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：
8381057
负责人：
Juergen A Richt
金额：
$ 52.73万
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 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8381057
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 Deer Detection 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 human PrP 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.

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。虽然是罕见病，但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) 增加了人们对可能出现的问题的担忧人类健康。这个研究项目围绕我最近的三个重要发现而建立实验室：1.) 在美国牛群中发现不寻常的 BSE 病例。 2.) 发现 2006 年美国疯牛病中首例也是迄今为止唯一的动物 TSE 基因型 (E211K) 病例案件。 3.) PrP 基因敲除牛的产生，健康发育至成年阶段。这些三项发现为我们提供了独特的工具来研究 BSE 发病机制的多个方面。这该项目的主要目标是产生突变基因敲入和基因敲除奶牛并对其进行表征使用以下方法评估不同形式的疯牛病的疾病传播、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，我们计划描述 PrP 的特征更详细地敲除牛，并生成和表征 PrP 敲入牛，表达 PrP 无效背景中的突变 E211K。在具体目标 2 中，我们将研究以下因素的敏感性： PrP 牛源化小鼠表达 E211K 突变，导致各种形式的 BSE。具体目标3将评估 E211K 牛朊病毒和其他 BSE 分离株向转基因小鼠的传播表达多种动物物种的 PrP，包括绵羊、鹿、人类以及野生型老鼠和仓鼠。在具体目标 4 中，我们计划评估 PrPc 的差异敏感性各种物种（人、羊、牛和鹿）可通过源自 PrPSc 的体外转化各种形式的疯牛病。该项目获得的研究结果将为我们的研究提供实质性进展了解疯牛病的发病机制、传播和物种屏障，可能会产生巨大的影响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。