TRANSGENETIC STUDIES OF PRION DISEASE IN CERVIDS

描述（改编自申请人摘要）：慢性消耗性疾病（CWD） 鹿科的一种疾病属于一组致命的可传播的 朊病毒引起的神经变性疾病。朊病毒的作用机制 复制是独特的，中心事件是宿主编码的胁迫， 朊病毒蛋白（PrPc）由疾病相关亚型（PrPSc）通过 感染性相关构象。起源和传播方式 CWD仍不清楚。也不知道是否有不同的菌株 慢性消耗病朊病毒或慢性消耗病是否对人类或其他物种构成风险。 了解慢性消耗病对人类造成的风险至关重要， 鉴于有证据表明，一种新的变异的克雅氏病（CJD）， 在英国，人类的vCJD是由于暴露于朊病毒引起的 从患有牛海绵状脑病或疯牛病的牛身上。的 拟议研究的主要目标是开发一种快速灵敏的 CWD朊病毒的生物测定，以研究CWD的发病机制， CWD朊病毒在哺乳动物间传播的可能性。表达外源 朊病毒蛋白（PrP）基因在转基因（Tg）小鼠中的表达一直是一个非常重要的问题。 研究人类和其他动物朊病毒疾病的有效手段。的 研究人员提出了三个具体目标：（1）开发Tg小鼠， cervid PrP或嵌合小鼠/cervid PrP将是第一个可靠的 生物测定法，用于快速和灵敏地检测慢性消耗病朊病毒;（2） 调查慢性消耗病朊病毒株在圈养和野生种群中的流行情况 的骡鹿，白色尾鹿和落基山麋鹿，并评估的影响， 鹿PrP基因129和138位密码子多态性与慢性消耗病易感性的关系;（3） 使用人和牛朊病毒病的Tg模型作为确定 慢性消耗病朊病毒对人类和牲畜造成的风险。的结果予以 研究将提供第一个可靠的检测传染性慢性消耗病的方法 并将提供有关慢性消耗病朊病毒物种障碍的关键信息 和菌株。在Tg小鼠中研究哺乳动物种间屏障将允许 更准确地评估对人类和牲畜造成的风险， 接触慢性消耗病朊病毒更普遍地说，这些研究将进一步促进我们的 了解朊病毒发病的分子机制， 最终导致人类和动物治疗的合理方法 朊病毒疾病

DESCRIPTION (adapted from applicant's abstract): Chronic wasting disease (CWD) of cervids is a disease belonging to a group of fatal transmissible neurodegenerative disorders caused by prions. The mechanism of prion replication is unique, the central event being the coercion of host encoded prion protein (PrPc) by the disease-associated isoform (PrPSc) to adopt to the infectivity-associated conformation. The origins and the mode of transmission of CWD remain unclear. It is also unknown whether there are different strains of CWD prions or whether CWD poses a risk to humans or to other species. Understanding the risk that CWD poses to humans is of paramount importance in light of evidence that a new variant of Creutzfldt-Jakob disease (CJD) in humans in the United Kingdom, known as vCJD, results from exposure to prions from cattle with bovine spongiform encephalopathy, or 'mad cow disease'. The major objectives of the proposed research are to develop a rapid and sensitive bioassay for CWD prions in which to study CWD pathogenesis and to address the potential for intermammalian transmission of CWD prions. Expression of foreign prion protein (PrP) genes in transgenic (Tg) mice has been an extremely effective means of studying human and other animal prion diseases. The investigators propose three Specific Aims: (l) To develop Tg mice expressing cervid PrP or chimeric mouse/cervid PrP that will be the first reliable bioassay for the rapid and sensitive detection of CWD prions; (2) To investigate the prevalence of CWD prion strains in captive and wild populations of mule deer, white tailed deer and Rocky Mountain elk and assess the effect of cervid PrP polymorphisms at codons 129 and 138 on CWD susceptibility; and, (3) To use Tg models of human and bovine prion diseases as a means of determining the risks that CWD prions pose to humans and livestock. The results of these studies will provide the first reliable assay for detecting infectious CWD prions and will provide crucial information about CWD prion species barriers and strains. The study of intermammalian species barriers in Tg mice will allow more accurate assessments of the risks posed to humans and livestock from exposure to CWD prions. More generally, these studies will further our understanding of the molecular mechanisms of prion pathogenesis that will ultimately result in rational approaches to therapies for human and animal prion diseases.