CHARACTERIZATION OF PRION STRAINS AND INFECTIVITY

朊病毒株的特征和感染性

• 批准号: 8095484
• 负责人: HEATHER L TRUE-KROB
• 金额: $ 7.6万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8095484
• 关键词: Address; Adopted; Alzheimer' s Disease; Amyloid; Amyloid fibers; Biochemical; Biological; Biological Models; Brain; Cells; Cellular Stress; Clinical; Data; Development; Disease; Fiber; Future; Genetic; Huntington Disease; In Vitro; Infection; Infectious Agent; Inherited; Kinetics; Laboratories; Methods; Modeling; Molecular Chaperones; Molecular Conformation; Mouse Strains; Nature; Neurodegenerative Disorders; Oxidative Stress; Parkinson Disease; Pathology; Pilot Projects; Positioning Attribute; PrP; Prion Diseases; Prions; Process; Protein Isoforms; Protein Structure Initiative; Proteins; Recombinants; Reporter; Sampling; Stress; Structure; System; Temperature; Thinking; Variant; Work; Yeasts; amyloid structure; base; chronic wasting disease of elk and deer; human disease; novel; prion-based; prion-like; protein aggregate; protein misfolding; recombinant PrP; sup35; three dimensional structure; transmission process; yeast prion

DESCRIPTION (provided by applicant): Most protein conformational disorders have both sporadic and inherited forms. Prion diseases, also known as Transmissible Spongiform Encephalopathies (TSEs), are unique in that they also have infectious origins. The TSE infectious agent is a self-propagating pathological isoform of the prion protein, PrP. Proteins involved in various other neurodegenerative diseases form similar self-propagating amyloid structures, but only recently have some of those protein aggregates been hypothesized to be potentially infectious. The infectious origin of TSEs relies upon transmission and propagation of the prion protein in its aggregation-prone conformation. Although the infectious mechanism and fundamental pathology is conserved in TSEs of different species, cross-species transmission can be very inefficient. The defining factors of this prion species barrier are unknown but are likely related to the capacity of prion proteins to propagate in different conformations (prion strains). In this pilot project make use of a yeast prion model system that does not rely on the development of clinical disease to assess prion transmissibility and the propensity for replication. We will address two important questions that will enhance our understanding of the prion strains and the differences between infectious and non-infectious amyloid 1) What makes an amyloid structure infectious or non-infectious? 2) What controls "species barriers" that limit infection and prion transmissibility? We are in a position to address these questions in a unique manner based on the systems that we have developed and the results we have obtained thus far. This pilot project will allow us to begin to utilize our system for structural work and develop and characterize a similar system for PrP. PUBLIC HEALTH RELEVANCE: The ability of a cell to stay alive and function normally depends on the concerted effort of many proteins. Proteins need to be properly folded in a particular three dimensional structure for full functionality and this folding process requires helper molecules called chaperones. The inability of proteins to maintain proper folding is the cause of several devastating human diseases. We are investigating how the process of protein misfolding occurs, how it propagates, and how these problems can be corrected in the cell.

描述（由申请人提供）：大多数蛋白质构象紊乱都有散发性和遗传性两种形式。朊病毒病也称为传染性海绵状脑病 (TSE)，其独特之处在于它们也具有传染性起源。 TSE 感染因子是朊病毒蛋白 PrP 的一种自我繁殖的病理亚型。参与各种其他神经退行性疾病的蛋白质形成类似的自我繁殖淀粉样蛋白结构，但直到最近才假设其中一些蛋白质聚集体具有潜在的传染性。 TSE 的感染起源依赖于易聚集构象的朊病毒蛋白的传播和繁殖。尽管不同物种的 TSE 的感染机制和基本病理学是保守的，但跨物种传播的效率可能非常低。这种朊病毒物种屏障的决定因素尚不清楚，但可能与朊病毒蛋白以不同构象（朊病毒株）繁殖的能力有关。在该试点项目中，利用酵母朊病毒模型系统，该系统不依赖于临床疾病的发展来评估朊病毒的传播性和复制倾向。我们将解决两个重要问题，以增强我们对朊病毒株以及传染性和非传染性淀粉样蛋白之间差异的理解：1) 淀粉样蛋白结构具有传染性或非传染性的原因是什么？ 2) 是什么控制着限制感染和朊病毒传播的“物种屏障”？我们能够根据我们开发的系统和迄今为止所获得的结果，以独特的方式解决这些问题。这个试点项目将使我们能够开始利用我们的系统进行结构工作，并开发和表征 PrP 的类似系统。 公共健康相关性：细胞保持活力和正常功能的能力取决于许多蛋白质的共同努力。蛋白质需要在特定的三维结构中正确折叠才能发挥全部功能，并且此折叠过程需要称为伴侣的辅助分子。蛋白质无法维持正确的折叠是导致多种毁灭性人类疾病的原因。我们正在研究蛋白质错误折叠过程如何发生、如何传播以及如何在细胞中纠正这些问题。