Maximizing research success in studies of naturally-occurring prion diseases

最大限度地提高自然发生的朊病毒疾病研究的成功率

• 批准号: 10665211
• 负责人: Glenn C Telling
• 金额: $ 47.12万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2031-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665211
• 关键词: Address; Animals; Biochemical; Biological; Cells; Central Nervous System; Chronic Wasting Disease; Dedications; Development; Disease; Economics; Epidemic; Evolution; Funding; Funding Mechanisms; Genomics; Goals; Human; In Vitro; Mentors; Molecular Conformation; Molecular Genetics; National Institute of Neurological Disorders and Stroke; Output; Peripheral; Phenotype; Play; PrP; Prevalence; Prion Diseases; Prions; Property; Proteins; Recurrence; Research; Research Personnel; Research Project Grants; Resolution; Resources; Risk; Role; Senior Scientist; Supervision; Transgenic Organisms; United States National Institutes of Health; Virus; Zoonoses; cervid; design; flexibility; improved; innovation; next generation; novel; prevent; success; transmission process

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.

项目总结/摘要 我的研究项目的广泛而长期的目标是了解控制朊病毒传播的参数 以及物种内部和物种之间的进化，并最终防止人类和动物的复发性流行病。 慢性消耗性疾病（CWD）是一种在鹿科动物中迅速流行的疾病， 是这一总体框架内的一个特别重点。我的研究小组是为数不多的 以及转基因、细胞生物学、生物化学、分子遗传学和体外方法研究朊病毒的专业知识 疾病我们的产品在该领域产生了强大而持久的影响。此应用程序利用了 与NINDS的长期关系，这是我作为一名研究人员不间断地获得NIH资助的一个特点。 独立调查员，任期26年。由于朊病毒的研究需要长期的实验 承诺，需要持续和高度协调的办法，本建议探讨的可行性， * 建立稳定性和灵活性更高的替代供资机制，从而提高效率， 提高我们已经很大的创新能力，进行变革性研究，并利用新的 发展理念这个应用程序的目的是建立在我们的研究的前进轨迹，通过解决 与自然发生的朊病毒疾病有关的关键问题，特别关注慢性消耗病。我们将解决 流行，性质和起源的紧急和建立慢性消耗病菌株;探讨如何应变构象 和物种特异性PrP一级结构差异调节种间朊病毒传播;研究 稳定菌株表型或促进朊病毒适应/进化的参数;说明所起的作用 通过外周隔室和中枢神经系统在宿主的菌株选择/适应中;确定 已建立和新出现的菌株对人类构成的风险;并确定慢性消耗病的结构特性 高分辨率的朊病毒株。拟议的机制还提供了更多的机会， 指导和监督学员和高级科学家，并优化我的能力，为 下一代独立调查员