动物造模,基因修饰,肿瘤动物模型 中国实验动物信息网 2022-01-22 1177

　　Human tumors or tumor-susceptible mouse models obtained through genetic modification technology have been generally accepted by scholars from all over the world. Compared with physical and chemical inducers, the characteristics of human tumor mouse models prepared by this type of technology are that the model mice have a single genetic background and the mutation effect is not affected by other somatic mutations. The phenotype of the tumor-mutant mice can be transmitted through the reproductive system. The human tumor mouse model established by the transgene or gene knock-out technology of conditional gene expression regulation components can observe the occurrence of tumors in different growth periods and in different tissues and organs, which is helpful for the study of tumorigenesis mechanisms, and can also be used in common use The establishment of a mouse model of tumor that is difficult to induce by physical and chemical inducers.

　　At present, several genetically modified animal models are commonly used: ①The expression of tetracycline operon can be activated by combining the tetracycline trans factor rtTA (reverse tetracycline responsive transactivator) with tetracycline or the tetracycline analogue doxycycline (doxycycline) tet-on transgenic mice, and tTA (tetracycline responsive activator) combined with doxycycline can inhibit the expression of tetracycline operon. In this way, tet-on transgenic mice can activate oncogene expression due to doxycycline intake; tet-off transgenic mice will continue to express oncogenes until they are specifically inhibited by doxycycline intake . ②The simian virus 40 large T antigen (SV40 Tag) has become a recognized oncogene. The SV40 Tag gene is used internationally to combine with promoters with different tissue expression specificities, that is, tissue-specific promoters are used. Expression or Cre-LoxP conditional expression of Tag, has successfully prepared various tumor mouse models of prostate, ovary, breast, bladder, lung, kidney, liver, brain, stomach and other tissues. SV40 Tag transgenic mice can spontaneously produce brain neuroma, primary ectodermal tumor, pituitary tumor and thyroid tumor.

　　It has been confirmed that the carcinogenic effect of SV40 Tag is related to its expression product and the tumor suppressor protein P53, pRb to form specific complexes to lose the latter's tumor suppressor activity, and to transactivate the abnormal expression of cell oncogenes and destroy the structure and stability of cell genes. . ③ Gene targeting or gene knock-out technology: For example, the P53-/- mouse, the first tumor suppressor gene animal model established by ES cell targeting technology, can develop normally, but is prone to neural tube defects. P53-/- mice spontaneous tumors occur early, and the tumor progression induced by chemical carcinogens is significantly accelerated, suggesting the tumor suppressor function of P53. In addition, the tumor suppressor gene knockout mouse model also involves genes such as Rb, Apc, Nf1, Nf2, Brcal, and Brca2. ④Conditional gene targeting: Since many tumor suppressor genes are homozygously deleted, they are often prone to early embryonic death, so it is impossible to analyze gene function. Therefore, conditional targeting is the use of recombinase to cause gene targeting in specific tissues and specific developmental stages in model organisms, which can effectively overcome the defects of common targeting and more realistically simulate the inactivation process of tumor suppressor genes in vivo. For example, using the enhancer of the rat elastase N gene and the activated H-ras gene to form a fusion gene, almost 100% of the transgenic mice prepared therefrom develop pancreatic cancer. It directly proves that oncogene mutations are the cause of tumorigenesis. Many genetically modified mice with a high incidence of tumors can be used to screen drugs for the treatment and prevention of tumors.

　　The preparation of animal models has achieved many results and is widely used in various aspects such as early diagnosis of human-related diseases as well as the evaluation of new drugs.