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中国生物工程杂志

China Biotechnology
China Biotechnology  2020, Vol. 40 Issue (4): 59-68    DOI: 10.13523/j.cb.1909072
    
Advances in Genetically Engineered Animal Models of Chronic Obstructive Pulmonary Disease
LIU Di1,2,ZHANG Hong-chun2,**()
1 Beijing University of Chinese Medicine, Beijing 100029, China
2 Department of TCM Pulmonary Diseases, China-Japan Friendship Hospital; Center of Respiratory Medicine, China-Japan Friendship Hospital; National Clinical Research Center for Respiratory Diseases, Beijing 100029, China
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Abstract  

Chronic obstructive pulmonary disease (COPD) is a common chronic airway inflammatory disease with high morbidity and mortality in China, and it has caused heavy social and economic burden. It is reported that the incidence of COPD is closely related to genetic and environmental factors. Animal model is an important tool to study its pathogenesis, prevention, treatment and identify potential therapeutic targets and biomarkers. With the development of genetic engineering technology and the continuous discovery of related targets and genes of COPD, gene modified animal models are increasingly established and used in COPD research. In this paper, we searched published papers in PubMed to analyze the animal species and modeling methods of previous models of COPD. Then we data-mined the susceptibility genes of COPD and reviewed the susceptibility genes of different species by literature and database tool analysis. Finally, we integrated and listed the information and research progress of COPD genetic engineering mouse and rat models. Those informations are convenient for researchers and clinicians to reference and use. Thereafter, they can facilitate the research of pathogenesis and prevention methods of COPD.



Key wordsChronic obstructive pulmonary disease      Animal model      Genetic engineering     
Received: 03 October 2019      Published: 18 May 2020
ZTFLH:  Q789  
Corresponding Authors: Hong-chun ZHANG     E-mail: 13701226664@139.com
Cite this article:

LIU Di,ZHANG Hong-chun. Advances in Genetically Engineered Animal Models of Chronic Obstructive Pulmonary Disease. China Biotechnology, 2020, 40(4): 59-68.

URL:

https://manu60.magtech.com.cn/biotech/10.13523/j.cb.1909072     OR     https://manu60.magtech.com.cn/biotech/Y2020/V40/I4/59

Fig.1 Development trend of COPD animal model literature in PubMed
Fig.2 Species classification of COPD animal models (by number of literatures)
Fig.3 622 susceptibility genes associated with COPD (top 20)
靶基因
Target
genes
靶基因全称
Target gene full name
遗传相关性
Genetic
association
总体相关性
Overall
association
FAM13A 家族序列相似性基因13A(family with sequence similarity 13 member A) 0.978 453 1
CHRNA3 胆碱能尼古丁受体α3(cholinergic receptor nicotinic alpha 3 subunit) 0.954 764 1
NPNT 肾连蛋白(nephronectin) 0.95 0.953 6
THSD4 I型血小板反应蛋白4(thrombospondin type 1 domain containing 4) 0.925 347 0.932 422
CHRNA5 胆碱能尼古丁受体α5(cholinergic receptor nicotinic alpha 5 subunit) 0.919 778 0.960 71
ADGRG6 粘附G蛋白偶联受体G6(adhesion G protein-coupled receptor G6) 0.906 82 0.912 22
HTR4 5-羟色胺受体4(5-hydroxytryptamine receptor 4) 0.876 396 0.886 893
ADAM19 ADAM金属肽酶19(ADAM metallopeptidase domain 19) 0.865 212 0.879 547
EEFSEC 硒特异延伸因子(eukaryotic elongation factor, selenocysteine-tRNA specific) 0.821 811 0.831 311
AGER 晚期糖基化终末产物特异性受体(advanced glycosylation end-product specific receptor) 0.807 588 0.823 249
CFDP1 颅面部发育蛋白1(craniofacial development protein 1) 0.799 618 0.804 618
TET2 甲基胞嘧啶双加氧酶2(tet methylcytosine dioxygenase 2) 0.787 572 0.791 272
RIN3 RAS相关/干扰蛋白3 (Ras and Rab interactor 3) 0.777 619 0.787 039
HHIP Hedgehog相互作用蛋白(hedgehog interacting protein) 0.771 856 0.825 219
CHRNB4 胆碱能受体烟碱β4(cholinergic receptor nicotinic beta 4 subunit) 0.767 843 0.824 281
INTS12 整合因子复合体12(integrator complex subunit 12) 0.764 856 0.775 156
ARMC2 犰狳重复内含蛋白2(armadillo repeat containing 2) 0.727 875 0.727 875
ARHGAP42 Rho家族GTP酶活化蛋白42(Rho GTPase activating protein 42) 0.694 175 0.694 175
SERPINA1 丝氨酸蛋白酶抑制剂A1(serpin family A member 1) 0.666 944 0.698 373
CDC123 细胞分裂周期蛋白123(cell division cycle 123) 0.65 0.65
Table 1 Top 20 susceptibility genes associated with COPD in Open Targets Platform

Human
小鼠
Mouse
大鼠
Rat
毛丝鼠
Chinchilla
倭黑猩猩
Bonobo

Dog

Pig
基因数 21 20 24 18 20 20 21
Table 1 Result of retrieving susceptibility genes of COPD in RGD database
Fig.4 Wayne diagram of cross-over of susceptibility genes of COPD in human, mice and rats
Fig.5 Chronic obstructive pulmonary disease related genes and animal models in MGI (Cited:http://www.informatics.jax.org/humanDisease.shtml)
Organism Gene symbol Associated human diseases Mice with
mutations
in this gene
(IMSR)
mouse
Fbn1
heart disease | Marfan syndrome | pulmonary emphysema | systemic scleroderma | Weill-Marchesani syndrome 7
mouse Fut8 pulmonary emphysema 30
mouse Itgb6 asthma | pulmonary emphysema 5
mouse Jun pulmonary emphysema 7
mouse Kl hyperphosphatemic familial tumoral calcinosis | pulmonary emphysema 36
mouse Ptma polycystic kidney disease | pulmonary emphysema 31
mouse Mus81 arterial tortuosity syndrome | Marfan syndrome | pulmonary emphysema 7
mouse Bloc1s6 Hermansky-Pudlak syndrome 9 | platelet storage pool deficiency | pulmonary emphysema 16
mouse Tg(Msr1-MMP9)#Apar pulmonary emphysema 1
mouse Tg(tetO-PLAGL2)P3Ysy pulmonary emphysema 1
mouse Smo medulloblastoma | pulmonary emphysema 9
mouse Tlr4 pulmonary emphysema 65
mouse Tg(Actb-Ptma)T12Clwu polycystic kidney disease | pulmonary emphysema 1
mouse Tg(HP-MMP1a)34-1Cha pulmonary emphysema 1
Total 217
Table 3 Genetically engineered mice model of COPD in MGI
Strain Name States Repository Mutation
types
Strain
types
Hhiptm1e(EUCOMM)Hmgu ES Cell EuMMCR targeted mutation mutant strain
STOCK Hhiptm1Amc/J embryo JAX targeted mutation mutant stock
KOMP ES cell line Hhiptm1(KOMP)Vlcg ES Cell MMRRC deletion mutant strain
B6;129S5-HhipGt(OST67903)Lex/Mmucd archived MMRRC gene trap unclassified
B6.129/Sv-Hhiptm1Kuv/Orl embryo EMMA targeted mutation mutant strain
B6.129/Sv-Hhiptm1.1Kuv/Orl embryo EMMA targeted mutation mutant strain
C57BL/6NTac-Hhiptm1(EGFP/Cre/ERT2)Wtsi/Ics sperm EMMA targeted mutation mutant strain
Hhiptm1(KOMP)Vlcg ES Cell KOMP targeted mutation mutant strain
C57BL/6J-MtgxR0356Btlr/Mmmh、C57BL/6J-MtgxR4448Btlr/Mmmh等(20种) archived MMRRC mutant strain
 
Strain name States Repository Mutation types Strain types
C57BL/6N-Fam13aem1(IMPC)Wtsi/WtsiOulu embryo sperm EMMA - mutant strain
Fam13atm1e(KOMP)Wtsi ES Cell KOMP targeted mutation mutant strain
Fam13atm1a(KOMP)Wtsi ES Cell KOMP targeted mutation mutant strain
Fam13atm1e(KOMP)Wtsi ES Cell KOMP targeted mutation mutant strain
Fam13atm1a(KOMP)Wtsi ES Cell sperm KOMP targeted mutation mutant strain
KOMP ES cell line Fam13atm1a(KOMP)Wtsi ES Cell MMRRC targeted mutation
targeted mutation
mutant strain
KOMP ES cell line Fam13atm1e(KOMP)Wtsi ES Cell MMRRC - mutant strain
KOMP ES cell line Fam13atm2a(KOMP)Wtsi ES Cell MMRRC targeted mutation
targeted mutation
targeted mutation
mutant strain
KOMP ES cell line Fam13atm2e(KOMP)Wtsi ES Cell MMRRC targeted mutation
targeted mutation
targeted mutation
mutant strain
C57BL/6N-Atm1BrdFam13atm2a(KOMP)Wtsi/MbpMmucd archived
sperm
MMRRC targeted mutation
targeted mutation
mutant strain
C57BL/6J-MtgxR1378Btlr/Mmmh等24种 archived MMRRC - mutant strain
Table 5 Fam13a mutant mouse model
基因名称
Symbol
基因全称
Name/Term/Title
染色体
Chr
起始位点
Start
终止位点
Stop
注释
Annotations
RGD编号
RGD ID /
Term_acc
Fam13a family with sequence similarity 13, member A 4 89183180 89281282 80 1309807
Serpina3m serine (or cysteine) proteinase inhibitor, clade A, member 3M 6 127808785 127816067 121 735068
Mir218-2 microRNA 218-2 10 20428661 20428770 9 2325546
Clca1 chloride channel accessory 1 2 250897980 250923711 87 1306258
Eefsec eukaryotic elongation factor, selenocysteine-tRNA-specific 4 120194335 120390203 46 1560552
Muc5ac mucin 5AC, oligomeric mucus/gel-forming 1 214725482 214756653 210 62001
Faim2 Fas apoptotic inhibitory molecule 2 7 141158769 141185781 74 628744
Bnip3 BCL2 interacting protein 3 1 211248098 211265282 407 620800
Mmp1 matrix metallopeptidase 1 8 5703206 5723593 467 1307917
Smpd3 sphingomyelin phosphodiesterase 3 19 38237963 38321572 227 619754
Stat4 signal transducer and activator of transcription 4 9 54340649 54457753 170 1305747
Il27 interleukin 27 1 198003615 198010112 70 1561420
Mtcl1 microtubule crosslinking factor 1 9 114493901 114632632 75 1308319
Il5ra interleukin 5 receptor subunit alpha 4 138796165 138834164 59 70938
Muc1 mucin 1, cell surface associated 2 188543137 188547874 230 3122
Smad4 SMAD family member 4 18 69626682 69657373 681 3033
Timp1 TIMP metallopeptidase inhibitor 1 X 1364771 1369451 648 621675
Slpi secretory leukocyte peptidase inhibitor 3 160799979 160802228 160 621768
Xrcc5 X-ray repair cross complementing 5 9 79659275 79748050 187 3976
Erbb3 erb-b2 receptor tyrosine kinase 3 7 2989202 3010610 308 69323
F2rl1 F2R like trypsin receptor 1 2 25222324 25235275 258 620866
Plaur plasminogen activator, urokinase receptor 1 81328171 81344954 281 620597
Gzma granzyme A 2 44968846 44981436 99 628640
Cd8a CD8a molecule 4 99217640 99243352 112 2316
Table 6 Chronic obstructive pulmonary disease-related rat gene
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