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.

项目概要/摘要 我的研究项目的广泛、长期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，最终防止人类和动物的流行病复发。 慢性消耗性疾病（CWD）是一种在鹿科动物中迅速流行的疾病，其人畜共患潜力越来越不确定， 是这个总体框架内的一个特别重点。我的研究小组是少数拥有资源的研究小组之一 以及在转基因、细胞生物学、生物化学、分子遗传学和体外研究朊病毒方法方面的专业知识 疾病。我们的成果对该领域产生了强大而持续的影响。该应用程序利用 与 NINDS 的长期关系是我作为 NIH 资助的不间断记录的一个特点 独立调查员任期长达26年。由于朊病毒研究需要长期实验 承诺需要持续和高度协调的方法，该提案探讨了 替代融资机制具有更高的稳定性和灵活性，从而提高效率，这将 增强我们本已强大的创新能力、进行变革性研究和利用新的能力 事态发展。该应用程序旨在通过解决我们研究的进展轨迹 与自然发生的朊病毒疾病相关的关键问题，特别关注 CWD。我们将解决 新出现和已建立的 CWD 菌株的流行率、特性和起源；探索如何应变构象 物种特异性 PrP 主要结构差异调节种间朊病毒传播；调查 稳定菌株表型或促进朊病毒适应/进化的参数；解决所扮演的角色 由外周区室和中枢神经系统进行宿主的菌株选择/适应；探明 既定菌株和新出现的菌株对人类造成的风险；并确定 CWD 的结构特性 高分辨率的朊病毒菌株。拟议的机制还为专门人员提供了更多机会 对受训者和资深科学家的指导和监督，并优化我为以下领域创造遗产的能力 下一代独立调查员。