基因修饰家兔研究进展

Genetically Modified Rabbit Models for Medical Sciences

基因修饰(GM)家兔是生物医学研究极其重要的动物模型,过表达人类基因的家兔模型已经广泛用于人类心血管疾病、艾滋病和肿瘤等研究领域。到目前为止,制作转基因家兔模型绝大多数使用显微注射的方法,使外源基因随机插入到家兔基因组中。基于胚胎干细胞(ES细胞)的基因打靶技术是实现基因敲除(KO)、研究基因功能最有效的方法之一,然而,家兔缺乏稳定、可商业化使用的ES细胞系,所以利用ES细胞对家兔基因组进行编辑修饰是不可能实现的。近年来,新发展起来的以CRISPR-Cas9为代表的新的基因编辑技术,使得我们对家兔基因定点打靶突变和基因定点导入成为可能,并且利用这些技术已经成功培育了一批基因敲除家兔模型。基于我们的研究经历,本文简要回顾了GM家兔模型发展历史、研究进展以及在生物医学研究领域的应用。

Genetically modified(GM) rabbits have been proved to be excellent animal models for biomedical research. GM rabbits expressing human genes have been widely used as models for cardiovascular disease, AIDS, and cancer research. So far, GM rabbits were almost generated by pronuclear microinjection, which randomly leads to additive genes integrated in the rabbit genome. Compared to this technology, gene targeting in ES cells is more powerful tool for deepening understanding of gene function.However, the rabbit lack stable ES cell lines. Thus, gene targeting, dependent on ES cells, is not possible used in rabbit. Instead, RNA interference is quickly becoming a valuable experimental tool that allows investigators to knock down the expression of specific genes, and makes it possible to create GM rabbit models. Recently, with the advent of novel genetic technologies, such as Zinc-finger nucleases,transcription-activator like effector nuclease, the RNA-guided CRISPR-Cas endonuclease, there have been a significant breakthroughs in gene targeting of rabbit. Researchers have successfully created some gene knock out rabbits using Zinc-finger nucleases, or transcription-activator like effector nuclease, or the RNA-guided CRISPR-Cas endonuclease. Based on our study in the area of GM rabbits, in this paper,we review the progress of GM technology in rabbits during the past years and emphasize their applications as a model in biomedicine.