Mechanisms of prion strain selection

朊病毒病是一组新出现的人和动物的传染性神经退行性疾病。 人类朊病毒疾病可通过种间传播引起，例如变异型克罗伊茨费尔特- 雅各布病是由牛海绵状脑病传播给人类引起的。以下 种间传播，朊病毒适应新的宿主物种可能涉及朊病毒之间的竞争 直到一种朊病毒株占优势。这个实验室的长期目标是描述 朊病毒适应新宿主物种的机制。为了实现这一目标，我们计划 研究朊病毒株选择的分子基础。我们建立了朊病毒株选择模型 其中仓鼠首先在坐骨神经（i.n.）传染性水貂的昏睡（DY）品系 脑病（TME），然后用TME的超（HY）菌株进行i.n.超感染。利用这个模型，我们有 将朊病毒株选择的位点定位于腰髓，最有可能在腹侧运动神经元内 （VMN）。我们假设朊病毒媒介物运输和/或朊病毒媒介物复制的改变是 在中枢神经系统中负责朊病毒株的选择。为了研究这个假设，我们 i）确定DY TME感染改变逆行示踪剂的轴突运输的程度，或 表位或荧光标记的PrPSc从坐骨神经到腰脊髓中的VMN ii）确定 通过Western印迹，发现VMN中DY TME复制对随后VMN中HY TME复制的影响 分析和/或动物生物测定，和iii）评估DY TME感染对 VMN的活力，VMN是在坐骨神经接种后被HY TME感染的第一种细胞类型， 使用无偏体视学定量VMN群体。本提案目标的结果将定义 朊病毒选择的机制开始解决朊病毒竞争的因素， 了解朊病毒在种间传播后如何适应新的宿主物种。

Prion diseases are a group of emerging transmissible neurodegenerative diseases of humans and animals. Prion diseases of humans can be caused by interspecies transmission, for example, variant Creutzfeldt- Jacob disease is caused by transmission of bovine spongiform encephalopathy to humans. Following interspecies transmission, adaptation of prions to a new host species can involve competition between prion strains until one prion strain predominates. The long-term goal of this laboratory is to describe the mechanism(s) of prion adaptation to a new host species. In a step to achieve this goal, we plan to investigate the molecular basis of prion strain selection. We have developed a prion strain selection model where hamsters are first infected in the sciatic nerve (i.n.) with the drowsy (DY) strain of transmissible mink encephalopathy (TME), then i.n.superinfected with the hyper (HY) strain of TME. Using this model, we have localized the site of prion strain selection to the lumbar spinal cord, most likely within ventral motor neurons (VMNs). We hypothesize that alterations in prion agent transport and/or prion agent replication are responsible for prion strain selection within the central nervous system. To investigate this hypothesis we will i) establishing the degree to which DY TME infection alters axonal transport of a retrograde tracer or epitope or fluorescently labeled PrPSc from the sciatic nerve to VMNs in the lumbar spinal cord ii) determine the effect of DY TME replication in VMNs has on subsequent HY TME replication in VMNs by Western blot analysis and/or animal bioassay of microdisseced VMNs and iii)assess the effect of DY TME infection on the viability of VMNs which are the first cell type infected by HY TME following sciatic nerve inoculation by quantifying VMN populations using unbiased stereology. Results from the aims in this proposal will define the mechanism(s) of prion selection, begin to address the factor(s) that prions compete for, and advance our understanding of how prions adapt to a new host species following interspecies transmission.