责人: Surachai Supattapone
• 金额: $ 55.38万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910466
• 关键词: Affect; Alzheimer' 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; Natural Resistance; 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; prion hypothesis; prion-like; public health relevance; recombinant PrP; reconstitution; targeted treatment; tool

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.

项目摘要 朊病毒病是由诱导的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， 构象异构体，PrPSc。目前，没有疫苗或治疗方法可用于这些疾病。 总是致命的疾病，主要是因为我们不了解的机制， PrPSc形成。 有趣的是，不同的宿主对朊病毒感染的易感性存在很大差异， 不同的动物物种。例如，兔子似乎对所有朊病毒株都有抵抗力， 而河岸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，以确定关键步骤PrPSc 所有物种共享的结构。使用我们在科学研究中开发的严格的生物化学工具， 实验室，我们将利用这些自然发生的差异，宿主易感性， 剖析朊病毒复制的机制具体来说，这种强大的比较 生物化学方法将用于实现以下目标： 1.直接检验朊病毒传染性的蛋白质假说。 2.识别和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。 这个项目的结果将大大推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朊病毒样疾病的理解， 如阿尔茨海默氏症和帕金森氏症。