Maximizing research success in studies of naturally-occurring prion diseases

项目摘要/摘要 我的研究项目的广泛的、长期的目标是了解控制普里子传播的参数 以及物种内部和物种之间的进化，并最终防止在人类和动物中反复流行流行病。 慢性消耗性疾病(CWD)是一种在宫颈中迅速流行的流行病，其人畜共患潜力越来越不确定， 是这一总框架内的一个特别重点。我的研究小组是少数几个拥有这些资源的人之一 在转基因、细胞生物学、生化、分子遗传学和体外研究普恩病毒方面的专业知识 疾病。我们的产量对该领域产生了强大而持久的影响。此应用程序利用 与NINDS的长期关系是我作为NIH不间断资助记录的一个特点 独立调查员，任期26年。由于Prion研究需要长期的实验 承诺需要持续和高度协调的方法，本提案探讨了 具有更好的稳定性和灵活性的替代筹资机制，从而提高效率，从而 增强我们在创新、进行变革性研究和利用新技术方面的重要能力 事态的发展。此应用程序旨在通过解决以下问题来构建我们研究的前进轨迹 与自然发生的普恩病毒疾病有关的关键问题，特别是慢性萎缩性脑病。我们将解决 新出现的和已确定的CWD菌株的流行率、特性和来源；探索菌株的构象 和物种特有的PrP一级结构差异调节物种间的PrP传播；调查 稳定菌株表型或促进普鲁恩适应/进化的参数；解决所扮演的角色 在寄主的品系选择/适应中通过外周隔间和中枢神经系统；确定 已建立的和新出现的菌株对人类构成的风险；并决定慢性萎缩性脑病的结构特性 分离出高分辨率的普恩病毒。拟议的机制还提供了更多机会， 指导和监督学员和资深科学家，并优化我为以下项目创造遗产的能力 下一代独立调查员。

Project Summary / Abstract The broad, long-term goal of my research project is to understand the parameters controlling prion transmission and evolution within and between species, and ultimately to prevent recurrent epidemics in humans and animals. Chronic wasting disease (CWD), a burgeoning epidemic in cervids of increasingly uncertain zoonotic potential, is a particular focus within this general framework. My research group is one of only a handful with the resources and expertise in transgenic, cell biological, biochemical, molecular genetic and in vitro approaches to study prion diseases. Our output has exerted a powerful and sustained influence on the field. This application leverages a longstanding relationship with NINDS which is a feature of my uninterrupted record of NIH funding as an independent investigator for a period covering 26 years. Since prion studies require long-term experimental commitments requiring sustained and highly coordinated approaches, this proposal explores the feasibility of an alternate funding mechanism with improved stability and flexibility leading to improved efficiency which will enhance our already significant capacity to innovate, conduct transformative research, and capitalize on new developments. This application is designed to build on the advancing trajectory of our research by addressing key questions relating to naturally-occurring prion diseases with a particular focus on CWD. We will address the prevalence, properties and origins of emergent and established CWD strains; explore how strain conformations and species-specific PrP primary structural differences regulate interspecies prion transmission; investigate the parameters which stabilize strain phenotypes or promote prion adaptation/evolution; address the roles played by peripheral compartments and the central nervous system in strain selection/adaptation by the host; ascertain the risks posed by established and emergent strains to humans; and determine the structural properties of CWD prion strains at high resolution. The proposed mechanism also provides enhanced opportunities for dedicated mentoring and supervision of trainees and senior scientists, and to optimize my ability to generate a legacy for the next generation of independent investigators.