CN111269944A - Mouse cataract animal model and application thereof - Google Patents
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- 208000002177 Cataract Diseases 0.000 title claims abstract description 42
- 238000010171 animal model Methods 0.000 title claims abstract description 16
- 101150011139 AQP5 gene Proteins 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 13
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 13
- 239000012634 fragment Substances 0.000 claims abstract description 12
- 238000010172 mouse model Methods 0.000 claims abstract description 9
- 229940079593 drug Drugs 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 7
- 230000008506 pathogenesis Effects 0.000 claims abstract description 7
- 238000010276 construction Methods 0.000 claims abstract description 6
- 241001465754 Metazoa Species 0.000 claims abstract description 5
- 210000000349 chromosome Anatomy 0.000 claims abstract description 5
- 230000000694 effects Effects 0.000 claims abstract description 5
- 108091033409 CRISPR Proteins 0.000 claims description 8
- 238000010354 CRISPR gene editing Methods 0.000 claims description 4
- 238000012217 deletion Methods 0.000 claims description 3
- 230000037430 deletion Effects 0.000 claims description 3
- 238000003209 gene knockout Methods 0.000 claims description 3
- 238000012258 culturing Methods 0.000 claims description 2
- 101100163079 Mus musculus Aqp5 gene Proteins 0.000 claims 1
- 150000007523 nucleic acids Chemical group 0.000 claims 1
- 102000004169 proteins and genes Human genes 0.000 claims 1
- 206010024214 Lenticular opacities Diseases 0.000 abstract description 8
- 238000011160 research Methods 0.000 abstract description 6
- 238000011156 evaluation Methods 0.000 abstract description 4
- 208000024891 symptom Diseases 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 230000001575 pathological effect Effects 0.000 abstract description 2
- 230000000750 progressive effect Effects 0.000 abstract description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 19
- 241000699670 Mus sp. Species 0.000 description 12
- 108090000976 Aquaporin 5 Proteins 0.000 description 5
- 102000004392 Aquaporin 5 Human genes 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- 210000000695 crystalline len Anatomy 0.000 description 4
- 206010064571 Gene mutation Diseases 0.000 description 3
- 238000012408 PCR amplification Methods 0.000 description 3
- 206010007747 Cataract congenital Diseases 0.000 description 2
- 108091027544 Subgenomic mRNA Proteins 0.000 description 2
- 238000009395 breeding Methods 0.000 description 2
- 230000001488 breeding effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 238000012163 sequencing technique Methods 0.000 description 2
- 208000031404 Chromosome Aberrations Diseases 0.000 description 1
- 102000014824 Crystallins Human genes 0.000 description 1
- 108010064003 Crystallins Proteins 0.000 description 1
- 206010067477 Cytogenetic abnormality Diseases 0.000 description 1
- 241000581650 Ivesia Species 0.000 description 1
- 208000005374 Poisoning Diseases 0.000 description 1
- 108010006785 Taq Polymerase Proteins 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 231100000089 gene mutation induction Toxicity 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000008120 lens development in camera-type eye Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 208000030212 nutrition disease Diseases 0.000 description 1
- 208000019180 nutritional disease Diseases 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
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- C12N15/90—Stable introduction of foreign DNA into chromosome
- C12N15/902—Stable introduction of foreign DNA into chromosome using homologous recombination
- C12N15/907—Stable introduction of foreign DNA into chromosome using homologous recombination in mammalian cells
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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- A01K67/0276—Knock-out vertebrates
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Abstract
The invention provides a construction method of a cataract animal model, which is characterized in that the cataract animal model is constructed by knocking out AQP5 gene in an animal; and cultured for not less than 6 months. The AQP5 gene is knocked out by 99589876-99594444 region on the 15 th chromosome of a mouse, and the length of the gene fragment is 4569 bp. The invention also provides a cataract mouse model which is constructed by knocking out the AQP5 gene by the method. The cataract mouse model provided by the invention is applied to research on the pathogenesis of cataract or evaluation on the effect of cataract treatment drugs. The AQP5-KO model mouse has high repeatability and stable model, is beneficial to the research of cataract pathological mechanism and drug intervention, and can avoid the influence of other influencing factors on experimental results. Furthermore, the AQP5-KO mouse model of the present invention showed progressive lenticular opacity symptoms at 6 months after birth and was free of gender differences.
Description
Technical Field
The invention belongs to the technical field of medical animal models, and particularly relates to a method for establishing a cataract animal model.
Background
Cataract refers to the degeneration of lens protein and opacity caused by metabolic disorder of lens due to various reasons such as aging, hereditary, local nutritional disorder, immune and metabolic disorders, trauma, poisoning, radiation, etc. At present, cataract is ranked at the head of pathogenic eye diseases in the world, and cataract prevention and treatment are the key points in ophthalmic research.
Since the transparency of the patient's lens is affected by a variety of high factors and the cataract exhibits a high degree of heterogeneity, a series of fundamental and clinical problems regarding the pathogenesis, diagnosis and treatment of cataracts are currently under intensive study. The establishment of the cataract animal model is an effective and practical means for researching the pathogenesis and exploring the treatment method. The congenital cataract may be caused by chromosome abnormality or gene mutation and other factors, at present, a model is mainly made by three ways, and the first way is a transgenic mouse established by a gene means or a gene mutated mouse strain; the second method is to induce gene mutation by physical or chemical method; the third is by targeted targeting or knockout of different genomic sites. The cataract has high genetic heterogeneity, and genetic cataract can be formed by any gene mutation related to lens development and differentiation, so that the pathogenic genes of the cataract are also many, many of the genes have not been specifically analyzed at present, and a lot of unknown genes exist. Therefore, more cataract animal models need to be manufactured, and important carriers are provided for basic and clinical researches such as the pathogenesis, the disease course progression, drug development and drug efficacy evaluation of cataract.
Disclosure of Invention
The invention aims to overcome the defects of the types of the existing models and provide a stable cataract animal model so as to make up the defects of the prior art.
The applicant designs sgRNA by using CRISPR/Cas9 technology, and obtains an AQP5 gene knockout mouse (AQP5-KO) by applying a high-flux electrotransformation fertilized egg mode. And the AQP5-KO mice are proved to be cataracts 6 months after birth for the first time, and the phenotype of the model is stable, thereby leading to the invention.
The invention firstly provides a construction method of a cataract animal model, which is to construct the cataract animal model by knocking out AQP5 gene in an animal;
the AQP5 gene is knocked out by a gene fragment of 99589876-99594444 on the 15 th chromosome of a mouse and the length of the gene fragment is 4569 bp;
the construction method is constructed by knocking out AQP5 gene of mouse and culturing for no less than 6 months at birth;
the AQP5 gene in the knockout animal is completed through a CRISPR/Cas9 system;
the invention also provides a cataract mouse model which is constructed by knocking out AQP5 gene by the method
The AQP5 gene is knocked out by a gene fragment of 99589876-99594444 on the 15 th chromosome of a mouse and the length of the gene fragment is 4569 bp;
the invention also provides a preparation for detecting AQP5-KO mice, which comprises a primer pair for detecting the deletion fragment;
wherein, the primer pair for detecting the deletion fragment has the following sequence information:
AQP5-F1:CAAAGTGCTCAAACACTAACCGTAC(SEQ ID NO:1)
AQP5-R1:GATTGGTGGTTTATTGGGAAACG(SEQ ID NO:2)。
AQP5-R3:TGCAGGTCTTTGTTTCTGCCG(SEQ ID NO:3)。
the cataract mouse model provided by the invention is applied to research on the pathogenesis of cataract or evaluation on the effect of cataract treatment drugs.
The AQP5-KO model mouse has high repeatability and stable model, is beneficial to the research of cataract pathological mechanism and drug intervention, and can avoid the influence of other influencing factors on experimental results. Furthermore, the AQP5-KO mouse model of the present invention showed progressive lenticular opacity symptoms at 6 months after birth and was free of gender differences.
Drawings
FIG. 1: A. b is the information and the KO region of the AQP5-KO mouse in the embodiment 1, and C is a sequencing identification result graph of the AQP5-KO mouse;
FIG. 2: the invention discloses an electrophoretogram of an AQP5-KO mouse gene identification result in example 1;
FIG. 3: wild type and AQP5-KO mice of different ages in example 1 of the present invention were slit lamp photographed;
FIG. 4: statistical results of lens opacity scores of wild type and AQP5-KO mice in example 1 of the present invention are shown.
Detailed Description
Applicants found that AQP5-KO mice knock-out of the Aquaporin5 gene (Aquaporin5, AQP5) exhibited symptoms of cataracts after 6 months of birth, with increasing clouding of the lens with age, and no gender differences.
The technical solution of the present invention will be further illustrated and described below with reference to the accompanying drawings by means of specific embodiments.
Example 1: construction of AQP5-KO mouse cataract animal model
1. Construction and identification of AQP5-KO mice
AQP5(NCBI ID:11830) is located on chromosome 15 of a mouse, information and a knockout region of an AQP5-KO mouse are shown in figure 1A, B, a sgRNA is designed by adopting a CRISPR/Cas9 technology, a gene fragment with the length of 4569bp in a chr15: 99589876-94444 region is knocked out by applying a high-flux electrotransformation fertilized egg mode, and the AQP5-KO mouse is obtained.
FIG. 1C shows the result of the sequencing identification of AQP5-KO mouse, and compared with the wild-type sequence, 4569bp sequence is deleted altogether, which indicates that the model mouse is successfully established. This mouse has been successfully bred in the laboratory of the applicant and a stable population of homozygous mice has been obtained.
In subsequent routine breeding, the knock-out effect of AQP5-KO mice was detected by PCR amplification.
PCR amplification of the fragment of interest: reaction conditions and reaction system:
(1) and (3) PCR reaction conditions: 3min at 94 ℃; 94 ℃ 30sec, 60 ℃ 30se, 65 ℃ 50sec, 33 cycles; 10min at 72 ℃.
(2) Reaction system: (TAKARA LA Taq polymerase)
Wherein the primer pairs are respectively
AQP5-F1:CAAAGTGCTCAAACACTAACCGTAC、
AQP5-R1:GATTGGTGGTTTATTGGGAAACG、
AQP5-F1:CAAAGTGCTCAAACACTAACCGTAC、
AQP5-R3:TGCAGGTCTTTGTTTCTGCCG。
The identification result of the breeding mouse is shown in figure 2, and the result of PCR amplification of the mouse tail genome DNA shows that the 1, 2, 6 and 7 columns only have 640bp fragments and are homozygote mice; 3. the two fragments of 640bp and 348bp are shown in columns 4 and 5, which are heterozygotes.
2. Lenticular opacity symptoms in AQP5-KO mice
Wild type and AQP5-KO mice are selected and bred conventionally, the AQP5-KO mice show obvious lenticular opacity at 6 months after birth, the lenticular opacity degree is increased at 9 months, and the experimental result is shown in figure 3. The degree of lenticular opacity was scored by the lenticular opacity classification criteria-LOCS II and the statistical results are shown in FIG. 4.
The animal model constructed by the invention can be used for researching the pathogenesis of the congenital cataract, in particular to the action and mechanism of aquaporin5 in the maintenance of the transparency of crystalline lens; and is used for screening or evaluating the action mechanism and effect evaluation of various cataract treatment medicines.
Sequence listing
<110> Qingdao university
<120> mouse cataract animal model and application thereof
<160>3
<170>SIPOSequenceListing 1.0
<210>1
<211>25
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>1
caaagtgctc aaacactaac cgtac 25
<210>2
<211>23
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>2
gattggtggt ttattgggaa acg 23
<210>3
<211>21
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>3
tgcaggtctt tgtttctgcc g 21
Claims (9)
1. A method for constructing a cataract animal model is characterized in that the method is used for constructing the cataract animal model by knocking out AQP5 gene in an animal.
2. The method as claimed in claim 1, wherein the AQP5 gene knock-out is a nucleic acid fragment of 99589876-99594444 region on chromosome 15 of a mouse.
3. The method of claim 1 or 2, wherein said method is performed by knocking out mouse AQP5 gene and culturing it for not less than 6 months after birth.
4. The method for constructing the protein of claim 1, wherein the AQP5 gene knockout is performed by a CRISPR/Cas9 system.
5. The method of claim 1, wherein the animal is a mouse.
6. A mouse model of cataract, wherein said model is constructed by the construction method of any one of claims 1 to 4.
7. A preparation for detecting the mouse model of cataract as claimed in claim 6, wherein the preparation comprises primer pair for detecting the deletion fragment of AQP5 gene.
8. The article of claim 8, wherein the primers of the primer pairs have the sequences of SEQ ID NOS: 1-3.
9. Use of the mouse model of cataract claimed in claim 6 for studying the pathogenesis of cataract or evaluating the effect of cataract-treating drugs.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112220446A (en) * | 2020-10-28 | 2021-01-15 | 中国人民解放军陆军特色医学中心 | Mouse cataract detection equipment |
| CN112251467A (en) * | 2020-10-18 | 2021-01-22 | 青岛大学 | Animal model of neurotrophic keratitis of mice and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000073509A2 (en) * | 1999-06-01 | 2000-12-07 | Incyte Genomics, Inc. | Molecules for diagnostics and therapeutics |
| CN107312859A (en) * | 2017-07-26 | 2017-11-03 | 青岛大学 | Application of the AQP5 genes in detection congenital cataract product is prepared |
| CN112608940A (en) * | 2020-12-17 | 2021-04-06 | 中国人民解放军陆军特色医学中心 | Construction method and application of animal model of congenital cataract disease |
-
2020
- 2020-02-05 CN CN202010080386.7A patent/CN111269944A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000073509A2 (en) * | 1999-06-01 | 2000-12-07 | Incyte Genomics, Inc. | Molecules for diagnostics and therapeutics |
| CN107312859A (en) * | 2017-07-26 | 2017-11-03 | 青岛大学 | Application of the AQP5 genes in detection congenital cataract product is prepared |
| CN112608940A (en) * | 2020-12-17 | 2021-04-06 | 中国人民解放军陆军特色医学中心 | Construction method and application of animal model of congenital cataract disease |
Non-Patent Citations (2)
| Title |
|---|
| S. SINDHU KUMARI ET AL.,: "Aquaporin 5 knockout mouse lens develops hyperglycemic catarac", 《BIOCHEM BIOPHYS RES COMMUN》 * |
| 陈智鸿等: "水通道蛋白敲除对支气管哮喘小鼠气道黏蛋白谱表达的影响", 《中华哮喘杂志（电子版）》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112251467A (en) * | 2020-10-18 | 2021-01-22 | 青岛大学 | Animal model of neurotrophic keratitis of mice and application thereof |
| CN112251467B (en) * | 2020-10-18 | 2024-01-30 | 青岛大学 | Mouse neurotrophic keratitis animal model and application thereof |
| CN112220446A (en) * | 2020-10-28 | 2021-01-15 | 中国人民解放军陆军特色医学中心 | Mouse cataract detection equipment |
| CN112220446B (en) * | 2020-10-28 | 2024-01-30 | 中国人民解放军陆军特色医学中心 | Mouse cataract detection equipment |
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