Pathogenesis, Transmission and Genetic forms of BSE

朊病毒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。虽然罕见的疾病， 牛海绵状脑病（BSE）在北美地区存在， 慢性消耗性疾病（CWD），增加了对可能的问题的关注， 人体健康这个研究项目围绕着我最近的三个重要发现展开。 实验室：1.）在美国牛群中发现不寻常的疯牛病病例。2.）的情况。发现 2006年美国疯牛病中第一例也是迄今为止唯一一例遗传形式（E211K）的动物TSE病例 案子3.）第三章PrP基因敲除牛的一代，健康发育至成年阶段。这些 这三个发现为我们研究疯牛病发病机制的几个方面提供了独特的工具。的 该项目的主要目标是产生和表征突变敲入和敲除奶牛， 评估不同形式BSE的疾病传播、易感性和物种屏障， 转基因小鼠和体外转化实验。在具体目标1中，我们计划表征PrP 更详细地敲除牛，并产生和表征表达PrP的PrP敲入牛， 突变E211K在PrP无效背景中。在具体目标2中，我们将研究 PrP牛源化小鼠表达E211K突变为各种形式的BSE。具体目标3将 评价E211K牛朊病毒和其他BSE分离株向转基因小鼠的传播 表达来自各种动物物种的PrP，包括绵羊、鹿和人以及野生型 老鼠和仓鼠。在具体目标4中，我们计划评估PrPc与 各种物种（人、羊、牛和鹿）在体外被来自 各种形式的BSE。在这个项目中获得的发现将为我们的研究提供实质性的进展。 了解疯牛病的发病机制，传播和物种障碍，并可能有很大的 对公共卫生的影响以及防止这种疾病进一步传播的监管措施。

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.