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

项目摘要/摘要 我们广泛的、长期的目标是了解 传染性朊病毒传播的运作机制，并最终预防 Pron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)是一种新兴的、高度传染性的颈蛋白疾病，它具有 达到全球流行状态。了解北美的特性， 欧洲和亚洲的CWD蛋白是这项提议的一个重要目标。我们建议 三个具体的目标来解决我们的中心假设：构象多变的 CWD Pron的特性导致具有新宿主范围的菌株的进化 财产，以及不可预测的人畜共患病潜力。我们的主要目标是试图描述 新出现的挪威和韩国CWD普里子的传输特性。它构建了 根据我们的初步发现，斯堪的纳维亚和北方的菌株特性 美国慢性萎缩性脑病的蛋白是不同的。我们将全面评估和比较 来自不同地理位置的CWD出射普里子的传输特性 利用具有良好特征的转基因和新的基因靶向小鼠模型的物种 表达易感物种的PrP基因。在AIM II中，我们将评估 新型EL ISA方法研究CWD新菌株的构象特性 以及识别确定的构象表位的单抗。我们将评估 CWD菌株在细胞培养模型和无细胞转化中的特性 化验。我们将定义不同CWD菌株的幅度和时间积累 在感染的小鼠中通过在敏感细胞中进行滴定。最后，使用转基因小鼠 建模，我们将评估PrP多态对菌株选择和 致病机制，并解决濒危物种的易感性问题。在我们的最终目标中，我们将 比较CWD病毒的寄主范围特性和人畜共患病潜力。我们的 描述新的NOR-CWD菌株的初步数据以及检测的可能性 更多新出现的CWD菌株，为CWD是否- 暴露在危险中的人类，或与野生鹿类有接触的物种，有可能开发出新的 普恩病毒病。我们将通过挑战传统的方式来评估各种物种壁垒 表达多种物种PrP的转基因小鼠模型，包括牛，羊， 还有人类，有慢性萎缩性脑病的普恩病毒。我们还将讨论CWD适应在 人类物种屏障上的外周组织。

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.