Humanized Animal Models for Pharmacological Studies

利用动物模型进行实验是药理学研究中最重要的项目之一。新药的开发，首先应该从理论上证明其作用，通过使用动物模型进行实验是可能的。然而，几乎总是有的。人和动物之间的一些差异虽然5-羟色胺通过5-羟色胺受体发挥作用，但小鼠5-羟色胺受体1B对为人5-羟色胺受体1B开发的激动剂或拮抗剂都不起作用。这种差异通过将人类蛋白质的第355个氨基酸残基苏氨酸改变为天冬氨酸来克服，这意味着即使人和动物之间的单一氨基酸差异也使动物实验的结果不可能推断为人类。我们开发了新的方法，用所需的序列替换目标基因，例如点突变、小缺失或人类同源基因，而不需要任何标记基因。在本研究中，我们将这种方法应用于5-羟色胺受体1B基因。因此，我们成功地制造了携带人源化的5-羟色胺1B基因的ES细胞系，取代了小鼠的基因。还产生了嵌合体小鼠，我们现在期待着获得这种生殖系传递的后代。

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.