Humanized Animal Models for Pharmacological Studies

动物模型实验是药理学研究的重要课题之一。新药的开发首先应该在理论上证明其作用，通过使用动物模型进行实验是可能的。然而，几乎总是有。人与动物之间的一些差异尽管5-羟色胺通过5-羟色胺受体起作用，但小鼠5-羟色胺受体1B对针对人5-羟色胺受体1B开发的激动剂或拮抗剂均不应答。这意味着，即使人类和动物之间存在单个氨基酸的差异，也无法将动物实验的结果外推到人类身上。用所需序列如点突变、小缺失或人同源物取代靶基因而不需要任何标记基因的新方法。在这项研究中，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5-羟色胺1B基因代替小鼠基因的ES细胞系，还制造了嵌合小鼠，我们现在期待着获得这种生殖系传播的后代。

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.