Characterizing the strain and host range properties of prions causing emergent forms of chronic wasting disease

表征导致慢性消耗性疾病的新兴形式的朊病毒的菌株和宿主范围特性

基本信息

批准号：
10208982
负责人：
Glenn C Telling
金额：
$ 46.9万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208982
关键词：
Address Affect American Amino Acid Sequence Asians Biological Assay Cattle Cell Culture Techniques Cells Chronic Wasting Disease Clinical Collaborations Data Deer Disease Outbreaks Economics Enzyme-Linked Immunosorbent Assay Epidemic Epitopes European Evolution Gene Targeting Gene Transfer Techniques Genetic Polymorphism Geographic Locations Goals Heritability Human In Vitro Infection International Koreans Lead Light Livestock Location Macaca Modeling Molecular Conformation Monoclonal Antibodies Mus Muscle Mutate Norway Pathogenesis Peripheral Physiological PrP PrP gene Predisposition Prion Diseases Prions Property Proteins Public Health Recurrence Reindeer Research Personnel Risk Risk Estimate Role Route Scandinavian Sheep South Korea Surface Time Tissues Titrations Transgenic Mice Transgenic Organisms Uncertainty Variant Zoonoses cervid combat cross-species transmission disease transmission exposed human population exposure route in vivo Model innovation mouse model nonhuman primate novel pressure prevent prion hypothesis protein misfolding cyclic amplification transmission process

项目摘要

PROJECT SUMMARY / ABSTRACT Our broad, long-term objectives are to understand the fundamental properties and operative mechanisms of infectious prion transmission, and ultimately to prevent unpredictable recurrences of prion epidemics. This application focuses on chronic wasting disease (CWD), a burgeoning, highly contagious cervid prion disease which has attained global epidemic status. Understanding the properties of North American, European, and Asian CWD prions is an important goal of this proposal. We propose three Specific Aims to address our central hypothesis: that the conformationally protean properties of CWD prions results in the evolution of strains with novel host range properties, and unpredictable zoonotic potential. Our Lead Aim seeks to characterize the transmission properties of emergent Norwegian and South Korean CWD prions. It builds upon our preliminary findings that the strain properties of Scandinavian and North American CWD prions are distinct. We will comprehensively assess and compare the transmission properties emergent CWD prions from different geographic locations and species using well characterized transgenic and novel gene-targeted mouse models expressing prion protein (PrP) genes from susceptible species. In Aim II, we will assess the conformational properties of novel CWD strains using innovative ELISA approaches and monoclonal antibodies recognizing defined conformational epitopes. We will assess the properties of CWD strains in cell culture models, and using cell free conversion assays. We will define the amplitude and temporal accumulation of various CWD strains in infected mice by titration in susceptible cells. Finally, using transgenic mouse modeling, we will assess the effects of PrP polymorphisms on strain selection and pathogenesis, and address the susceptibility of at risk species. In our final Aim, we will compare the host-range properties, and zoonotic potential of CWD prions. Our preliminary data describing novel Nor-CWD strains, and the possibility of detecting additional emergent CWD strains, provide additional uncertainty as to whether CWD- exposed humans, or species in contact with wild cervids, are at risk for developing novel prion diseases. We will assess a variety of species barriers by challenging conventional transgenic mouse models expressing PrP from various species including cattle, sheep, and humans, with CWD prions. We will also address the role of CWD adaptation in peripheral tissues on the human species barrier.

项目概要/摘要我们广泛的长期目标是了解基本属性和传染性朊病毒传播的运作机制，并最终预防朊病毒流行病的复发不可预测。该应用程序专注于慢性病消耗性疾病（CWD），一种新兴的、高度传染性的鹿朊病毒病，达到全球流行状态。了解北美的特性，欧洲和亚洲的 CWD 朊病毒是该提案的一个重要目标。我们建议解决我们的中心假设的三个具体目标：构象千变万化 CWD朊病毒的特性导致具有新宿主范围的菌株的进化特性和不可预测的人畜共患潜力。我们的主要目标旨在描述挪威和韩国新出现的 CWD 朊病毒的传播特性。它构建了根据我们的初步发现，斯堪的纳维亚和北方的应变特性美国 CWD 朊病毒是独特的。我们将综合评估和比较来自不同地理位置的新出现的 CWD 朊病毒的传播特性使用特征明确的转基因和新型基因靶向小鼠模型的物种表达来自易感物种的朊病毒蛋白（PrP）基因。在目标 II 中，我们将评估使用创新 ELISA 方法研究新型 CWD 菌株的构象特性和识别特定构象表位的单克隆抗体。我们将评估细胞培养模型中 CWD 菌株的特性，并使用无细胞转化化验。我们将定义各种 CWD 菌株的振幅和时间累积通过在易感细胞中进行滴定来对受感染的小鼠进行治疗。最后，使用转基因小鼠建模时，我们将评估 PrP 多态性对菌株选择和发病机制，并解决高危物种的易感性问题。在我们的最终目标中，我们将比较 CWD 朊病毒的宿主范围特性和人畜共患潜力。我们的描述新型 Nor-CWD 菌株的初步数据以及检测的可能性其他新出现的 CWD 菌株，为 CWD 是否-提供了额外的不确定性接触过的人类或与野生鹿科动物接触的物种面临着出现新型冠状病毒的风险朊病毒疾病。我们将通过挑战传统的方法来评估各种物种障碍转基因小鼠模型表达来自不同物种的 PrP，包括牛、羊、和人类，患有 CWD 朊病毒。我们还将讨论 CWD 适应在人类物种屏障上的外周组织。