遗传修饰猪模型在生物医学及农业领域研究进展及应用

doi:10.16288/j.yczz.22-313

遗传 ›› 2023, Vol. 45 ›› Issue (1): 6-28.doi: 10.16288/j.yczz.22-313

遗传修饰猪模型在生物医学及农业领域研究进展及应用

高菲¹(), 王煜²(), 杜嘉祥³(), 杜旭光¹(), 赵建国²(), 潘登科⁴(), 吴森¹(), 赵要风¹()

1.中国农业大学生物学院，农业生物技术国家重点实验室，北京 100193
2.中国科学院动物研究所，北京 100101
3.成都中科奥格生物科技有限公司，成都 610000
4.四川省医学科学院四川省人民医院，临床免疫转化医学四川省重点实验室，成都 610072

收稿日期:2022-10-08 修回日期:2022-11-26 出版日期:2023-01-20 发布日期:2022-12-28
通讯作者: 杜旭光,赵建国,潘登科,吴森,赵要风 E-mail:gaofei2020019@cau.edu.cn;wangyu950306@163.com;jxdu@clonorgan.com;xuguangdu@cau.edu.cn;zhaojg@ioz.ac.cn;pandengke2002@163.com;swu@cau.edu.cn;yaofengzhao@cau.edu.cn
作者简介:高菲，博士，工程师，研究方向：畜禽干细胞与胚胎工程。E-mail: gaofei2020019@cau.edu.cn|王煜，在读博士研究生，研究方向：大动物遗传修饰。E-mail: wangyu950306@163.com|杜嘉祥，硕士，研究方向：异种器官移植。E-mail: jxdu@clonorgan.com;
高菲、王煜和杜嘉祥并列第一作者。|赵要风，教授，博士生导师，国家杰出青年科学基金获得者，科技部重点领域创新团队负责人，“万人计划”科技创新领军人才入选者，国家“模式动物(猪)表型与遗传研究设施”副首席科学家。目前担任中国农业生物技术学会动物生物技术分会理事长，农业生物技术国家重点实验室主任。先后承担863计划、973计划、转基因重大专项、国家自然科学基金等国家级项目10余项。赵要风课题组主要研究方向为动物免疫遗传学。近5年围绕家养动物重要免疫相关基因开展了一系列研究工作：建立了猪口蹄疫、蓝耳病等病毒性疾病抗病基因高通量筛选平台，为通过基因编辑进行分子抗病育种奠定了基础；深入研究了家养动物免疫球蛋白(抗体)和其他重要免疫基因的表达和转运机制，探讨了这些基因在疾病抗性中的可能功能；建立了动物纳米抗体及家养动物单克隆抗体创制平台，深入研究了抗体在家养动物疾病防控中的可能途径。相关研究成果发表在PNAS、Journal of Immunology、Nature Communications等期刊上。
基金资助:
国家重点研发计划(2021YFA0805900);海南省崖州湾种子实验室“揭榜挂帅”项目(B21HJ0103)

Advances and applications of genetically modified pig models in biomedical and agricultural field

Fei Gao¹(), Yu Wang²(), Jiaxiang Du³(), Xuguang Du¹(), Jianguo Zhao²(), Dengke Pan⁴(), Sen Wu¹(), Yaofeng Zhao¹()

1. State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China
2. Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
3. Chengdu Clonorgan Biotechnology Co., Ltd, Chengdu 610000, China
4. Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu 610072, China

Received:2022-10-08 Revised:2022-11-26 Online:2023-01-20 Published:2022-12-28
Contact: Du Xuguang,Zhao Jianguo,Pan Dengke,Wu Sen,Zhao Yaofeng E-mail:gaofei2020019@cau.edu.cn;wangyu950306@163.com;jxdu@clonorgan.com;xuguangdu@cau.edu.cn;zhaojg@ioz.ac.cn;pandengke2002@163.com;swu@cau.edu.cn;yaofengzhao@cau.edu.cn
Supported by:
Supported by the National Key Research and Development Program of China No(2021YFA0805900);Hainan Yazhou Bay Seed Laboratory No(B21HJ0103)

摘要/Abstract

摘要：

猪在解剖结构、代谢、生理生化等特征方面比啮齿类动物更接近人类，因此在模拟某些人类疾病以及提供异种移植器官等方面具有其他动物不可替代的优势，是理想的人类疾病动物模型和异种器官的供体。另外，猪作为我国畜牧业最重要的物种之一，猪的品种改良、疫病防控以及动物福利等问题都与人民生活息息相关。本文主要介绍了遗传修饰猪模型在分子育种、人类疾病模型以及异种器官移植领域的研究进展及未来应用前景，希望增进相关领域研究人员对基因编辑等前沿技术的了解，理解遗传修饰猪模型在生命科学研究中的重要意义。

关键词: 遗传修饰猪, 分子育种, 疾病模型, 异种器官移植

Abstract:

Compared with rodents, pigs are closer to humans in terms of anatomy, metabolism and physiology, so they are ideal animal models of human diseases and xenotransplantation donors. In addition, as one of the most important livestock in China, pigs are closely related to our lives in terms of breeding improvement, disease prevention and animal welfare. In this review, we mainly summarize the research progress and future application of genetically modified pig models in the fields of xenotransplantation, molecular breeding and human disease models. We wish to take this opportunity to raise the awareness of researchers in related fields on cutting-edge technologies such as gene editing and understand the significance of genetically modified pig models in life science research.

Key words: genetically modified pig models, molecular breeding, disease models, xenotransplantation

高菲, 王煜, 杜嘉祥, 杜旭光, 赵建国, 潘登科, 吴森, 赵要风. 遗传修饰猪模型在生物医学及农业领域研究进展及应用[J]. 遗传, 2023, 45(1): 6-28.

Fei Gao, Yu Wang, Jiaxiang Du, Xuguang Du, Jianguo Zhao, Dengke Pan, Sen Wu, Yaofeng Zhao. Advances and applications of genetically modified pig models in biomedical and agricultural field[J]. Hereditas(Beijing), 2023, 45(1): 6-28.

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育种方向	靶基因	编辑类型	表型	参考文献
提高生产性能	MSTN	基因敲除	提高产肉量	[17~22]
	IGF2	突变ZBED6结合位点	提高产肉量	[26, 27]
	FBXO40	基因敲除	提高产肉量	[30]
	UCP1	基因插入	提高抗寒能力和瘦肉率	[32]
提高抗病力	CD163	基因敲除/片段缺失/同源替换	抵抗PRRSV	[38~45]
	APN	基因敲除	抵抗TGEV	[47]~49
	-	过表达shRNA	抵抗CSFV	[53,54]
优良性状聚合	CD163/APN	基因敲除	同时抵抗PRRSV和TGEV	[51]
优良性状聚合	CD163/MSTN/IGF2	基因敲除/基因过表达	提高产肉量同时抵抗PRRSV	[58]

人类疾病	基因	修饰方式	参考文献
阿尔兹海默症	APP695sw	敲入	[65]
	PSEN1^M146I	重组酶介导的盒式置换	[66]
	APP^SW、PSEN1^M146I	突变	[67]
	hAPP、hTau、hPS1	多顺反子介导的突变	[68]
亨廷顿舞蹈症	HTT	转基因	[69]
亨廷顿舞蹈症	HTT	定点敲入	[70]
帕金森综合征	Parkin、DJ-1	敲除	[71]
	PARK2、DJ-1、PINK1	敲除	[72]
	PARK2、PINK1	敲除	[73]
	SNCA	点突变	[74]
肌萎缩侧索硬化症	SOD1^G93A	转基因	[75]

人类疾病	基因	修饰方式	参考文献
囊性纤维化	CFTR	敲除	[76]
	CFTR	敲除	[77]
	CFTR	敲除和突变	[78,79]
杜氏肌营养不良	DMD	敲除	[80]
杜氏肌营养不良	DMD	敲除	[81]
哈钦森-吉尔福德早衰综合征	LMNA	点突变	[82]
酪氨酸血症	FAH	敲除	[83]
苯丙酮尿症	PAH	敲除	[84]
血友病B	hF9	敲入	[85]
血管性血友病	vWF	敲除	[86]

人类疾病	基因	修饰方式	参考文献
乳腺癌	BRCA1	敲除	[95]
结直肠癌	APC¹³¹¹、APC¹⁰¹⁶	点突变	[96]
胃癌	RUNX3	敲除	[97]
肺癌	EML4、ALK	敲入和重排	[98]
骨肉瘤	TP53	敲除	[99]
多种肿瘤	KRAS^G12D、TP53^R167H	点突变	[100]
淋巴瘤、肾母细胞瘤和骨源性肿瘤	TP53^R167H	点突变	[101]

人类疾病	基因	修饰方式	参考文献
人类永久性新生儿糖尿病	INS	点突变	[102]
糖尿病	INS	敲除	[103]
3型成熟型青年糖尿病	HGF1α	转基因	[104]
2型糖尿病	GIPR	转基因	[105]
	hIAPP	敲入	[106]
	11β-HSD1、HIAPP、CHOP	敲入	[107]
非酒精性脂肪肝	GIPR^dn、hIAPP、PNPLA3^I148M	定点敲入	[108]
高甘油三酯血症	ApoCIII	转基因	[109]
高胆固醇血症、自发动脉粥样硬化	PCSK9	转基因	[110]
高胆固醇血症、自发动脉粥样硬化	ApoE	敲除	[111]
高胆固醇血症、自发动脉粥样硬化、饮食诱导加速疾病发生	LDLR	敲除	[112]
血清LDL-C和TC水平升高	ApoE和LDLR	敲除	[113]
胆固醇吸收失调	NPC1L1	敲除	[114]

遗传修饰猪模型在生物医学及农业领域研究进展及应用

Advances and applications of genetically modified pig models in biomedical and agricultural field

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