Pathogenesis, Transmission and Genetic forms of BSE

Pron病或传染性海绵状脑病(TSE)是一组传染性疾病 影响人类和动物的神经退行性疾病。尽管罕见的疾病，事实是 牛海绵状脑病(BSE)在北美出现并持续蔓延 慢性消耗性疾病(CWD)的存在，加剧了人们对 人类健康。这个研究项目建立在我最近的三个重要发现之上 实验室：1.)在美国牛群中发现了不寻常的疯牛病病例。2.)这一发现 2006年美国疯牛病中首例也是迄今为止唯一例动物TSE遗传型(E211K) 凯斯。3.)PrP基因敲除的一代牛，发育健康到成年阶段。这些 三个发现为我们提供了独特的工具来研究BSE发病的几个方面。这个 这个项目的主要目标是产生和表征突变的敲入和敲除奶牛和 评估不同形式的疯牛病的疾病传播、易感性和物种障碍 转基因小鼠和体外转化实验。在具体目标1中，我们计划描述PrP 更详细的基因敲除牛，并产生和表征PrP基因敲除牛表达 PrP零背景中的突变E211K。在特定目标2中，我们将研究 将E211K突变的PRP牛化小鼠表达为各种形式的BSE。具体目标3将 评价E211K牛病毒和其他疯牛病分离株在转基因小鼠中的传播 表达多种动物的PrP，包括绵羊、鹿、人和野生型 老鼠和仓鼠。在特定目标4中，我们计划评估PrPc从 各种物种(人、羊、牛和鹿)将通过PrPSc进行体外转化，这些物种来自于 各种形式的疯牛病。在这个项目中获得的发现将为我们的 了解疯牛病的发病机制、传播和物种障碍，可能会有很大的帮助 对公共卫生的影响以及为防止该疾病进一步传播而采取的监管措施。

Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are a group of infectious neurodegenerative disorders affecting humans and animals. Although rare diseases, the fact that Bovine Spongiform Encephalopathy (BSE) is present in North America and the continuous spread of Chronic Wasting Disease (CWD), have augmented concerns about a possible problem for human health. This research project builds around three important recent findings from my laboratory: 1.) The discovery of unusual BSE cases in the U.S. cattle population. 2.) The discovery of the first and so far only case of a genetic form (E211K) of an animal TSE in the 2006 U.S. BSE case. 3.) The generation of PrP knock-out cattle that develop healthy up to an adult stage. These three findings provide us with unique tools to investigate several aspects of BSE pathogenesis. The major goal of this project is to generate and characterize mutant knock-in and knock-out cows and assess disease transmission, susceptibility and species barrier in diverse forms of BSE using transgenic mice and in vitro conversion experiments. In specific aim 1 we plan to characterize PrP knock-out cattle in more detail and generate and characterize PrP knock-in cattle expressing the mutation E211K in the PrP null background. In specific aim 2 we will study the susceptibility of PrP bovinized mice expressing the E211K mutation to various forms of BSE. Specific aim 3 will evaluate transmission of E211K bovine prions and other BSE isolates to transgenic mice expressing PrP from various animal species, including sheep, deer, and human as well as wild type mice and hamsters. In specific aim 4 we plan to evaluate the differential susceptibility of PrPc from various species (human, sheep, cattle and deer) to be converted in vitro by PrPSc derived from various forms of BSE. The findings obtained in this project will provide a substantial advance on our understanding of BSE pathogenesis, transmission and species barrier and will likely have great impact in public health and the regulatory measures to prevent further spreading of this disease.