Generation of hyperlipidemic rabbit models using multiple sgRNAs targeted CRISPR/Cas9 gene editing system View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-03-18

AUTHORS

Tingting Yuan, Yi Zhong, Yingge Wang, Ting Zhang, Rui Lu, Minya Zhou, Yaoyao Lu, Kunning Yan, Yajie Chen, Zhehui Hu, Jingyan Liang, Jianglin Fan, Yong Cheng

ABSTRACT

ObjectiveTo generate novel rabbit models with a large-fragment deletion of either LDL receptor (LDLR) and/or apolipoprotein (apoE) genes for the study of hyperlipidemic and atherosclerosis.MethodsCRISPR/Cas9 system directed by a multiple sgRNAs system was used in rabbit embryos to edit their LDLR and apoE genes. The LDLR and apoE genes of founder rabbits were sequenced, and their plasma lipids and lipoprotein profiles on a normal chow diet were analyzed, western blotting was also performed to evaluate the expression of apolipoprotein. Sudan IV and HE staining of aortic were performed to confirm the formation of atherosclerosis.ResultsSix knockout (KO) rabbits by injection of both LDLR and apoE sgRNAs were obtained, including four LDLR KO rabbits and two LDLR/apoE double- KO rabbits. Sequence analysis of these KO rabbits revealed that they contained multiple mutations including indels, deletions, and substitutions, as well as two rabbit lines containing biallelic large fragment deletion in the LDLR region. Analysis of their plasma lipids and lipoprotein profiles of these rabbits fed on a normal chow diet revealed that all of these KO rabbits exhibited remarkable hyperlipidemia with total cholesterol levels increased by up to 10-fold over those of wild-type rabbits. Pathological examinations of two founder rabbits showed that KO rabbits developed prominent aortic and coronary atherosclerosis.ConclusionLarge fragment deletions can be achieved in rabbits using Cas9 mRNA and multiple sgRNAs. LDLR KO along with LDLR/apoE double KO rabbits should provide a novel means for translational investigations of human hyperlipidemia and atherosclerosis. More... »

PAGES

69

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s12944-019-1013-8

DOI

http://dx.doi.org/10.1186/s12944-019-1013-8

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1112852196

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30885208


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30 schema:description ObjectiveTo generate novel rabbit models with a large-fragment deletion of either LDL receptor (LDLR) and/or apolipoprotein (apoE) genes for the study of hyperlipidemic and atherosclerosis.MethodsCRISPR/Cas9 system directed by a multiple sgRNAs system was used in rabbit embryos to edit their LDLR and apoE genes. The LDLR and apoE genes of founder rabbits were sequenced, and their plasma lipids and lipoprotein profiles on a normal chow diet were analyzed, western blotting was also performed to evaluate the expression of apolipoprotein. Sudan IV and HE staining of aortic were performed to confirm the formation of atherosclerosis.ResultsSix knockout (KO) rabbits by injection of both LDLR and apoE sgRNAs were obtained, including four LDLR KO rabbits and two LDLR/apoE double- KO rabbits. Sequence analysis of these KO rabbits revealed that they contained multiple mutations including indels, deletions, and substitutions, as well as two rabbit lines containing biallelic large fragment deletion in the LDLR region. Analysis of their plasma lipids and lipoprotein profiles of these rabbits fed on a normal chow diet revealed that all of these KO rabbits exhibited remarkable hyperlipidemia with total cholesterol levels increased by up to 10-fold over those of wild-type rabbits. Pathological examinations of two founder rabbits showed that KO rabbits developed prominent aortic and coronary atherosclerosis.ConclusionLarge fragment deletions can be achieved in rabbits using Cas9 mRNA and multiple sgRNAs. LDLR KO along with LDLR/apoE double KO rabbits should provide a novel means for translational investigations of human hyperlipidemia and atherosclerosis.
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37 CRISPR/Cas9 gene editing system
38 Cas9 system
39 HE staining
40 KO
41 KO rabbits
42 LDL receptor
43 LDLR-KO
44 ObjectiveTo
45 Sudan IV
46 Western blotting
47 analysis
48 aortic
49 apoE
50 apolipoproteins
51 atherosclerosis
52 blotting
53 cholesterol levels
54 chow diet
55 coronary atherosclerosis
56 deletion
57 diet
58 editing system
59 embryos
60 examination
61 expression
62 expression of apolipoproteins
63 formation
64 formation of atherosclerosis
65 founder rabbits
66 fragment deletion
67 gene editing system
68 generation
69 genes
70 human hyperlipidemia
71 hyperlipidemia
72 hyperlipidemic rabbit model
73 indels
74 injection
75 investigation
76 knockout rabbits
77 large fragment deletion
78 levels
79 lines
80 lipids
81 lipoprotein profile
82 mRNA
83 means
84 model
85 multiple mutations
86 multiple sgRNAs
87 mutations
88 normal chow diet
89 novel means
90 novel rabbit model
91 pathological examination
92 plasma lipids
93 profile
94 rabbit embryos
95 rabbit lines
96 rabbit model
97 rabbits
98 receptors
99 region
100 sequence analysis
101 sgRNAs
102 staining
103 study
104 substitution
105 system
106 total cholesterol levels
107 translational investigations
108 wild-type rabbits
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