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

朊病毒蛋白秘书表达模型小鼠的传播实验

• 批准号: 12480224
• 负责人: KITAMOTO Tetsuyuki
• 金额: $ 8.96万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12480224/
• 关键词: prion diseases; prion protein; secretory form; GPI form; transgenic mouse; knock-in mouse

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.

本课题的目的是建立导入无义突变的转基因小鼠模型，该无义突变使通常具有GPI（Glycosyl Phosphatidyl inositol，糖基磷脂酰肌醇）锚的朊蛋白的GPI锚信号失效，揭示分泌型朊蛋白。我们已经成功地建立了以小鼠朊蛋白231密码子为终止密码子的转基因小鼠，并成功地建立了具有许多淀粉样斑块的模型动物。对于这种分泌型小鼠朊病毒蛋白，在重组分泌型的低表达水平的情况下，朊病毒接种后150天的潜伏期在90天时显著缩短，然而，在与野生型小鼠相同的中等表达水平的情况下，潜伏期的缩短并不明显。另外，虽然引入了人鼠嵌合型基因，但同时表现出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朊蛋白的淀粉样斑块的形成。目前，同时表达分泌型和完整人型GPI型的小鼠模型已经建立，其缩短潜伏期的效果正在观察中。令人惊讶的是，小鼠分泌型朊病毒蛋白达到了显示蛋白酶抗性的程度，该蛋白酶抗性是朊病毒蛋白转化的标志。该模型对朊病毒蛋白异常转化的机理研究具有重要意义。此外，分泌形式的朊病毒蛋白增强了模型动物滤泡树突状细胞检测朊病毒感染的敏感性。这些发现作为目前正在申请中的新专利特征出现。

项目成果

Shin RW, Kruck TP, Murayama H, Kitamoto T: "A novel trivalent cation chelator Feralex dissociates binding of aluminum and iron associated with hyperphosphorylated tau of Alzheimer's disease"Brain Res. 961. 139-146 (2003)

Shin RW、Kruck TP、Murayama H、Kitamoto T：“一种新型三价阳离子螯合剂 Feralex 可解离与阿尔茨海默氏病过度磷酸化 tau 蛋白相关的铝和铁的结合”Brain Res。

Yamamoto S, Furukawa H, Kitamoto T, Takamaru Y, Morita N, Yasuda M, Okada Y, Sawa H, Nagashima K: "An atypical form of sporadic panencephalopathic Creutzfeldt-Jakob disease in Japan"Neuropathol Appl Neurobiol. 29. 77-80 (2003)

Yamamoto S、Furukawa H、Kitamoto T、Takamaru Y、Morita N、Yasuda M、Okada Y、Sawa H、Nagashima K：“日本散发性全脑病克雅氏病的非典型形式”Neuropathol Appl Neurobiol。

Ishida C, Kakishima A, Okino S, Furukawa Y, Kano M, Oda Y, Nakanishi I, Makifuchi T, Kitamoto T, Yamada M: "Sporadic Creutzfeldt-Jakob disease with MM1-type prion protein and plaques"Neurology. 60. 514-517 (2003)

Ishida C、Kakishima A、Okino S、Furukawa Y、Kano M、Oda Y、Nakanishi I、Makifuchi T、Kitamoto T、Yamada M：“伴有 MM1 型朊病毒蛋白和斑块的散发性克雅氏病”神经病学。

Shin RW, Kruck TP, Murayama H, Kitamoto T.: "A novel trivalent cation chelator Feralex dissociates binding of aluminum and iron associated with hyperphosphorylated tau of Alzheimer's disease"Brain Res. 961. 139-146 (2003)

Shin RW、Kruck TP、Murayama H、Kitamoto T.：“一种新型三价阳离子螯合剂 Feralex 可解离与阿尔茨海默氏病过度磷酸化 tau 相关的铝和铁的结合”Brain Res。

Yamamoto A, Shin RW, Hasegawa K, Naiki H, Sato H, Yoshimasu F, Kitamoto T.: "Iron (III) induces aggregation of hyperphosphorylated tau and its reduction to iron (II) reverses the aggregation : implications in the formation of neurofibrillary tangles of Al

Yamamoto A、Shin RW、Hasekawa K、Naiki H、Sato H、Yoshimasu F、Kitamoto T.：“铁 (III) 诱导过度磷酸化 tau 蛋白聚集，并且铁 (II) 还原成铁 (II) 可逆转聚集：对神经原纤维形成的影响