PMCA Detection of CWD Infection in Cervid and Non-Cervid Species

PMCA 检测鹿科动物和非鹿科动物的 CWD 感染

• 批准号: 9237318
• 负责人: EDWARD Arthur HOOVER
• 金额: $ 40.99万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237318
• 关键词: Address; Alzheimer' s Disease; Autopsy; Biochemical; Biological Assay; Blood; Body Fluids; Brain; Canada; Cells; Characteristics; Chronic Wasting Disease; Clinical; Confocal Microscopy; Deer; Detection; Development; Disease; Domestic Animals; Dose; Drug or chemical Tissue Distribution; Environmental Pollution; Epithelial; Feces; Fluorescence Microscopy; Future; Goals; Harvest; Histologic; Horizontal Disease Transmission; Human; Immunohistochemistry; Infection; Interruption; Kinetics; Korea; Lesion; Liquid substance; Longitudinal Studies; Methodology; Milk; Modeling; Mucous Membrane; Mus; Nerve Degeneration; Nose; Oral; Parkinson Disease; Pathogenesis; Pathogenicity; Pathway interactions; Peptide Hydrolases; Peripheral; PrPCWD; Prion Diseases; Prion Pathway; Prions; Process; Province; Research Design; Risk; Route; Saliva; Sample Size; Sampling; Severities; Site; Source; Tail; Time; Tissue Harvesting; Tissues; Urine; Variant; Work; biophysical properties; cervid; cohort; disease phenotype; in vivo; misfolded protein; prevent; prion hypothesis; protein misfolding; public health relevance; transmission process

DESCRIPTION (provided by applicant): Chronic wasting disease (CWD) of deer and elk is an emerging highly transmissible prion disease now recognized in 18 States, 2 Canadian provinces, and Korea. We have shown that Infected deer harbor and shed high levels of infectious prions in saliva, blood, urine, and feces, and in the tissues generating those body fluids and excreta, thereby leading to facile transmission by direct contact and environmental contamination. We have also shown that CWD can infect some non-cervid species, thus the potential risk CWD represents to domestic animal species and to humans remains unknown. Whether prions borne in blood, saliva, nasal fluids, milk, or excreta are generated or modified in the proximate peripheral tissue sites, may differ in subtle ways from those generated in brain, or may be adapted for mucosal infection remain open questions. The increasing parallels in the pathogenesis between prion diseases and human neurodegenerative conditions, such as Alzheimer's and Parkinson's diseases, add relevance to CWD as a transmissible protein misfolding disease. The overall goal of this work is to elucidate the process of CWD prion transmission from mucosal secretory and excretory tissue sites by addressing these questions: (a) What are the kinetics and magnitude of CWD prion shedding post-exposure? (b) Are excreted prions biochemically distinct, or not, from those in the CNS? (c) Are peripheral epithelial or CNS tissues, or both, the source of excreted prions? and (d) Are excreted prions adapted for horizontal transmission via natural/trans-mucosal routes? The specific aims of this proposal are: (1) To determine the onset and consistency of CWD prion shedding in deer and cervidized mice; (2); To compare the biochemical and biophysical properties of excretory vs. CNS prions; (3) To determine the capacity of peripheral tissues to support replication of CWD prions; (4) To determine the protease- sensitive infectious fraction of excreted vs. CNS prions; and (5) To compare the mucosal infectivity of excretory vs. CNS prions. Understanding the mechanisms that enable efficient prion dissemination and shedding will help elucidate how horizontally transmissible prions evolve and succeed, and is the basis of this proposal. Understanding how infectious misfolded proteins (prions) are generated, trafficked, shed, and transmitted will aid in preventing, treating, and managing the risks associated with these agents and the diseases they cause.

描述（由申请人提供）：鹿和麋鹿的慢性浪费疾病（CWD）是一种正在出现的高度可传播的prion病，目前在18个州，2个加拿大省和韩国被认可。我们已经表明，被感染的鹿港和唾液，血液，尿液和粪便中的高水平感染性prions，以及产生这些体液和排泄物的组织中，从而通过直接接触和环境污染引起轻松的传播。我们还表明，CWD可以感染某些非颈体物种，因此CWD的潜在风险代表了家养动物物种，对人类仍然未知。 无论是在血液，唾液，鼻液，牛奶还是排泄物中生存的葡萄酒是在附近的外围组织部位产生或修饰的，都可能与大脑中产生的细微差异，或者可以适应粘膜感染的细微差异。 prion疾病和人类神经退行性疾病（例如阿尔茨海默氏病和帕金森氏病）之间发病机理的相似之处的增加，使与CWD相关的是一种可传播的蛋白质错误折叠疾病。 这项工作的总体目的是通过解决以下问题来阐明从粘膜分泌和排泄组织部位传播CWD Prion的过程：（a）CWD Prion在暴露后脱落的动力学和幅度是什么？ （b）是否与中枢神经系统中的王室排泄在生化上是不同的？ （c）是外周上皮或中枢神经系统组织，还是两者兼而有之排泄王室的来源？ （d）是否可以通过自然/跨粘膜途径排出用于水平传播的王室？ 该提案的具体目的是：（1）确定鹿和颈颈小鼠中CWD prion脱落的发作和一致性； （2）;比较排泄物与中枢神经系统的生化和生物物理特性； （3）确定外围组织支持CWD Prions复制的能力； （4）确定排泄物与中枢神经系统的蛋白酶敏感的传染性部分； （5）比较排泄物与中枢神经系统prions的粘膜感染性。 了解能够有效传播和脱落的机制将有助于阐明水平传播的王室如何发展和成功，并且是该提议的基础。了解如何产生，贩运，脱落和传播的传染性错误折叠蛋白（prions）将有助于预防，治疗和管理与这些药物及其引起的疾病相关的风险。