Mechanisms of Transmissibility in Prion Diseases

朊病毒疾病的传播机制

• 批准号: 8930045
• 负责人: WITOLD K SUREWICZ
• 金额: $ 153.2万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8930045
• 关键词: Address; Advanced Development; Affect; Amino Acids; Amyloid Fibrils; Animals; Area; Biochemical; Biological Assay; Brain; Characteristics; Clinical; Collaborations; Data; Development; Disease; Environment; Genetic Polymorphism; Goals; Human; In Vitro; Indium; Individual; Knowledge; Laboratories; Length; Modeling; Molecular; Neurodegenerative Disorders; Organ; Outcomes Research; Participant; Pathogenesis; Phenotype; Population; PrP; PrPSc Proteins; Preparation; Prion Diseases; Prions; Process; Property; Protein Glycosylation; Proteins; Public Health; Recombinants; Research; Research Project Grants; Resolution; Rodent; Role; Safety; Self Concept; Series; Services; Structure; Technology; Tissues; animal tissue; base; cervid; conformational conversion; conformer; disease diagnosis; disease phenotype; disease transmission; fundamental research; glycosylation; human tissue; neuropathology; novel; novel therapeutics; pathogen; preference; prion-based; programs; public health intervention; public health relevance; therapeutic development; tool; treatment strategy

 DESCRIPTION (provided by applicant): The long-term objective of this Program Project is to advance the understanding of the pathogenic process in prion diseases, with a special focus on elucidating the mechanisms by which these diseases are transmitted. The major specific goals are: (i) Determine structural mechanisms of prion protein conformational conversion and prion propagation; (ii) Advance molecular level understanding of prion strains and transmissibility barriers; (iii) Elucidate molecular and structural determinants that control transmissibility and phenotypic variability of familial and atypical forms of human prion diseases. Answers to questions addressed in this research are of fundamental importance for understanding the pathogenic process and from a more practical perspective of pharmacological intervention and public health safety. The Program has been structured into three integrated and interactive Research Projects supported by three Cores. Each individual Research Project addresses different, yet closely related, aspects of the overall goals, approaching them using different experimental tools and at different levels of organization and complexity. The main focus of Research Project 1 is on elucidating the structural basis of prion protein conversion and the structure of the infectious PrPSc conformer. This Project also seeks to identify specific structura differences in PrPSc that underlie phenotypic variability of human prion diseases. Research Project 2 focuses on issues related to prion strains and transmissibility barriers as well as prion therapy. Using PMCA technology, structural studies and bioassays, this Project seeks to (i) elucidate the mechanisms involved in controlling barriers for prion transmissibility from animals to humans; (ii) explore the mechanism by which the specific environment of different organs affects the selection of prion strains and their replication potential; (iii) develop a novel therapeutic strategy in prion disease. The focus of Research Project 3 is on human prion diseases, seeking to (i) develop better understanding of mechanisms controlling phenotypic variability of these disorders; (ii) understand the role of prion protein glycosylation in some fors of these diseases and (iii) elucidating the biochemical and structural basis of large differences i transmissibility between different forms of human prion diseases (in collaboration with Project 1). Each of these three Research Projects will be supported by the Administrative, Animal and Neuropathology Cores that will provide common services with regard to research administration and coordination, all aspects of animal studies, and preparation and neuropathological characterization of animal and human tissue.

 描述（由适用提供）：该计划项目的长期目的是提高对病毒疾病的致病过程的理解，特别着重于阐明这些疾病传播的机制。主要的具体目标是：（i）确定prion蛋白构象转化率和prion传播的结构机制； （ii）提高分子水平对王室菌株和传播障碍的理解； （iii）阐明分子和结构确定源，以控制家族和非典型形式的人类主要疾病的传播和表型变异性。这项研究中解决的问题的答案对于理解病原过程以及从更实际的药物干预和公共卫生安全的角度而言至关重要。该计划已结构为三个核心支持的三个集成和互动研究项目。每个单独的研究项目都解决了整体目标的不同但密切相关的各个方面，并使用不同的实验工具以及不同的组织和复杂性来接触它们。研究项目1的主要重点是阐明主要蛋白转化率的结构基础和感染性PRPSC构象异构体的结构。该项目还旨在确定人类pr疾病的表型变异性的PRPSC的特定结构差异。研究项目2重点介绍与王室应变和传输障碍以及prion的问题 治疗。该项目使用PMCA技术，结构研究和生物测定仪，旨在（i）阐明控制从动物向人类传播的障碍物传播障碍所涉及的机制； （ii）探索不同器官的特定环境影响prion菌株及其复制潜力的机制； （iii）制定一种新型的病毒疾病治疗策略。研究项目3的重点在于人类学术疾病，试图（i）更好地理解控制这些疾病的表型变异性的机制； （ii）了解prion蛋白糖基化在这些疾病的某些孔中的作用，以及（iii）阐明不同形式的人类prion疾病之间的巨大差异的生化和结构性基础（与项目1合作）。这三个研究项目中的每一个都将得到行政，动物和神经病理学核心的支持，这些核心将提供有关研究管理和协调，动物研究的各个方面以及动物和人类组织的制备和神经病理学表征的共同服务。