Pathogenesis, Transmission and Detection of Zoonotic Prion Diseases (P01)

描述（由申请人提供）：传染性海绵状脑病（tse）是一组影响人类和动物的致命神经退行性疾病。虽然罕见，但最近爆发的牛海绵状脑病（BSE）和牛慢性消耗性疾病（CWD）及其从牛向人类的传播引起了极大关注。由于缺乏有效、敏感和早期诊断，以及围绕感染原的前所未有的性质、其传播机制和控制朊病毒传播的物种屏障的许多不确定性，这一问题更加严重。本项目的主要目标是了解疯牛病和CWD朊病毒的传播机制和发病机制，估计这些传染性病原体将疾病传播给其他动物特别是人类的风险，评估朊病毒在动物之间传播的机制和途径，并制定死前检测受感染动物的新策略。一组在该领域具有广泛认可的专业知识和贡献记录的有成就的科学家将共同努力实现这些目标。Project 1 （Juergen right， PL）提出详细研究突变和敲除奶牛，评估疯牛病遗传形式在疾病传播、易感性和物种屏障中的作用。在这些研究中，我们计划在表达最近在美国自然疯牛病病例中发现的PrP突变的转基因牛中产生和表征knock。我们还将使用表达野生型和突变型牛PrP的转基因小鼠模型以及使用PMCA进行PrP复制的体外研究。Project 2 （Glenn Telling， PL）提出建立并使用转基因小鼠模型来评估各种物种屏障的强度和朊病毒毒株的影响。我们将研究各种模型对CWD感染的易感性，以及鹿模型被其他物种朊病毒感染的可能性。为了实现这一目标，实验将在转基因小鼠模型中进行，并使用体外转化研究。项目3 （Claudio Soto， PL）提出研究CWD和BSE朊病毒的体外复制，评估感染蛋白的组织分布，揭示传播途径并建立诊断方法。为此，我们将使用索托博士实验室最近开发的PMCA技术来模拟朊病毒的复制过程。行政核心（核心A） （Claudio Soto，主任）将促进和整合项目和核心，并负责该计划顺利运作所需的所有行政方面。组织核心（核心B） （Pierluigi Gambetti，主任）将处理、分析和存储生成的组织样本，并为成员提供生物安全设施，以操作疯牛病传染性材料。本项目的研究结果无疑将有助于了解这两种令人担忧的人畜共患朊病毒疾病的发病机制、传播途径和早期发现。

DESCRIPTION (provided by applicant): Transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative disorders affecting humans and animals. Although rare, the recent outbreak of Bovine Spongiform Encephalopathy(BSE) in cattle and Chronic Wasting disease (CWD) in cervids and the transmission of the disease from cattle to humans have caused great concern. This problem is aggravated by the lack of an efficient, sensitive and early diagnosis as well as many uncertainties surrounding the unprecedented nature of the infectious agent, its mechanism of propagation and the species-barrier that controls prion transmission. The major goals of this Program Project are to understand the mechanism of transmission and pathogenesis of BSE and CWD prions, to estimate the risk of these infectious agents to propagate disease to other animals and especially to humans, to assess the mechanisms and routes of prion dissemination among animals and to develop novel strategies for ante-mortem detection of infected animals. A team of accomplished scientists with widely recognized expertise and track record of contributions in this field will work collaboratively to reach these goals. Project 1 (Juergen Richt, PL) proposes to study in detail mutant and knock out cows and assess the role of genetic forms of BSE in disease transmission, susceptibility and species barrier. For these studies, we plan to generate and characterize knock in transgenic cattle expressing a PrP mutation recently identified in a natural BSE case in USA. We will also use transgenic mice models expressing wild type and mutant bovine PrP and in vitro studies of PrP replication using the PMCA. Project 2 (Glenn Telling, PL) proposes to generate and use transgenic mice models to assess the strength of various species barriers and the influence of prion strains. We will study the susceptibility of various models to be infected by CWD as well as the possibility that deer models may be infected by prions from other species. To address this aim, experiments will be done in transgenic mice models and using in vitro conversion studies. Project 3 (Claudio Soto, PL) proposes to study the replication of CWD and BSE prions in vitro, evaluate tissue distributions of infectious protein, enlighten the routes of transmission and develop a diagnostic assay. For this purpose, we will use the PMCA technology, recently developed in Dr Soto's lab to mimic the prion replication process. The Administration Core (core A) (Claudio Soto, Director) will facilitate and integrate Projects and Cores and take care of all administrative aspects needed for the smooth operation of the Program. The Tissue Core (core B) (Pierluigi Gambetti, Director) will process, analyze and store the tissue samples generated and provide access to the members to a biosafety facility to manipulate BSE infectious material. The findings generated in this Program will have undoubtedly contribute to understand the pathogenesis, route of propagation and early detection of these two worrisome zoonotic prion diseases.