Pathogenesis, Transmission and Genetic forms of BSE

BSE 的发病机制、传播和遗传形式

基本信息

批准号：
8129594
负责人：
Juergen A Richt
金额：
$ 49.28万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8129594
关键词：
Ablation Address Adult Affect Age-Months Alleles Animals Bovine Spongiform Encephalopathy Brain Cattle Cell Line Cell Surface Proteins Cells Characteristics Chronic Wasting Disease Codon Nucleotides Collaborations Control Animal Creutzfeldt-Jakob Syndrome Deer Development Disease E211K Familial Creutzfeldt-Jakob Disease Fibroblasts Future Gene Targeting Gene Transfer Techniques Generations Genes Genetic Glycoproteins Goals Hamsters Health Human In Vitro Infectious Agent Knock-in Mouse Knock-out Knockout Mice Laboratories Lesion Livestock Longevity Lymphocyte Measures Modeling Molecular Monitor Mouse Strains Mus Mutate Mutation Nature Neurodegenerative Disorders Neurons Normal Cell North America Pathogenesis Phenotype Population PrP PrP gene PrPSc Proteins Predisposition Prion Diseases Prions Production Protein Isoforms Public Health Rare Diseases Reporting Research Research Personnel Research Project Grants Resistance Scrapie Sheep Source Staging Surface Symptoms System Techniques Technology Time Transgenic Animals Transgenic Mice Transgenic Organisms Uncertainty Wild Type Mouse Work cervid disease transmission established cell line in vivo insight loss of function molecular phenotype mutant novel nuclear transfer offspring prevent prion-based programs protein misfolding cyclic amplification research study tool transmission process

项目摘要

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.

病毒疾病或可传染的海绵状脑病（TSE）是一组感染性的影响人类和动物的神经退行性疾病。虽然罕见的疾病，但事实牛海绵状脑病（BSE）存在于北美和连续的传播慢性浪费疾病（CWD）的问题增加了对可能的问题的担忧人类健康。该研究项目围绕着我的三个重要发现。实验室：1。）在美国牛群中发现异常的BSE病例。 2.）发现在2006年美国BSE中，动物TSE的遗传形式（E211K）的第一个也是唯一的情况案件。 3.）在成人阶段发展健康的PRP敲除牛的产生。这些三个发现为我们提供了独特的工具来研究BSE发病机理的几个方面。这该项目的主要目标是产生和表征突变的敲击和敲除母牛，并且使用使用多种形式的BSE评估疾病传播，易感性和物种障碍转基因小鼠和体外转化实验。在特定目标1中，我们计划表征PRP 更详细地淘汰牛，并产生和表征PRP敲打牛表达 PRP无效背景中的突变E211K。在特定目标2中，我们将研究 PRP牛的小鼠表达E211K突变为各种形式的BSE。具体的目标3将评估E211K牛pr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，鹿和人类以及野生型老鼠和仓鼠。在特定目标4中，我们计划评估PRPC的差异敏感性各种物种（人类，绵羊，牛和鹿）由PRPSC在体外转化，源自各种形式的BSE。该项目中获得的发现将为我们的了解BSE发病机理，传播和物种障碍，可能会有很大的对公共卫生和监管措施的影响，以防止这种疾病进一步传播。