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）：这是第二次修订的重新提交，利用我们开发的转基因（tg）模型研究鹿和麋鹿慢性消耗性疾病（CWD）的发病机制。在上次审查中，赠款得到了13%的分数，不足以提供资金。为了提高这项赠款的竞争力，在以前的两个具体目标中，只有一个被认为是最积极的目标被保留下来。目的是确定感染性鹿痒病的组织分布和滴度接种到tg小鼠，其鼠PrP基因ko和替换为鹿PrP由鼠PrP启动子控制。当不治疗或给予鼠瘙痒症时，这样的tg小鼠在600+天内不发展疾病。相比之下，当接种即或口服来自患有CWD的鹿的脑时，它们分别在200至230天和350至365天内发展出经典的TSE疾病。慢性消耗病是一种传染性海绵状脑病（TSE，朊病毒病，羊瘙痒病）。TSE疾病是人类和其他动物罕见的致命性神经退行性疾病。最近的一个问题是鹿科动物的TSE病。农场中的大多数鹿（在某些情况下约80%）以及野外20%的鹿和1%的麋鹿都患有慢性消耗病。这种疾病是如何传播的，人类是否会被感染还不清楚。体外研究强调了潜在的危险，其中正常的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，我们成功地培育了可用于检测鹿组织感染性的tg小鼠。为了达到这一目标，我们已经获得了从鹿/麋鹿以规定的间隔收集的唾液、血液、血浆、血沉棕黄层细胞、尿液、粪便、扁桃体、淋巴结、脾脏、骨骼肌和脑的样品。材料收集从鹿实验接种鹿痒病，直到他们成为濒死和牺牲，以及从圈养鹿自然感染的样品在现场。我们的假设是，在我们的tg小鼠中接种这些材料将允许我们：1）确定哪些身体排泄物、液体或组织含有传染性鹿痒病; 2）定量这些样品中的传染性水平; 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慢性消耗病的发病机制和最终控制。