Transmissible Spongiform Encephalopathy (Prion) Disease of Deer and Elk

鹿和麋鹿的传染性海绵状脑病（朊病毒）病

• 批准号: 7251637
• 负责人: Laura Solforosi
• 金额: $ 28.54万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-13 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7251637
• 关键词: Address; Animals; Biological Assay; Body Fluids; Brain; Chronic Wasting Disease; Data; Deer; Disease; Drug or chemical Tissue Distribution; Excretory function; Farming environment; Feces; Funding; Glycocalyx; Goals; Grant; Grant Review; Human; In Vitro; Liquid substance; Modeling; Mus; Neurodegenerative Disorders; Pathogenesis; Plasma; PrP gene; Prion Diseases; Rare Diseases; Saliva; Sampling; Score; Scrapie; Skeletal Muscle; Spleen; Tissues; Tonsil; Transgenic Organisms; Urine; cervid; chronic wasting disease of elk and deer; day; human disease; lymph nodes; mouse model; promoter; transmission process

DESCRIPTION (provided by applicant): This is the second revised resubmission to utilize a transgenic (tg) model we developed to study the pathogenesis of chronic wasting disease (CWD) of deer and elk. At the last review the grant received a 13% score, not sufficient for funding. To enhance the competitiveness of this grant, of the two previous specific aims, only the one that was considered with the highest enthusiasm was retained. That aim was to determine the tissue distribution and titers of infectious deer scrapie inoculated into tg mice that have their murine PrP gene ko and replaced by deer PrP controlled by murine PrP promoter. When not treated or given murine scrapie, such tg mice do not develop disease over 600+ days. In contrast, when inoculated i.e. or orally with brains from deer with CWD, they developed classic TSE disease within 200 to 230 and 350 to 365 days, respectively. CWD is a transmissible spongiform encephalopathy (TSE, prion disease, scrapie). TSE diseases are rare, fatal neurodegenerative illness of humans and other animals. A recent concern has been TSE disease of cervids. The majority of deer on farms (in some cases -80%) as well as 20% of deer and 1% of elk free in the field develop CWD. How the disease is transmitted and if humans (hu) can be infected are unknown. The potential danger is underscored by in vitro studies in which normal hu PrPsen, when mixed with CWD PrPres can be converted to the hu disease form (hu PrPres). To address the issue of transmission, pathogenesis and eventual treatment, we successfully generated tg mice that can be used to assay infectivity of deer tissue. To reach this goal we have obtained samples of saliva, blood, plasma, buffy coat cells, urine, feces, tonsils, lymph nodes, spleen, skeletal muscle and brain collected at defined intervals from deer/elk. Materials were collected from deer either experimentally inoculated with deer scrapie until they became moribund and were sacrificed as well as samples from captive deer naturally infected in the field. Our hypothesis is that the inoculation of these materials in our tg mice will allow us to: 1) determine which body excreta, fluids or tissues contain infectious deer scrapie; 2) quantitate the levels of infectivity in these samples; 3) utilize results in 1) & 2) to determine the likely ways deer scrapie is/can be transmitted from one animal to another; 4) begin to use this data to understand the pathogenesis and eventual control of CWD.

描述（由申请人提供）：这是第二次修订重新提交，以利用我们开发的转基因（tg）模型来研究鹿和麋鹿的慢性消耗性疾病（CWD）的发病机制。在上次审查中，赠款获得了 13% 的分数，不足以提供资金。为了增强本次资助的竞争力，在之前的两个具体目标中，仅保留了最受关注的一个。该目的是确定接种到 tg 小鼠中的传染性鹿痒病的组织分布和滴度，这些小鼠的鼠 PrP 基因 ko 并被鼠 PrP 启动子控制的鹿 PrP 取代。如果不进行治疗或给予鼠痒病，此类 tg 小鼠在 600 多天内不会发病。相比之下，当接种或口服患有 CWD 的鹿的大脑时，它们分别在 200 至 230 和 350 至 365 天内患上典型的 TSE 疾病。 CWD 是一种传染性海绵状脑病（TSE、朊病毒病、痒病）。 TSE 疾病是人类和其他动物罕见的致命性神经退行性疾病。最近的一个关注点是鹿科动物的 TSE 病。农场中的大多数鹿（在某些情况下为-80%）以及野外 20% 的鹿和 1% 的麋鹿都患有 CWD。该疾病如何传播以及人类 (hu) 是否会被感染尚不清楚。体外研究强调了潜在的危险，其中正常 hu PrPsen 与 CWD PrPres 混合时可以转化为 hu 疾病形式 (hu PrPres)。为了解决传播、发病机制和最终治疗的问题，我们成功培育了可用于检测鹿组织感染性的转基因小鼠。为了实现这一目标，我们按照规定的时间间隔从鹿/麋鹿身上采集了唾液、血液、血浆、血沉棕黄层细胞、尿液、粪便、扁桃体、淋巴结、脾脏、骨骼肌和大脑样本。材料是从鹿身上收集的，或者是实验性接种了鹿痒病直至它们垂死并被处死的鹿，以及来自在田间自然感染的圈养鹿的样本。我们的假设是，将这些材料接种到我们的 tg 小鼠体内将使我们能够：1）确定哪些身体排泄物、液体或组织含有传染性鹿痒病； 2) 定量这些样本的感染性水平； 3) 利用 1) 和 2) 中的结果来确定鹿痒病从一种动物传播到另一种动物的可能方式； 4) 开始使用这些数据来了解 CWD 的发病机制和最终控制。