Please wait a minute...
浙江大学学报（医学版）
浙江大学学报（医学版）  2018, Vol. 47 Issue (6): 665-670    DOI: 10.3785/j.issn.1008-9292.2018.12.16
综述     
基于基因敲除的炎性肠疾病复合动物模型研究进展
赵慧慧(),汤慧芳*()
浙江大学医学院, 浙江 杭州 310058
Research progress on composite animal models of inflammatory bowel disease based on gene knockout
ZHAO Huihui(),TANG Huifang*()
Zhejiang University School of Medicine, Hangzhou 310058, China
 全文: PDF(1015 KB)   HTML( 10 )
摘要：

建立合适的动物模型对于研究炎症性肠疾病（IBD）的机制以及探索新的治疗途径具有重要意义。单敲除某些与人类IBD易感性相关的基因并不表现为IBD的症状或症状较轻，而结合其他造模因素建立的复合动物模型能更好地模拟IBD的临床特征。本文主要介绍了三类新型复合动物模型的具体特点：基因双重敲除动物模型较单基因敲除模型的建立周期更短、疾病症状更明显；螺杆菌复合基因敲除模型有助于研究微生物感染在IBD发病机制中的作用；在基因敲除的基础上特异性缺失某种免疫细胞可用于研究该免疫细胞在IBD发展中的作用。这些模型在一定程度上有助于探索IBD的机制，其中Muc2/IL-10双重敲除模型有望成为IBD遗传学研究的重要动物模型。
关键词： 炎性肠疾病;  小鼠, 基因敲除;  疾病模型, 动物;  综述    
Abstract:

Establishing a suitable animal model is important for studying the mechanism of inflammatory bowel disease (IBD) and exploring new therapeutic approaches. Although a large number of IBD single gene knockout animal models have been established, single knockout of certain genes associated with human IBD susceptibility does not manifest symptoms of IBD or manifest extremely milder symptoms, while composite animal models based on other modeling factors can better simulate the clinical features of IBD. This article mainly introduces three novel composite animal models and elaborates the possible pathogenesis of each composite model:animal models established by gene double knockout have more obvious and earlier symptoms than single-knockout models; single gene knockout model with Helicobacter infection can help to study the role of microbial infections in the pathogenesis of IBD; on the basis of gene knockout, specific deletion of certain immune cells can be used to study the role of the immune cells in the development of IBD. Among the above composite animal models, Muc2/IL-10 double knockout mice may be important animal models for IBD study.
Key words: Inflammatory bowel diseases    Mice, knockout    Disease models, animal    Review
收稿日期: 2018-04-10 出版日期: 2019-03-15
:  R574  
基金资助: 国家自然科学基金(81570056);浙江省自然科学基金(Y18H310007)
通讯作者: 汤慧芳     E-mail: 3140104256@zju.edu.cn;tanghuifang@zju.edu.cn
作者简介: 赵慧慧(1996-), 女, 大学生, 主要从事抗炎免疫药理学研究; E-mail:3140104256@zju.edu.cn; https://orcid.org/0000-0002-1763-9594
服务　　
把本文推荐给朋友
加入引用管理器
E-mail Alert
RSS
作者相关文章　　
赵慧慧
汤慧芳

引用本文:

赵慧慧,汤慧芳. 基于基因敲除的炎性肠疾病复合动物模型研究进展[J]. 浙江大学学报（医学版）, 2018, 47(6): 665-670.

ZHAO Huihui,TANG Huifang. Research progress on composite animal models of inflammatory bowel disease based on gene knockout. J Zhejiang Univ (Med Sci), 2018, 47(6): 665-670.

链接本文:

http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2018.12.16    或    http://www.zjujournals.com/med/CN/Y2018/V47/I6/665

1 ZHANG Y Z , LI Y Y . Inflammatory bowel disease:pathogenesis[J]. World J Gastroenterol, 2014, 20 (1): 91- 99
doi: 10.3748/wjg.v20.i1.91
2 MIZOGUCHI A . Animal models of inflammatory bowel disease[J]. Prog Mol Biol Transl Sci, 2012, 105:263- 320
doi: 10.1016/B978-0-12-394596-9.00009-3
3 KHOR B , GARDET A , XAVIER R J . Genetics and pathogenesis of inflammatory bowel disease[J]. Nature, 2011, 474 (7351): 307- 317
doi: 10.1038/nature10209
4 KVHN R , L?HLER J , RENNICK D et al. Interleukin-10-deficient mice develop chronic enterocolitis[J]. Cell, 1993, 75 (2): 263- 274
doi: 10.1016/0092-8674(93)80068-P
5 RENNICK D M , FORT M M . Lessons from genetically engineered animal models. Ⅻ. IL-10-deficient (IL-10(-/-) mice and intestinal inflammation[J]. Am J Physiol Gastrointest Liver Physiol, 2000, 278 (6): G829- G833
doi: 10.1152/ajpgi.2000.278.6.G829
6 VAN DER SLUIS M , DE KONING B A , DE BRUIJN A C et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection[J]. Gastroenterology, 2006, 131 (1): 117- 129
doi: 10.1053/j.gastro.2006.04.020
7 VAN DER SLUIS M , BOUMA J , VINCENT A et al. Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation:mucin 2-interleukin 10-deficient mice[J]. Lab Invest, 2008, 88 (6): 634- 642
doi: 10.1038/labinvest.2008.28
8 PODOLSKY D K . Inflammatory bowel disease[J]. N Engl J Med, 2002, 347 (6): 417- 429
doi: 10.1056/NEJMra020831
9 RUIZ P A , SHKODA A , KIM S C et al. IL-10 gene-deficient mice lack TGF-beta/Smad signaling and fail to inhibit proinflammatory gene expression in intestinal epithelial cells after the colonization with colitogenic Enterococcus faecalis[J]. J Immunol, 2005, 174 (5): 2990- 2999
doi: 10.4049/jimmunol.174.5.2990
10 FENTON J I , HURSTING S D , PERKINS S N et al. Interleukin-6 production induced by leptin treatment promotes cell proliferation in an Apc (Min/+) colon epithelial cell line[J]. Carcinogenesis, 2006, 27 (7): 1507- 1515
doi: 10.1093/carcin/bgl018
11 NISHIYAMA T , MITSUYAMA K , TOYONAGA A et al. Colonic mucosal interleukin 1 receptor antagonist in inflammatory bowel disease[J]. Digestion, 1994, 55 (6): 368- 373
doi: 10.1159/000201167
12 AKITSU A , KAKUTA S , SAIJO S et al. Rag2-deficient IL-1 receptor antagonist-deficient mice are a novel colitis model in which innate lymphoid cell-derived IL-17 is involved in the pathogenesis[J]. Exp Anim, 2014, 63 (2): 235- 246
doi: 10.1538/expanim.63.235
13 SHINKAI Y , RATHBUN G , LAM K P et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement[J]. Cell, 1992, 68 (5): 855- 867
doi: 10.1016/0092-8674(92)90029-C
14 HANSEN R , THOMSON J M , FOX J G et al. Could Helicobacter organisms cause inflammatory bowel disease?[J]. FEMS Immunol Med Microbiol, 2011, 61 (1): 1- 14
doi: 10.1111/fim.2011.61.issue-1
15 FOX J G , GE Z , WHARY M T et al. Helicobacter hepaticus infection in mice:models for understanding lower bowel inflammation and cancer[J]. Mucosal Immunol, 2011, 4 (1): 22- 30
doi: 10.1038/mi.2010.61
16 WARD J M , ANVER M R , HAINES D C et al. Inflammatory large bowel disease in immunodeficient mice naturally infected with Helicobacter hepaticus[J]. Lab Anim Sci, 1996, 46 (1): 15- 20
17 KULLBERG M C , WARD J M , GORELICK P L et al. Helicobacter hepaticus triggers colitis in specific-pathogen-free interleukin-10(IL-10)-deficient mice through an IL-12-and gamma interferon-dependent mechanism[J]. Infect Immun, 1998, 66 (11): 5157- 5166
18 WEST N R , HEGAZY A N , OWENS B M J et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease[J]. Nat Med, 2017, 23 (5): 579- 589
19 SHEN Z , FENG Y , RICKMAN B et al. Helicobacter cinaedi induced typhlocolitis in Rag-2-deficient mice[J]. Helicobacter, 2015, 20 (2): 146- 155
doi: 10.1111/hel.2015.20.issue-2
20 BOIVIN M A , ROY P K , BRADLEY A et al. Mechanism of interferon-gamma-induced increase in T84 intestinal epithelial tight junction[J]. J Interferon Cytokine Res, 2009, 29 (1): 45- 54
doi: 10.1089/jir.2008.0128
21 MA T Y , IWAMOTO G K , HOA N T et al. TNF-alpha-induced increase in intestinal epithelial tight junction permeability requires NF-kappa B activation[J]. Am J Physiol Gastrointest Liver Physiol, 2004, 286 (3): G367- G376
doi: 10.1152/ajpgi.00173.2003
22 DIJKSTRA G , ZANDVOORT A J , KOBOLD A C et al. Increased expression of inducible nitric oxide synthase in circulating monocytes from patients with active inflammatory bowel disease[J]. Scand J Gastroenterol, 2002, 37 (5): 546- 554
doi: 10.1080/00365520252903099
23 THELESTAM M , FRISAN T . Cytolethal distending toxins[J]. Rev Physiol Biochem Pharmacol, 2004, 152:111- 133
24 SHEN Z , FENG Y , ROGERS A B et al. Cytolethal distending toxin promotes Helicobacter cinaedi-associated typhlocolitis in interleukin-10-deficient mice[J]. Infect Immun, 2009, 77 (6): 2508- 2516
doi: 10.1128/IAI.00166-09
25 SAGAMI S , UENO Y , TANAKA S et al. Cholinedeficiency causes colonic type Ⅱ natural killer T (NKT) cell loss and alleviates murine colitis under type Ⅰ NKT cell deficiency[J]. PLoS One, 2017, 12 (1): e0169681
doi: 10.1371/journal.pone.0169681
26 DE WINTER B Y , VAN DEN WIJNGAARD R M , DE JONGE W J . Intestinal mast cells in gut inflammation and motility disturbances[J]. Biochim Biophys Acta, 2012, 1822 (1): 66- 73
doi: 10.1016/j.bbadis.2011.03.016
27 CHICHLOWSKI M , WESTWOOD G S , ABRAHAM S N et al. Role of mast cells in inflammatory bowel disease and inflammation-associated colorectal neoplasia in IL-10-deficient mice[J]. PLoS One, 2010, 5 (8): e12220
doi: 10.1371/journal.pone.0012220
28 ZHU H , LI Y R . Oxidative stress and redox signaling mechanisms of inflammatory bowel disease:updated experimental and clinical evidence[J]. Exp Biol Med(Maywood), 2012, 237 (5): 474- 480
doi: 10.1258/ebm.2011.011358
29 ZHANG H , XUE Y , WANG H et al. Mast cell deficiency exacerbates inflammatory bowel symptoms in interleukin-10-deficient mice[J]. World J Gastroenterol, 2014, 20 (27): 9106- 9615
30 MIZOGUCHI A , TAKEUCHI T , HIMURO H et al. Genetically engineered mouse models for studying inflammatory bowel disease[J]. J Pathol, 2016, 238 (2): 205- 219
doi: 10.1002/path.4640
[1] 曹丽芹,施继敏. 异基因造血干细胞移植植入失败研究进展[J]. 浙江大学学报（医学版）, 2018, 47(6): 651-658.
[2] 唐和孝,白玉泉,申武林,赵金平. 白介素6在肺癌中的作用研究进展[J]. 浙江大学学报（医学版）, 2018, 47(6): 659-664.
[3] 向一郎,吴子衡,张鸿坤. 胸主动脉覆膜支架原位开窗技术的应用现状[J]. 浙江大学学报（医学版）, 2018, 47(6): 617-622.
[4] 李高鹏,何佳,王青青. 肿瘤相关成纤维细胞对肿瘤免疫调控作用的研究进展[J]. 浙江大学学报（医学版）, 2018, 47(5): 558-563.
[5] 王晓玲,欧阳旭梅,孙晓译. 基于间充质干细胞的小分子化学药物肿瘤靶向递送系统研究进展[J]. 浙江大学学报（医学版）, 2018, 47(5): 525-533.
[6] 胡彩琴,朱彪. 进行性多灶性脑白质病的发病机制研究进展[J]. 浙江大学学报（医学版）, 2018, 47(5): 534-540.
[7] 史庭,叶琇锦. CCAAT增强子结合蛋白α与急性髓细胞白血病的发生[J]. 浙江大学学报（医学版）, 2018, 47(5): 552-557.
[8] 叶建宇,孙自玉,胡薇薇. 星形胶质细胞在脑梗死中的作用及相关治疗策略[J]. 浙江大学学报（医学版）, 2018, 47(5): 493-498.
[9] 卢战军,胡洋洋,李思思,臧丽娟,蒋巍亮,吴坚炯,巫协宁,曾悦,王兴鹏. 白介素35在炎性肠疾病中的抗炎作用机制[J]. 浙江大学学报（医学版）, 2018, 47(5): 499-506.
[10] 何佳怡,张信美. 氧化应激在子宫内膜异位症发病机制中的研究进展[J]. 浙江大学学报（医学版）, 2018, 47(4): 419-425.
[11] 徐至理,崔一怡,李妍,郭勇. 乳腺癌非特异性免疫微环境的研究进展[J]. 浙江大学学报（医学版）, 2018, 47(4): 426-434.
[12] 王星星,王盼盼,杨旭燕. 系统性红斑狼疮合并器官特异性自身免疫性疾病的相关研究进展[J]. 浙江大学学报（医学版）, 2018, 47(4): 435-440.
[13] 张丽凤,张信美. 维生素D在子宫内膜异位症中的作用研究进展[J]. 浙江大学学报（医学版）, 2018, 47(4): 413-418.
[14] 钱波,张彦玲,莫绪明. 先天性食管闭锁相关转录因子及信号通路研究进展[J]. 浙江大学学报（医学版）, 2018, 47(3): 239-243.
[15] 张小燕,康利军. 秀丽隐杆线虫嗅觉适应性的分子细胞生物学机制[J]. 浙江大学学报（医学版）, 2018, 47(3): 307-312.