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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：
9789386
负责人：
Glenn C Telling
金额：
$ 49.6万
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/9789386
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 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.

项目总结/摘要我们广泛的，长期的目标是了解基本属性，感染性朊病毒传播的操作机制，并最终防止朊病毒流行病的不可预测的复发。此应用程序侧重于慢性消耗性疾病（CWD），一种新兴的，高度传染性的鹿朊病毒疾病，成为全球流行病。了解北美的特性，欧洲和亚洲的慢性消耗病朊病毒是这项建议的一个重要目标。我们提出三个具体的目标，以解决我们的中心假设：构象多变， CWD朊病毒的特性导致了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病可能性。我们的主要目标是描述挪威和韩国CWD朊病毒的传播特性。它建立根据我们的初步发现，斯堪的纳维亚和北美国慢性消耗病朊病毒是不同的。我们将全面评估和比较来自不同地理位置的CWD朊病毒的传播特性，使用充分表征的转基因和新型基因靶向小鼠模型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方法的新型CWD菌株的构象特性和识别确定的构象表位的单克隆抗体。我们将评估 CWD菌株在细胞培养模型中的特性，以及使用无细胞转化测定。我们将定义各种CWD应变的幅度和时间积累通过在易感细胞中滴定来检测感染小鼠。最后，利用转基因小鼠通过建模，我们将评估PrP多态性对菌株选择的影响，发病机制，并解决风险物种的易感性。在我们的最终目标中，我们将比较宿主范围特性和慢性消耗病朊病毒的人畜共患潜力。我们描述新型Nor-CWD菌株的初步数据，以及检测额外出现的CWD菌株，为CWD- 暴露的人类或与野生鹿科动物接触的物种，朊病毒疾病我们将评估各种物种的障碍，挑战传统的表达来自不同物种（包括牛、绵羊）的PrP的转基因小鼠模型，和人类的慢性消耗病朊病毒。我们还将讨论慢性消耗病适应的作用，人类物种屏障上的外周组织。