Mechanisms of prion strain selection

Pron病是一组新出现的人和动物的遗传性神经退行性疾病。 人类的Pron疾病可以由物种间传播引起，例如，变异的CreutzFeldt- 雅各布病是由牛海绵状脑病传播给人类引起的。跟随 种间传播，普鲁恩对新寄主物种的适应可能涉及到普恩之间的竞争 直到有一种普恩病毒菌株占主导地位。该实验室的长期目标是描述 朊病毒对新寄主物种的适应机制(S)。为了实现这一目标，我们计划 研究PrP菌株选择的分子基础。我们已经开发了一个普利子菌株选择模型。 仓鼠首先感染坐骨神经的地方(I.N.)与昏昏欲睡(DY)品系的可传播水貂 脑病(TME)，然后I.N.重叠感染高(HY)株TME。使用这个模型，我们有 定位于腰髓，最有可能是在腹侧运动神经元 (VMNS)。我们假设Pron试剂运输和/或Pron试剂复制的改变是 负责中枢神经系统内的Prion品系选择。为了研究这一假设，我们 将确定DY TME感染改变逆行示踪剂轴突运输的程度或 从坐骨神经到腰髓VMN的PrPSc表位或荧光标记II)测定 免疫印迹法检测VMNS中DY-TME复制对后续HY-TME复制的影响 显微解剖VMN的分析和/或动物生物测定和III)评估DY TME感染对 HY-TME感染坐骨神经后第一种细胞株VMN的活性 使用无偏见的体视学对VMN种群进行量化。本提案中目标的结果将定义 普恩选择的机制(S)，开始解决普恩竞争的因素(S)，并推进我们的 了解在物种间传播后，普恩如何适应新的寄主物种。

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.