Transmission experiment of the model mouse expressed with the secretary from of the prion protein

本项目的目的是建立转基因小鼠模型，引入无义突变，使通常具有GPI(糖基磷脂酰肌醇)锚定的Prion蛋白的GPI锚定信号失效，揭示分泌型Prion蛋白。我们已经成功地培育出了以小鼠PrP蛋白第231位密码子为终止密码子的转基因小鼠，成功地建立了具有多个淀粉样蛋白斑块的模型动物。对于这种分泌型的小鼠蛋白，在重组分泌型表达水平较低的情况下，接种后150天的潜伏期在90天时显著缩短，而在中等表达水平与野生型小鼠相同的情况下，在该潜伏期内并不明显缩短。此外，虽然引入了人鼠的嵌合体型基因，但同时具有GPI型和分泌型的模型动物潜伏期延长，甚至出现了类似于小鼠Pron蛋白的淀粉样斑块的形成。目前，已建立了分泌型和GPI型兼有的完整人型小鼠模型，其缩短潜伏期的效果正在观察中。令人惊讶的是，分泌型的普鲁恩蛋白达到了抗蛋白酶的地步，这是普鲁恩蛋白转换的标志。该模型有助于阐明蛋白异常转化的机制。此外，Prion蛋白的分泌型提高了检测模型动物滤泡树突状细胞中Prion感染的敏感性。这些发现被认为是目前正在申请中的新的专利特征。

The purpose of this project is to produce the transgenic mouse model that is introduced the nonsense mutation which makes the GPI anchor signal of the prion protein which usually possesses the GPI (Glycosyl Phosphatidyl inositol) anchor invalid reveals the prion protein of secretion type. We already produced the transgenic mouse which designates the codon 231 of the prion protein of the mouse as the stop codon, it has succeeded in the development of the model animal which has many amyloid plaques. As for this secretion type mouse prion protein, in case of the low expression level of the recombinant secretory form, the incubation period after the prion inoculation from 150 days is shortened dramatically on the 90 days, however, in case of the moderate expression level the same as the wild type mouse, it did not become clear for shortening in that incubation period. In addition, although the chimera type gene of the human mouse was introduced, the model animal which reveals the both of GPI type and secretion type had the elongated incubation period, even have the formaiton of amyloid plaques which were similar to the mouse prion protein. Presently, the mouse model which express the both of secretion type and GPI type of complete human type is produced, the shortening effect of the incubation period it is in the midst of observing. Surprisingly, the prion protein of secretion type of the mouse reached the point where the protease resistance which is a hallmark of the conversion of the prion protein is shown. This model is useful to the mechanism elucidation of abnormality conversion of the prion protein. In addition, the secretory form of prion protein enhanced the sensitivity to detect the prion infection in the follicular dendritic cells in the model animals. These findings is followed as the new patent characteristic which presently is in the midst of applying apperared.