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Humanized Animal Models for Pharmacological Studies

用于药理学研究的人源化动物模型

基本信息

批准号：
07557012
负责人：
MOTOYA Katsuki
金额：
$ 9.73万
依托单位：
The University of Tokyo (1996-1997)Kyushu University (1995)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07557012/
关键词：
animal models pharmacology serotonin receptor serotonin gene targeting gene replacement ES cell humanized mouse ジーンターゲッテイング

项目摘要

An experiment using animal models is one of the most important projects for pharmacological studies. The development of novel drugs, in which the action should first be proved theoretically, may be possible by performing experiments using animal models. However, there are almost always. some differences between humans and animals Although serotonin acts through serotonin receptors, the mouse serotonin receptor 1B does not respond to either the agonists or antagonists developed for human serotonin receptor 1B.This difference was overcome by changing the 355th amino acid residue, threonin, of the human protein to aspargine, which is the equivalent residue of the mouse protein This means that even the single amino acid difference between humans and animals thus made it impossible to extrapolate the results from animal experiments to human beings.We developed novel methods to replace the target gene with the desired sequences, such as a point mutation, small deletion, or human homologue, without any marker genes. In this study, we applied this method to the serotonin receptor 1B gene. We thereby succeeded in making the ES cell lines which carry the humanized serotonin 1B gene in place of the mouse gene .Chimera mice were also produced and we are now looking forward to obtaining the offspring of this germ line transmission.

使用动物模型的实验是药理学研究最重要的项目之一。新药的开发首先应从理论上证明其作用，通过使用动物模型进行实验可能是可能的。然而，几乎总是有的。人类和动物之间的一些差异虽然血清素通过血清素受体发挥作用，但小鼠血清素受体 1B 不会对为人血清素受体 1B 开发的激动剂或拮抗剂产生反应。通过将人类蛋白质的第 355 个氨基酸残基苏氨酸改为天冬酰胺（与小鼠蛋白质的等效残基），克服了这种差异。这意味着即使是小鼠蛋白质的单个氨基酸差异因此，不可能将动物实验的结果外推到人类身上。我们开发了新方法，用所需的序列（例如点突变、小缺失或人类同源物）替换目标基因，而无需任何标记基因。在本研究中，我们将此方法应用于血清素受体 1B 基因。由此，我们成功地制备了携带人源化血清素1B基因代替小鼠基因的ES细胞系。还产生了嵌合体小鼠，我们现在期待着获得这种种系传递的后代。