TRANSGENETIC STUDIES OF PRION DISEASE IN CERVIDS

描述(摘自申请人摘要)：慢性消耗性疾病(CWD) 宫颈萎缩症是一种属于一组致命的传染性疾病 由蛋白引起的神经退行性疾病。普恩病毒的作用机制 复制是独一无二的，中心事件是主机编码的强制 PrPc通过疾病相关亚型(PrPSc)来适应 传染性相关构象。病毒的来源和传播方式 CWD的具体情况仍不清楚。是否有不同的菌株也是未知的 或CWD是否对人类或其他物种构成风险。 了解慢性WD对人类构成的风险在以下方面至关重要 有证据表明，克雅氏病(CJD)的一个新变种 在英国，人类被称为vCJD，是由于暴露在普恩病毒中而导致的 来自患有牛海绵状脑病或“疯牛病”的牛。这个 拟议研究的主要目标是开发一种快速和灵敏的 用于研究CWD发病机制和解决CWD的 慢性萎缩性脑病病毒在哺乳动物间传播的可能性。外来语言的表达 在转基因(TG)小鼠中，PrP基因已经成为一种极端的 研究人类和其他动物病毒病的有效手段。这个 研究人员提出了三个具体目标：(L)培育表达Tg的小鼠 Cervid PrP或嵌合小鼠/cervid PrP将是第一个可靠的 快速、灵敏地检测CWD病毒的生物测定法；(2) CWD病毒株在圈养和野生种群中的流行情况调查 对马鹿、白尾鹿和落基山麋鹿的影响进行评估 Cervid PrP第129和138位密码子多态性与CWD易感性的关系；以及，(3) 用人和牛病毒病的Tg模型作为确定疾病的手段 CWD普恩病毒对人类和牲畜构成的风险。这些研究的结果 研究将提供第一个可靠的检测传染性CWD的方法 并将提供有关CWD Prion物种障碍的重要信息 和菌株。对转基因小鼠哺乳动物间物种障碍的研究将使 更准确地评估以下物质对人类和牲畜构成的风险 暴露于慢性萎缩性脑病的普恩病毒。更广泛地说，这些研究将进一步推动我们的 了解Pron致病的分子机制将会 最终导致人类和动物治疗的合理方法 普恩病毒病。

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.