Mechanisms of Transmissibility in Prion Diseases

 描述(由申请者提供)：该计划项目的长期目标是促进对Pron疾病的致病过程的了解，特别关注阐明这些疾病的传播机制。主要的具体目标是：(I)确定Pron蛋白构象转换和Pron繁殖的结构机制；(Ii)促进对Prion菌株和传递性障碍的分子水平的了解；(Iii)阐明控制家族型和非典型型人类Pron疾病的传播性和表型变异的分子和结构决定因素。对这项研究中提出的问题的回答对于理解致病过程以及从更实用的药物干预和公共卫生安全的角度来说是至关重要的。该方案由三个核心支持的三个综合和互动研究项目构成。每个单独的研究项目处理总体目标的不同但密切相关的方面，使用不同的实验工具，在不同的组织和复杂程度上接近它们。研究项目1的重点是阐明PrPSc蛋白转化的结构基础和具有感染性的PrPSc构象的结构。该项目还试图确定PrPSc中的特定结构差异，这些差异是人类PrPSc疾病表型差异的基础。研究项目2侧重于与Pron菌株和传播性障碍以及Prion有关的问题 心理治疗。利用PMCA技术、结构研究和生物测定，本项目试图(I)阐明控制Pron从动物向人类传播的障碍所涉及的机制；(Ii)探索不同器官的特定环境影响Pron菌株的选择及其复制潜力的机制；(Iii)开发Pron病的新治疗策略。研究项目3的重点是人类Prion疾病，力求(I)更好地了解这些疾病的表型变异的控制机制；(Ii)了解Prion蛋白糖基化在某些类型的这些疾病中的作用；以及(Iii)阐明不同形式的人类Prion疾病之间传播性大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、动物和神经病理学中心的支持，这些中心将在研究管理和协调、动物研究的所有方面以及动物和人类组织的准备和神经病理学特征方面提供共同服务。

 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.