Transmissible Spongiform Encephalopathy (Prion) Disease of Deer and Elk

描述（由申请人提供）：这是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）发病机制的第二次修订申请。在最后一次审查中，该赠款获得了13%的分数，不足以获得资金。为了提高这项赠款的竞争力，在以前的两个具体目标中，只保留了最热心考虑的目标。目的是确定感染性鹿痒病的组织分布和滴度，这些鹿痒病接种于小鼠PrP基因被小鼠PrP启动子控制的鹿PrP取代的小鼠。当不治疗或给予小鼠痒病时，这种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的鹿脑时，它们分别在200至230天和350至365天内发展为典型的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的罕见、致命的神经退行性疾病。最近引起关注的是宫颈TSE疾病。农场中的大多数鹿（在某些情况下-80%）以及20%的鹿和1%的野外麋鹿患CWD。目前尚不清楚这种疾病是如何传播的，以及人类是否会被感染。体外研究强调了潜在的危险，在这些研究中，正常的hu PrPsen与CWD PrPres混合后可以转化为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，我们成功地产生了tg小鼠，可用于测定鹿组织的传染性。为了达到这一目标，我们在规定的时间间隔内收集了鹿/麋鹿的唾液、血液、血浆、灰白色被细胞、尿液、粪便、扁桃体、淋巴结、脾脏、骨骼肌和大脑样本。材料收集的鹿要么是实验性地接种鹿痒病直至死亡并被处死，要么是野外自然感染的圈养鹿的样本。我们的假设是，在我们的tg小鼠中接种这些材料将使我们能够：1)确定哪些身体排泄物、液体或组织含有传染性鹿痒病；2)量化这些样本的传染性水平；3)利用1)和2)的结果来确定鹿痒病在动物之间传播的可能方式；4)开始使用这些数据来了解CWD的发病机制和最终控制。

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.