Mechanisms of Transmissibility in Prion Diseases

 描述（由申请人提供）：本计划项目的长期目标是促进对朊病毒疾病致病过程的理解，特别关注阐明这些疾病传播的机制。主要的具体目标是：（i）确定朊病毒蛋白构象转换和朊病毒繁殖的结构机制;（ii）推进对朊病毒株和传播障碍的分子水平理解;（iii）阐明控制家族性和非典型形式人类朊病毒疾病的传播性和表型变异性的分子和结构决定因素。在这项研究中解决的问题的答案是至关重要的了解致病过程，并从更实际的角度来看，药理学干预和公共卫生安全。该计划已被结构化为三个综合和互动的研究项目，由三个核心支持。每个单独的研究项目都涉及总体目标的不同但密切相关的方面，使用不同的实验工具以及不同的组织和复杂程度来接近它们。研究项目1的主要重点是阐明朊病毒蛋白转化的结构基础和感染性PrPSc构象异构体的结构。该项目还试图确定PrPSc的特定结构差异，这些差异是人类朊病毒疾病表型变异的基础。研究项目2的重点是与朊病毒株和传播障碍以及朊病毒有关的问题 疗法本项目利用PMCA技术、结构研究和生物测定，旨在（i）阐明朊病毒从动物到人类传播障碍的控制机制;（ii）探索不同器官的特定环境影响朊病毒菌株选择及其复制潜力的机制;（iii）开发朊病毒疾病的新治疗策略。研究项目3的重点是人类朊病毒疾病，旨在（i）更好地了解控制这些疾病表型变异的机制;（ii）了解朊病毒蛋白糖基化在这些疾病中的作用;（iii）阐明不同形式的人类朊病毒疾病之间传播性差异的生化和结构基础（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、动物研究的所有方面以及动物和人体组织的制备和神经病理学表征的共同服务。

 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.