Methods for constructing eye disease models and their uses

Abstract

A method for constructing an eye disease model is provided, which comprises infecting a model carrier with a microorganism. Also provided is an eye model carrier infected with a microorganism produced by this method. The eye model carrier can be used for research on eye diseases and screening of drugs for treating eye diseases. The eye disease is retinal degeneration, and the microorganism is an intestinal bacterium or the same bacterium as an intestinal bacterium.

Description

[Technical field]

[0001] The present invention belongs to the technical field of diagnosis and treatment of eye diseases, and specifically relates to a method for constructing an eye disease model, and the use of the eye disease model and model carrier obtained by said method in research on eye diseases and screening of therapeutic drugs. [Background technology]

[0002] Inherited retinal degenerations (IRDs) are genetic disorders that are the most common cause of vision loss in the working population of industrialized countries. They are genetic disorders characterized by progressive loss of photoreceptor cells and include congenital amaurosis (LCA), retinitis pigmentosa (RP), early-onset rod-cone dystrophy, rod-rod dystrophy, congenital stationary night blindness and color vision deficiency, and Stargardt disease (Broadgate et al., 2017). It is the most common cause of vision loss in the working population of industrialized countries, with an estimated incidence of 1:2000 (Kutluer et al., 2020). Due to genetic and clinical heterogeneity, the treatment of IRDs requires highly individualized therapeutic approaches. Neuroprotection, gene therapy, and cell replacement therapy have been proposed as treatments for various stages of IRD, but to date, only one gene therapy to correct mutations in the RPE65 gene (Luxturna) has been approved by the FDA for the treatment of LCA ( Botto et al., 2021 ; Ikelle et al., 2020 ; Kutluer et al., 2020 ).

[0003] More than 200 genes have been implicated in IRD. Among these, the CRB1 gene has long been recognized as a key gene whose mutations result in various ophthalmic phenotypes, including LCA and RP (Ehrenberg et al., 2013). CRB1 is a key regulator of adhesion molecule junctions and plays a key role in establishing cell polarity and maintaining the integrity of the ocular barrier. The frequency of IRD-induced CRB1 mutations varies considerably worldwide. For example, the frequency of CRB1 mutant alleles in LCA cases is 6.7% in the United States, 1.7% in Canada, 0% in the Netherlands, 16.7% in Spain, and 11.5% in China (Li et al., 2011; Vallespin et al., 2007; Zernant et al., 2005), and CRB1 is the gene with the highest mutation frequency in all Spanish patients with LCA, early-onset RP, and non-early-onset RP (Vallespin et al., 2007). In general, CRB1 gene mutations account for 4% of RP and 10–15% of LCA cases worldwide ( Richard et al., 2006 ). Therefore, therapeutic approaches to rescue vision loss due to CRB1 are urgently needed. Summary of the Invention [Problem to be solved by the invention]

[0004] An object of the present invention is to provide a method for constructing an eye disease model or an eye disease model carrier, in particular a method for constructing a retinal degeneration model or model carrier, and a model or model carrier constructed by said method, as well as the use of said method, disease model and / or disease model carrier in eye disease research and screening of related pharmaceuticals. [Means for solving the problem]

[0005] The object of the present invention is achieved by the following technical solutions:

[0006] The present invention provides a method for constructing an ocular disease model, the method comprising infecting the ocular disease model with a microorganism.

[0007] Preferably, the infection comprises direct contact with a microorganism or indirect contact with a microorganism. In one specific embodiment, the eye disease model in which the eye is infected with a microorganism is obtained by rearing a non-human animal in an SPF environment.

[0008] Preferably, said microorganisms are derived from or are identical to the intestinal bacteria of the same individual.

[0009] Preferably, said eye disease comprises retinal degeneration, more preferably said retinal degeneration is progressive retinal degeneration.

[0010] Preferably, said retinal degeneration is an inherited retinal degeneration (IRD).

[0011] Preferably, the eye disease comprises LCA, RP, arRP, EORD, EORP, PPRPE, rettelangiectasia and / or choroideremia like fundus.

[0012] Preferably, the eye disease includes ocular inflammatory diseases such as uveitis, glaucoma, age-related macular degeneration (AMD), vitreitis, choroiditis, retinitis, retinal vasculitis, and optic neuritis, as well as uveitis, Behcet's disease, Vogt-Koyanagi-Harada disease, uveitis, retinopathy, sympathetic ophthalmia, cataract, conjunctivitis, and glaucoma.

[0013] Preferably, said model is a non-human animal, preferably a monkey, dog, chimpanzee, rat or mouse.

[0014] Preferably, said model carrier is a cell, tissue or organ, said cell, tissue or organ being derived from a human or non-human animal.

[0015] Preferably, the cells are primary cells or cell lines.

[0016] Preferably, the tissue is an ocular tissue and the organ is an ocular organ.

[0017] Preferably, the tissue or organ is a regenerative tissue or organ.

[0018] Preferably, the model harbors a pathogenic mutation in a gene.

[0019] Preferably, the gene harboring a pathogenic mutation is a gene involved in maintaining the structure of the retinal barrier, said retinal barrier being the outer blood-retinal barrier and / or the inner blood-retinal barrier.

[0020] Preferably, the model or model carrier has a pathogenic eye disease associated gene mutation, and the gene having a pathogenic eye disease associated gene mutation is selected from one or a combination of two or more of the following genes: ABCA4, ABCC6, ABCC9, ACBD5, ACO2, ACO2, ACTG1, ADGRV1, AHI1, AIPL1, ALMS1, AMY2B, APC, ARFGEF1, ARL13B, ARL13B, ARL6, ARMC9, ATOH7, B9D1, BAG3, BBS1, BBS2, BBS5, BEST1, C2CD3, CACD4, CACD5, CACD6, CACD7, CACD8, CACD9, CACD1, CACD1, CACD2, CACD1, CACD1, CACD2, CACD3, CACD4, CACD5, CACD1, CACD1, CACD2 ...1, CACD2, CACD1, CACD1, CACD1, CACD1, CACD1, CACD1, CACD2, CACD1, CACD1, CACD1, CACD1, CACD1, CACD1, CACD1, CACD1, CACD1, CACD1, CACD1, CACD1, CACD1 4, CABP4, CACNA1F, CBS, CC2D2A, CDH23, CDH23, CDHR1, CEMIP2, CEP104, CEP250, CEP290, CEP290, CEP41, CEP78, CERKL, CFAP410, CFAP418, CHM, CLCC1, CLCN7, CLN3, CLN5, CLN8, CLRN1, CLRN1, CNGA1, CNGA1, CNGA3, CNGB1, CNGB3, CNNM4, COL11A1, COL11A2, COL18A1, COL2A1, COL4A1, COL9A1, COL9A2, CP, C P, CPLANE1, CRB1, ERCC4, CSPP1, CTNNA1, CYP4V2, DHDDS, DYNC2H1, DYNC2I1, DYNC2I2, ENPP1, ERCC4, EVC2, EYS, EYS, F5, FAM161A, FBN1, FKRP, FKTN, FL G, FLVCR1, FOXE3, FUZ, GLB1, GMPPB, GNAT1, GRK1, GRM6, GUCA1A, GUCA1B, GUCY2D, HADHA, HGSNAT, HPS3, HPS5, IDH3B, IFT122, IFT140, IFT140, IFT43, IF T52, IFT74, IFT80, IFT80, IFT81, IFT88, IKBKG, IMPDH1, IMPG2, INPP5E, INTU, IQCB1, IQCE, IREB2, KCNJ13, KCNQ1, KCNV2, KIAA0586, KIAA0753, KIF7, KIZ, KIZ-AS1, KLHL7, KRIT1, LBR, LCA5, LOC101927157, LOC111365204, LRP2, LRP5, MAK, MAPKAPK3, MATK, MCOLN1, MERTK, MKS1, MPDZ, MT-ATP6, MT-CO3,MT-TE, MT-TL1, MTHFR, MUTYH, MYO7A, MYO7A, NMNAT1, NPHP1, NR2E3, OCA2, OTX2, PANK2, PAX6, PCARE, PC DH15, PDE6A, PDE6B, PDE6B, PDE6D, PEX1, PEX1, PEX12, PEX26, PEX6, PHF3, PITPNM3, PKD2, PLA2G5, POC5 , POMT1, PRCD, PRDM13, PROM1, PRPF3, PRPF31, PRPF8, PRPH2, RAD51C, RBP3, RBP4, RD3, RDH12, RDH5, RGR , RGR, RHO, RIMS1, RLBP1, ROM1, RP1, RP1L1, RP2, RPE65, RPE65, RPGR, RPGRIP1, RPGRIP1L, RS1, SACS, SA G, SCAPER, SDCCAG8, SIX6, SLC19A1, SLC22A5, SLC26A4, SLC2A9, SLTM, SNRNP200, SPAG17, SPATA7, SPG1 1, TFAP2A, TGFB2, TGFBR2, TMEM107, TMEM237, TMEM67, TOGARAM1, TOPORS, TPP1, TRAF3IP1, TREX1, TRIM 59-IFT80, TSPAN12, TTC21B, TTC21B, TTC8, TULP1, USH1C, USH2A, USH2A, USH2A, USH2A, USH2A-AS1, VAC 14, VCAN, VCAN, VCAN-AS1, VHL, VPS13B, WDR19, WDR19, WDR35, WDR73, YARS1, ZFYVE26, ZFYVE26, ZNF408. ,

[0021] In one specific embodiment, the model or model carrier comprises the CRB1 gene among the eye disease-associated genes having a pathogenic mutation.

[0022] Preferably, the mutations in the CRB1 gene of said model or model carrier include one or more of the following mutations: c.107C>G, c.111delT, c.135C>G, c.257_258dupTG, c.258C>T, c.428_432delGATTC, c.430T>G, c.470G>C, c.481dupG, c.482C>T, c.584G>T, c.613_619del, c.717_718insG, c.750T>G, c.915T>A, c.929G>A, c.936T>G, c.998G>A, c.1084C>T, c.11 25C>G, c.1148G>A, c.1208C>G, c.1269C>A, c.1298A>G, c.1313G>A, c.1438T> C, c.1438T>G, c.1576C>T, c.1604T>C, c.1690G>T, c.1733T>A, c.1750G>T, c.1 760G>A, c.1834T>C, c.1963delC, c.2025G>T, c.2042G>A, c.2128G>C, c.2129C >T, c.2185_2186insAlu, c.2219C>T, c.2222T>C, c.2234C>T, c.2245_2247del 3bp(TCA), c.2258T>C, c.2290C>T, c.2365_2367del AAT, in-frame deletion, c.2401A>T, c.2438_2439ins>100A, c.2441_2442del, c.2465G>A, c.2479G>T, c.2506C>A, c.2509G>C, c.2536G>A, c .2548_2551delGGCT, c.2548G>A, c.2555T>C, c.2611_2613insT, c.2671T>G, c.2676delG, c.2681A>G, c.2688T>A, c.2816G>A, c.28 43G>A, c.2853dupT, c.2884_2886delTTA, c.2957A>T, c.2966T>C, c.2983G>T, c.3002A>T, c.3008T>C, c.3035T>C, c.3037C>T, c.30 74G>A, c.3074G>T, c.3122T>C, c.3212T>C, c.3296C>A, c.3299T>C, c.3299T>G, c.3307G>A / C, c.3320T>C, c.3320T>G, c.3331G>T, c.3343_3352del、c.3347delT、c.3343_3352del、c.3347delT、c.3427delT、c.3482A>G、c.3493T>C、c.3655T>G、c.3541T>C、c.3542dupG、c.3593A>G、c.3613G>A、c.3653G>T、c.3659_3660delinsA、c.3664C>T、c.3668G>C、c.3676G>T、c.3713_3716dup、c.3879G>A、c.3914C>T、c.3949A>C、c.3961T>A、c.3988delG、c.3988G>T、c.3995G>T、c.3996C>A、c.3997G>T、c.4094C>A、c.4121_4130del、c.4142C>T、c.4148G>A、c.2128+2T>G、c.2842+5G>A、c.3878+1G>T、c.4005+1G>A、c.4005+2T>G、c.4006-2A>G、c.4006-1G>T、c.619G>A、c.614T>C、c.1472A>T、c.1903T>C、c.2809G>A、c.3103C>T、c.4082G>A、c.4060G>A、c.866C>T、c.1463T>C、c.2035C>G、c.2306_2307GC>AG、c.2306G>A、c.2714G>A、c.2875G>A、c.3992G>A。.

[0023] More preferably, the mutation in the CRB1 gene of said model or model carrier comprises one or more of the following mutations: c.4006-1G>T, c.3686G>C, (p.Cys1229Ser), c.2842+1delinsAA, c.4060G>A, (p.Ala1354Thr), c.3991C>T, (p.Arg1331Cys), c.3014A>T, (p.Asp1005Val), c.4005+1G>A, c.2680_2684del, (p.Asn894 fs), c.1733T>A, (p.Val578Glu), c.455G>A, (p.Cys152Tyr), c.3462_3463del, (p.Cys1154_Glu1155delinsTer), c.3037C>T, (p.Gln 1013Ter), c.2673C>A, (p.Cys891Ter), c.2230C>T, (p.Arg744Ter), c.3676G>T, (p.Gly1226Ter), c.2842+5G>A, c.2842T>C, (p.Cys94 8Arg), c.3988del, (p.Glu1330fs), c.2506C>A, (p.Pro836Thr), c.2291G>A, (p.Arg764His), c.1576C>T, (p.Arg526Ter), c.613_619 del, (p.Ile205fs), c.3320T>C, (p.Leu1107Pro), c.2688T>A, (p.Cys896Ter), c.2555T>C, (p.Ile852Thr), c.2222T>C, (p.Met741Thr ), c.1148G>A, (p.Cys383Tyr), c.2843G>A, (p.Cys948Tyr), c.4121_4130del, (p.Ala1374fs), c.3307G>A, (p.Gly1103Arg), c.484G>A , (p.Val162Met), c.2401A>T, (p.Lys801Ter), c.2234C>T, (p.Thr745Met), c.2290C>T, (p.Arg764Cys), c.3122T>C, (p.Met1041Thr).

[0024] Preferably, the mutation in the CRB1 gene of said model or model carrier is the Rd8 mutation.

[0025] Preferably, the mutation is a homozygous or heterozygous mutation.

[0026] Preferably, said model or model carrier either aboriginally harbours said genetic mutation in vivo or has acquired the mutation as a result of recombinant genetic manipulation.

[0027] Preferably, said model or model carrier comprises a humanized or human CRB1 gene in vivo in which the endogenous CRB1 gene is deleted or not expressed.

[0028] Preferably, said non-human animal has colonic epithelial barrier dysfunction and / or associated inflammation of the colon wall.

[0029] In one specific embodiment, the occludin protein is significantly deleted in the model, and in one specific embodiment, the occludin protein is significantly deleted in the model and claudin 1 expression is not evident.

[0030] The microorganism is one or a combination of two or more of bacteria, archaea, protists, fungi, or viruses. Preferably, the microorganism is a bacterium, and the bacterium is selected from the group consisting of Anearostipes, Bifidobacterium, Megamonas, Nitrosomonas, Oscillibacter, Tatumella, Thiobacillus, and the like. sp.), Clostridium, Acinetobacter, Streptococcus, Mannheimia, Fibrobacter, Prevotella, Campylobacter, Actinomyces, Hymenobacter, Escherichia, Tissierella, Klebsiella, Porphyromonas, Azospira, Aquimarina, The bacterium is one or more selected from the genera quimarina, Achromobacter, Acidithiobacillus, Burkholderia, Marinobacter, Treponema, Actinosporangium, Vibrio, Ruminococcus, Methanobrevibacter, Shigella, Frankia, Anaeroplasma, and Coprococcus.

[0031] Specifically, the bacteria include Anearostipes hadrus, Bifidobacterium pseudocatenulatum, Nitrosomonas sp. Is79A3, Oscillibacter valericigenes, Tatumella sp. TA1, Megamonas funiformis, Thiobacillus denitrificans, and the like. denitrificans), Clostridium tetani, Clostridium perfringens, Clostridium botulinum, Acinetobacter calcoaceticus, Acinetobacter ruvofii, Acinetobacter baumannii, Acinetobacter haemolyticus, Acinetobacter junii, Acinetobacter johnsonii, Streptococcus pyogenes, Streptococcus hemolyticus, Fibrobacter succinogenes, Fibrobacter intestinalis, Porphyromonas asaccharolytica, Porphyromonas endodontalis, Porphyromonas gingivicanis, Campylobacter jejuni, Campylobacter coli, Campylobacter lari, Campylobacter upsaliensis, Campylobacter concisus, Campylobacter fetus, Actinomyces cerevisiae, Actinomyces israelii, Actinomyces naeslundii, Actinomyces odontotricus, Actinomyces viscosus, Actinomyces nouii, Escherichia coli, Escherichia bullatae, Escherichia fergussoni, Escherichia hermannii, Escherichia vulneris, Tisserella praeacuta, Klebsiella pneumoniae, Klebsiella pneumoniae, Sierra osaenae, Azospirillum brasirense, Achromobacter, Thiobacillus denitrificans, Thiobacillus ferrooxidans, Thiobacillus thiooxidans, Thiobacillus neapolitanus, Burkholderia, Mycobacterium marinum, Treponema pallidum, Treponema hyodysenteriae, Vibrio metschnikoffii, Ruminococcus albus,Ruminococcus flavefaciens, Methanobrevibacter ruminantium, Shigella flexneri, Shigella boydii, Shigella sonnei, Frankia, Coprococcus oitactus, Streptomyces albus, Pseudomonas mendocina, Micrococcus sedentarius, Alicycliphilus denitrificans, Achromobacter xylosoxidans, Sphingomonas, Mycobacterium abscessus, Arthrobacter aurescens, Prevotella, Sinorhizobium medicae, Acid Yeast, Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus Lactobacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hatchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter calcoaceticus, Comamonas testosteroni, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter koseri, Diadobacter fermentans, Serratia marcescens, Sphingomonas wittichii, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia pickettii, Lactobacillus crispatus, Burkholderia purpurea, Lactobacillus delbrueckii, Meiothermus sylvanus silvanus)(Meiothermus silvanus)(D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium auricum, Finegordia magna.

[0032] Preferably, the infection method includes direct or indirect contact of the microorganism with the target site of infection of the model carrier, said indirect contact being such that there is a blood-retinal barrier, preferably an outer blood-retinal barrier or an inner blood-retinal barrier, between the microorganism and the target site of infection.

[0033] In one specific embodiment, the infection method comprises infecting the eye with enterobacteria via peripheral blood.Specifically, the intestinal epithelial barrier of the non-human animal model is significantly damaged, and enterobacteria enter the peripheral blood.In one model, the retinal barrier is also significantly damaged, and enterobacteria in the peripheral blood infect the retina.In one specific embodiment, the non-human animal model has a mutation in the CRB1 gene, and in one specific embodiment, the mutation in the CRB1 gene is the Rd8 mutation.

[0034] Furthermore, the present invention provides a method for preparing an ocular inflammation model, said method models a non-human animal infected with a microorganism.

[0035] Preferably, said ocular inflammation is caused by intestinal flora or a bacterial flora identical to intestinal flora.

[0036] The non-human animal is an animal as described above.

[0037] The microorganism is a microorganism as described above.

[0038] Furthermore, the present invention provides a method for preparing a retinal degenerative disease model, said method comprising infecting a non-human animal suffering from retinal degeneration with a microorganism.

[0039] Preferably, the ocular inflammatory retinal degenerative disease is a retinal disease as described above.

[0040] The non-human animal is an animal as described above.

[0041] The microorganism is a microorganism as described above.

[0042] Furthermore, the present invention provides a model carrier having ocular inflammation, said ocular inflammation being caused by a microbial infection.

[0043] Preferably, said microorganisms are derived from or are identical to the intestinal bacteria of the same individual.

[0044] Preferably, said eye disease comprises retinal degeneration, more preferably said retinal degeneration is progressive retinal degeneration.

[0045] Preferably, said retinal degeneration is an inherited retinal degeneration (IRD).

[0046] Preferably, the retinal degeneration is a disease of the model animal itself, or the model animal is induced to develop retinal degeneration by genetic manipulation.

[0047] Preferably, the eye disease comprises LCA, RP, arRP, EORD, EORP, PPRPE, rettelangiectasia and / or choroideremia like fundus.

[0048] Preferably, the eye disease includes ocular inflammatory diseases such as uveitis, glaucoma, age-related macular degeneration (AMD), vitreitis, choroiditis, retinitis, retinal vasculitis, and optic neuritis, as well as uveitis, Behcet's disease, Vogt-Koyanagi-Harada disease, uveitis, retinopathy, sympathetic ophthalmia, cataract, conjunctivitis, and glaucoma.

[0049] Preferably, said model is a non-human animal, preferably a monkey, dog, chimpanzee, rat or mouse.

[0050] Preferably, said model carrier is a cell, tissue or organ, said cell, tissue or organ being derived from a human or non-human animal.

[0051] Preferably, the cells are primary cells or cell lines.

[0052] Preferably, the tissue is an ocular tissue and the organ is an ocular organ.

[0053] Preferably, the tissue or organ is a regenerative tissue or organ.

[0054] Preferably, the model harbors a pathogenic mutation in a gene.

[0055] Preferably, the gene harboring a pathogenic mutation is a gene involved in maintaining the structure of the retinal barrier, said retinal barrier being the outer blood-retinal barrier and / or the inner blood-retinal barrier.

[0056] Preferably, the model carrier has a mutation in one or more of the following genes: ABCA4, ABCC6, ABCC9, ACBD5, ACO2, ACO2, ACTG1, ADGRV1, AHI1, AIPL1, ALMS1, AMY2B, APC, ARFGEF1, ARL13B, ARL13B, ARL6, ARMC9, ATOH7, B9D1, BAG3, BBS1, BBS1, BBS2, BBS5, BEST1, C2CD3, CA4, CABP4, CACNA1F, CBS, CC2D2A, CDH23, CDH23, CDHR1, CEMIP. 2, CEP104, CEP250, CEP290, CEP290, CEP41, CEP78, CERKL, CFAP410, CFAP418, CHM, CLCC1, CLCN7, CLN3, CLN5, CLN8, CLRN1, CLRN1, CNGA1, CNGA1, CNGA3 , CNGB1, CNGB3, CNNM4, COL11A1, COL11A2, COL18A1, COL2A1, COL4A1, COL9A1, COL9A2, CP, CP, CPLANE1, CRB1, ERCC4, CSPP1, CTNNA1, CYP4V2, DHDDS, DYN C2H1, DYNC2I1, DYNC2I2, ENPP1, ERCC4, EVC2, EYS, EYS, F5, FAM161A, FBN1, FKRP, FKTN, FLG, FLVCR1, FOXE3, FUZ, GLB1, GMPPB, GNAT1, GRK1, GRM6, GUCA 1A, GUCA1B, GUCY2D, HADHA, HGSNAT, HPS3, HPS5, IDH3B, IFT122, IFT140, IFT140, IFT43, IFT52, IFT74, IFT80, IFT80, IFT81, IFT88, IKBKG, IMPDH1, IMP G2, INPP5E, INTU, IQCB1, IQCE, IREB2, KCNJ13, KCNQ1, KCNV2, KIAA0586, KIAA0753, KIF7, KIZ, KIZ-AS1, KLHL7, KRIT1, LBR, LCA5, LOC101927157, LOC1 11365204, LRP2, LRP5, MAK, MAPKAPK3, MATK, MCOLN1, MERTK, MKS1, MPDZ, MT-ATP6, MT-CO3, MT-TE, MT-TL1, MTHFR, MUTYH, MYO7A, MYO7A, NMNAT1, NPHP1,NR2E3, OCA2, OTX2, PANK2, PAX6, PCARE, PCDH15, PDE6A, PDE6B, PDE6B, PDE6D, PEX1, PEX1, PEX12, P EX26, PEX6, PHF3, PITPNM3, PKD2, PLA2G5, POC5, POMT1, PRCD, PRDM13, PROM1, PRPF3, PRPF31, PRPF 8, PRPH2, RAD51C, RBP3, RBP4, RD3, RDH12, RDH5, RGR, RGR, RHO, RIMS1, RLBP1, ROM1, RP1, RP1L1, RP 2, RPE65, RPE65, RPGR, RPGRIP1, RPGRIP1L, RS1, SACS, SAG, SCAPER, SDCCAG8, SIX6, SLC19A1, SLC22 A5, SLC26A4, SLC2A9, SLTM, SNRNP200, SPAG17, SPATA7, SPG11, TFAP2A, TGFB2, TGFBR2, TMEM107, TMEM237, TMEM67, TOGARAM1, TOPORS, TPP1, TRAF3IP1, TREX1, TRIM59-IFT80, TSPAN12, TTC21B, TTC21B, TTC8, TULP1, USH1C, USH2A, USH2A, USH2A, USH2A-AS1, VAC14, VCAN, VCAN, VCAN-AS1, VHL, VPS13B, WDR19, WDR19, WDR35, WDR73, YARS1, ZFYVE26, ZFYVE26, ZNF408.

[0057] In one specific embodiment, the model carrier comprises the CRB1 gene among the eye disease-associated genes having a pathogenic mutation.

[0058] Preferably, the mutation in the CRB1 gene of the model carrier includes one or more of the following mutations: c.107C>G, c.111delT, c.135C>G, c.257_258dupTG, c.258C>T, c.428_432delGATTC, c.430T>G, c.470G>C, c.481dupG, c.482C>T, c.584G>T, c.613_619del, c.717_718insG, c.750T>G, c.915T>A, c.929G>A, c.936T>G, c.998G>A, c.1084C>T, c.1125C>G, c.1148G>A, c.1208C>G, c.1269C>A, c.1298A>G, c.1313G>A, c.1438T>C, c.1438T>G, c.1576C>T, c.1604T>C, c.1690G>T, c.1733T>A, c.1750G>T, c.1760G>A, c.1834T>C, c.1963delC, c.2025G>T, c.2042G>A, c.2128G>C, c.2129C>T, c.2185_2186insAlu, c.2219C>T, c.2222T>C, c.2234C>T, c.2245_2247del 3bp (TCA), c.2258T>C, c.2290C>T, c.2365_2367del AAT, in-frame deletion, c.2401A>T, c.2438_2439ins>100A, c.2441_2442del, c.2465G>A, c.2479G>T, c.2506C>A, c.2509G>C, c.2536G>A, c.2548_2551delGGCT, c.2548G>A, c.2555T>C, c.2611_2613insT, c.2671T>G, c.2676delG, c.2681A>G, c.2688T>A, c.2816G>A, c.2843G>A, c.2853dupT, c.2884_2886delTTA, c.2957A>T, c.2966T>C, c.2983G>T, c.3002A>T, c.3008T>C, c.3035T>C, c.3037C>T, c.3074G>A, c.3074G>T, c.3122T>C, c.3212T>C, c.3296C>A, c.3299T>C, c.3299T>G, c.3307G>A / C, c.3320T>C, c.3320T>G, c.3331G>T, c.3343_3352del、c.3347delT、c.3343_3352del、c.3347delT、c.3427delT、c.3482A>G、c.3493T>C、c.3655T>G、c.3541T>C、c.3542dupG、c.3593A>G、c.3613G>A、c.3653G>T、c.3659_3660delinsA、c.3664C>T、c.3668G>C、c.3676G>T、c.3713_3716dup、c.3879G>A、c.3914C>T、c.3949A>C、c.3961T>A、c.3988delG、c.3988G>T、c.3995G>T、c.3996C>A、c.3997G>T、c.4094C>A、c.4121_4130del、c.4142C>T、c.4148G>A、c.2128+2T>G、c.2842+5G>A、c.3878+1G>T、c.4005+1G>A、c.4005+2T>G、c.4006-2A>G、c.4006-1G>T、c.619G>A、c.614T>C、c.1472A>T、c.1903T>C、c.2809G>A、c.3103C>T、c.4082G>A、c.4060G>A、c.866C>T、c.1463T>C、c.2035C>G、c.2306_2307GC>AG、c.2306G>A、c.2714G>A、c.2875G>A、c.3992G>A。.

[0059] More preferably, the mutation in the CRB1 gene of said model or model carrier comprises one or more of the following mutations: c.4006-1G>T, c.3686G>C, (p.Cys1229Ser), c.2842+1delinsAA, c.4060G>A, (p.Ala1354Thr), c.3991C>T, (p.Arg1331Cys), c.3014A>T, (p.Asp1005Val), c.4005+1G>A, c.2680_2684del, (p.Asn894 fs), c.1733T>A, (p.Val578Glu), c.455G>A, (p.Cys152Tyr), c.3462_3463del, (p.Cys1154_Glu1155delinsTer), c.3037C>T, (p.Gln 1013Ter), c.2673C>A, (p.Cys891Ter), c.2230C>T, (p.Arg744Ter), c.3676G>T, (p.Gly1226Ter), c.2842+5G>A, c.2842T>C, (p.Cys94 8Arg), c.3988del, (p.Glu1330fs), c.2506C>A, (p.Pro836Thr), c.2291G>A, (p.Arg764His), c.1576C>T, (p.Arg526Ter), c.613_619 del, (p.Ile205fs), c.3320T>C, (p.Leu1107Pro), c.2688T>A, (p.Cys896Ter), c.2555T>C, (p.Ile852Thr), c.2222T>C, (p.Met741Thr ), c.1148G>A, (p.Cys383Tyr), c.2843G>A, (p.Cys948Tyr), c.4121_4130del, (p.Ala1374fs), c.3307G>A, (p.Gly1103Arg), c.484G>A , (p.Val162Met), c.2401A>T, (p.Lys801Ter), c.2234C>T, (p.Thr745Met), c.2290C>T, (p.Arg764Cys), c.3122T>C, (p.Met1041Thr).

[0060] Preferably, the mutation in the CRB1 gene of the model carrier is an Rd8 mutation.

[0061] Preferably, the mutation is a homozygous or heterozygous mutation.

[0062] Preferably, said model carrier either aboriginally harbours said genetic mutation in vivo or has acquired the mutation as a result of recombinant genetic manipulation.

[0063] Preferably, said model carrier comprises a humanized or human CRB1 gene in vivo in which the endogenous CRB1 gene is deleted or not expressed.

[0064] Preferably, said non-human animal has colonic epithelial barrier dysfunction and / or associated inflammation of the colon wall.

[0065] In one specific embodiment, the occludin protein is significantly deleted in the model, and in one specific embodiment, the occludin protein is significantly deleted in the model and claudin 1 expression is not evident.

[0066] The microorganism is one or a combination of two or more of bacteria, archaea, protists, fungi, or viruses. Preferably, the microorganism is a bacterium, and the bacterium is selected from the group consisting of Anearostipes, Bifidobacterium, Megamonas, Nitrosomonas, Oscillibacter, Tatumella, Thiobacillus, and the like. sp.), Clostridium, Acinetobacter, Streptococcus, Mannheimia, Fibrobacter, Prevotella, Campylobacter, Actinomyces, Hymenobacter, Escherichia, Tissierella, Klebsiella, Porphyromonas, Azospira, Aquimarina, The bacterium is one or more selected from the genera quimarina, Achromobacter, Acidithiobacillus, Burkholderia, Marinobacter, Treponema, Actinosporangium, Vibrio, Ruminococcus, Methanobrevibacter, Shigella, Frankia, Anaeroplasma, and Coprococcus.

[0067] Specifically, the bacteria include Anearostipes hadrus, Bifidobacterium pseudocatenulatum, Nitrosomonas sp. Is79A3, Oscillibacter valericigenes, Tatumella sp. TA1, Megamonas funiformis, Thiobacillus denitrificans, and the like. denitrificans), Clostridium tetani, Clostridium perfringens, Clostridium botulinum, Acinetobacter calcoaceticus, Acinetobacter ruvofii, Acinetobacter baumannii, Acinetobacter haemolyticus, Acinetobacter junii, Acinetobacter johnsonii, Streptococcus pyogenes, Streptococcus hemolyticus, Fibrobacter succinogenes, Fibrobacter intestinalis, Porphyromonas asaccharolytica, Porphyromonas endodontalis, Porphyromonas gingivicanis, Campylobacter jejuni, Campylobacter coli, Campylobacter lari, Campylobacter upsaliensis, Campylobacter concisus, Campylobacter fetus, Actinomyces cerevisiae, Actinomyces israelii, Actinomyces naeslundii, Actinomyces odontotricus, Actinomyces viscosus, Actinomyces nouii, Escherichia coli, Escherichia bullatae, Escherichia fergussoni, Escherichia hermannii, Escherichia vulneris, Tisserella praeacuta, Klebsiella pneumoniae, Klebsiella pneumoniae, Sierra osaenae, Azospirillum brasirense, Achromobacter, Thiobacillus denitrificans, Thiobacillus ferrooxidans, Thiobacillus thiooxidans, Thiobacillus neapolitanus, Burkholderia, Mycobacterium marinum, Treponema pallidum, Treponema hyodysenteriae, Vibrio metschnikoffii, Ruminococcus albus,Ruminococcus flavefaciens, Methanobrevibacter ruminantium, Shigella dysenteriae, Shigella flexneri, Shigella boydii, Shigella sonnei, Frankia, Coprococcus oitactus, Streptomyces albus, Pseudomonas mendocina, Micrococcus sedentarius, Alicycliphilus denitrificans, Achromobacter xylosoxidans, Sphingomonas, Mycobacterium abscessus, Arthrobacter aurescens, Prevotella, Sinorhizobium medicae, Acid Yeast, Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus S. megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hatchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter calcoaceticus, Comamonas testosteroni, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter koseri, Diadobacter fermentans, Serratia marcescens, Sphingomonas wittichii, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia pickettii, Lactobacillus crispatus, Burkholderia purpurea, Lactobacillus delbrueckii, Meiothermus sylvanus silvanus (D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium auricum, Finegordia magna, or one or more selected from the group consisting of

[0068] Preferably, the infection method includes direct or indirect contact of the microorganism with the target site of infection of the model carrier, said indirect contact being such that there is a blood-retinal barrier, preferably an outer blood-retinal barrier or an inner blood-retinal barrier, between the microorganism and the target site of infection.

[0069] In one specific embodiment, the infection method comprises infecting the eye with enterobacteria via peripheral blood.Specifically, the intestinal epithelial barrier of the non-human animal model is significantly damaged, and enterobacteria enter the peripheral blood.In one model, the retinal barrier is also significantly damaged, and enterobacteria in the peripheral blood infect the retina.In one specific embodiment, the non-human animal model has a mutation in the CRB1 gene, and in one specific embodiment, the mutation in the CRB1 gene is the Rd8 mutation.

[0070] The model carrier having inflammation is derived from a disease model prepared by the above-mentioned method, or is obtained by infecting ocular cells, tissues, or organs derived from the above-mentioned non-human animals with a microorganism.

[0071] The invention provides the use of the above method in assessing the efficacy of targeted therapy for eye diseases, including eye diseases as described above.

[0072] In one specific embodiment, the above-mentioned model or model carrier is subjected to targeted therapy against the above-mentioned gene mutation, and the model or model carrier is divided into two groups, the model or model carrier that has been subjected to targeted therapy and the model or model carrier that has not been subjected to targeted therapy, and an eye disease model is constructed by the above-mentioned method for each group. When compared, if the group that has been subjected to targeted therapy does not succeed in modeling eye disease, it indicates that the targeted therapy has achieved a beneficial effect.

[0073] In one specific embodiment, the targeted therapy targets one or a combination of two or more of the following genes: ABCA4, ABCC6, ABCC9, ACBD5, ACO2, ACO2, ACTG1, ADGRV1, AHI1, AIPL1, ALMS1, AMY2B, APC, ARFGEF1, ARL13B, ARL13B, ARL6, ARMC9, ATOH7, B9D1, BAG3, BBS1, BBS1, BBS2, BBS5, BEST1, C2CD3, CA4, CABP4, CACNA1F, CBS, CC2D2A, CDH23, CDH2 3, CDHR1, CEMIP2, CEP104, CEP250, CEP290, CEP290, CEP41, CEP78, CERKL, CFAP410, CFAP418, CHM, CLCC1, CLCN7, CLN3, CLN5, CLN8, CLRN1, CLRN1, CNGA 1, CNGA1, CNGA3, CNGB1, CNGB3, CNNM4, COL11A1, COL11A2, COL18A1, COL2A1, COL4A1, COL9A1, COL9A2, CP, CP, CPLANE1, CRB1, ERCC4, CSPP1, CTNNA1, CYP 4V2, DHDDS, DYNC2H1, DYNC2I1, DYNC2I2, ENPP1, ERCC4, EVC2, EYS, EYS, F5, FAM161A, FBN1, FKRP, FKTN, FLG, FLVCR1, FOXE3, FUZ, GLB1, GMPPB, GNAT1, G RK1, GRM6, GUCA1A, GUCA1B, GUCY2D, HADHA, HGSNAT, HPS3, HPS5, IDH3B, IFT122, IFT140, IFT140, IFT43, IFT52, IFT74, IFT80, IFT80, IFT81, IFT88, IKB KG, IMPDH1, IMPG2, INPP5E, INTU, IQCB1, IQCE, IREB2, KCNJ13, KCNQ1, KCNV2, KIAA0586, KIAA0753, KIF7, KIZ, KIZ-AS1, KLHL7, KRIT1, LBR, LCA5, LOC1 01927157, LOC111365204, LRP2, LRP5, MAK, MAPKAPK3, MATK, MCOLN1, MERTK, MKS1, MPDZ, MT-ATP6, MT-CO3, MT-TE, MT-TL1, MTHFR, MUTYH, MYO7A, MYO7A,<h2 style=";text-align:left;direction:ltr">NMNAT1、NPHP1、NR2E3、OCA2、OTX2、PANK2、PAX6、PCARE、PCDH15、PDE6A、PDE6B、PDE6B、PDE6D、PEX 1、PEX1、PEX12、PEX26、PEX6、PHF3、PITPNM3、PKD2、PLA2G5、POC5、POMT1、PRCD、PRDM13、PROM1、PRP F3、PRPF31、PRPF8、PRPH2、RAD51C、RBP3、RBP4、RD3、RDH12、RDH5、RGR、RGR、RHO、RIMS1、RLBP1、RO M1、RP1、RP1L1、RP2、RPE65、RPE65、RPGR、RPGRIP1、RPGRIP1L、RS1、SACS、SAG、SCAPER、SDCCAG8、SI X6、SLC19A1、SLC22A5、SLC26A4" 、TGFBR2、TMEM107、TMEM237、TMEM67、TOGARAM1、TOPORS、TPP1、TRAF3IP1、TREX1、TRIM59-IFT80、T SPAN12、TTC21B、TTC21B、TTC8、TULP1、USH1C、USH2A、USH2A、USH2A、USH2A、USH2A-AS1、VAC14、VCA N、VCAN、VCAN-AS1、VHL、VPS13B、WDR19、WDR19、WDR35、WDR73、YARS1、ZFYVE26、ZFYVE26、ZNF408。、<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0074] <h2 style=";text-align:left;direction:ltr"> In one specific embodiment, the targeted therapy targets one or more of the following mutations in the CRB1 gene: c.257_258dupTG, c.258C>T, c.428_432delGATTC, c.430T>G, c.470G>C, c.481dupG, c.482C>T, c.584G>T, c.613_619del, c.717_718insG, c.750T>G, c.915T>A, c.929G>A, c.936T>G, c.998G>A, c.1084C>T, c.1125C>G, c.1148G>A, c.1208C>G, c.1269C>A, c.1298A>G, c.1313G>A, c.1438T>C, c.1438T>G, c.1576C>T, c.1604T>C, c.1690G>T, c.1733T>A, c.1750G>T, c.1760G>A, c.1834T>C, c.1963delC, c.2025G>T, c.2042G>A, c.2128G>C, c.2129C>T, c.2185_2186insAlu, c.2219C>T, c.2222T>C, c.2234C>T, c.2245_2247del 3bp (TCA), c.2258T>C, c.2290C>T, c.2365_2367del AAT, in-frame deletion, c.2401A>T, c.2438_2439ins>100A, c.2441_2442del, c.2465G>A, c.2479G>T, c.2506C>A, c.2509G>C, c.2536G>A, c.2548_2551delGGCT, c.2548G>A, c.2555T>C, c.2611_2613insT, c.2671T>G, c.2676delG, c.2681A>G, c.2688T>A, c.2816G>A, c.2843G>A, c.2853dupT, c.2884_2886delTTA, c.2957A>T, c.2966T>C, c.2983G>T, c.3002A>T, c.3008T>C, c.3035T>C, c.3037C>T, c.3074G>A, c.3074G>T, c.3122T>C, c.3212T>C, c.3296C>A, c.3299T>C, c.3299T>G, c.3307G>A / C, c.3320T>C, c.3320T>G, c.3331G>T, c.3343_3352del, c.3347delT, c.3343_3352del, c.3347delT, c.3427delT, c.3482A>G, c.3493T>C, c.3655T>G, c.354 1T>C, c.3542dupG, c.3593A>G, c.3613G>A, c.3653G>T, c.3659_3660delinsA, c.3664 C>T, c.3668G>C, c.3676G>T, c.3713_3716dup, c.3879G>A, c.3914C>T, c.3949A>C, c .3961T>A, c.3988delG, c.3988G>T, c.3995G>T, c.3996C>A, c.3997G>T, c.4094C>A, c .4121_4130del, c.4142C>T, c.4148G>A, c.2128+2T>G, c.2842+5G>A, c.3878+1G>T, c.4005+1G>A, c.4005+2T>G, c.4006-2A>G, c.4006-1G>T, c.619G>A, c.614T>C, c.147 2A>T, c.1903T>C, c.2809G>A, c.3103C>T, c.4082G>A, c.4060G>A, c.866C>T, c.1463 T>C, c.2035C>G, c.2306_2307GC>AG, c.2306G>A, c.2714G>A, c.2875G>A, c.3992G>A. .

[0075] In a specific embodiment, the targeted therapeutic comprises a modified cell, a modified protein, an RNA targeting a gene as described above or a mutation site as described above, and / or a DNA targeting a gene as described above or a mutation site as described above.

[0076] The present invention provides the use of a disease model produced by the method as described above in research related to eye diseases, including eye diseases as described above, including the mutual response between diseases related to inherited retinal degeneration and gut microbiota.

[0077] In one specific embodiment, the disease model is infected with one enterobacteria, and when the pathogenic mutations it has are treated by cells, the effectiveness of administering and not administering a drug is observed, and the drug is a small molecule drug, preferably a broad-spectrum antibiotic or an antibiotic that targets the infecting bacteria. In one specific embodiment, the disease model is infected with one enterobacteria, and when the pathogenic mutations it has are treated by RNA, the effectiveness of administering and not administering a drug is observed, and the drug is a small molecule drug, preferably a broad-spectrum antibiotic or an antibiotic that targets the infecting bacteria. In one specific embodiment, the disease model is infected with two or more enterobacteria, and when the pathogenic mutations it has are treated by cells, the effectiveness of administering and not administering a drug is observed, and the drug is a small molecule drug, preferably a broad-spectrum antibiotic or an antibiotic that targets the infecting bacteria. In one specific embodiment, the disease model is infected with two enterobacteria and when the pathogenic mutations it harbors are treated with RNA, the efficacy of administering and not administering a drug is observed, the drug being a small molecule drug, preferably a broad spectrum antibiotic or an antibiotic that targets the infecting bacteria.

[0078] Preferably, the pathogenic mutation occurs in a gene as defined above or the pathogenic mutation is a mutation in the CRB gene as defined above.

[0079] The present invention provides the use of the disease model carrier produced by the above-mentioned method in research related to eye disease, including the eye disease as described above. The research includes the synergistic effect between diseases related to inherited retinal degeneration and intestinal microflora, etc.

[0080] In one specific embodiment, the disease model carrier is infected with one enterobacteria, and when the pathogenic mutation carried by the disease model carrier is treated by cells, the effectiveness of administration and non-administration of a drug is observed, and the drug is a small molecule drug, preferably a broad-spectrum antibiotic or an antibiotic that targets the infectious bacteria. In one specific embodiment, the disease model carrier is infected with one enterobacteria, and when the pathogenic mutation carried by the disease model carrier is treated by RNA, the effectiveness of administration and non-administration of a drug is observed, and the drug is a small molecule drug, preferably a broad-spectrum antibiotic or an antibiotic that targets the infectious bacteria. In one specific embodiment, the disease model carrier is infected with two or more enterobacteria, and when the pathogenic mutation carried by the disease model carrier is treated by cells, the effectiveness of administration and non-administration of a drug is observed, and the drug is a small molecule drug, preferably a broad-spectrum antibiotic or an antibiotic that targets the infectious bacteria. In one specific embodiment, the disease model carrier is infected with two intestinal bacteria, and when the pathogenic mutation it harbors is treated by RNA, the effectiveness of administering and not administering a drug is observed, and the drug is a small molecule drug, preferably a broad-spectrum antibiotic or an antibiotic that targets the infecting bacteria.

[0081] Preferably, the pathogenic mutation occurs in a gene as defined above or the pathogenic mutation is a mutation in the CRB gene as defined above.

[0082] The present invention provides the use of the disease model or disease model carrier as described above in screening drugs related to eye disease.The drugs include small molecule drugs, chemical drugs, polymeric drugs, biological drugs or natural drugs (such as Chinese herbal medicines or Chinese herbal medicine extracts), cell drugs, RNA drugs, and DNA drugs, or combinations of two or more of them.

[0083] The eye disease includes eye diseases as described above.

[0084] Preferably, the small molecule compound is an antibiotic, said antibiotic being a broad spectrum antibiotic commonly known to those skilled in the art.

[0085] Preferably, the small molecule compound is a non-broad spectrum antibiotic that targets specific bacteria.

[0086] Preferably, the cells include modified immune cells, such as one or a combination of two or more of T cells, B cells or stem cells.

[0087] Preferably, the RNA comprises mRNA, siRNA, sgRNA, miRNA, ASO and / or replicon RNA.

[0088] In one specific embodiment, the disease model or disease model carrier is subjected to a targeted therapy, and a drug as described above is administered or not administered to the disease model or disease model carrier subjected to the targeted therapy and to the disease model or disease model carrier not subjected to the targeted therapy, and the progression of inflammation in multiple groups is observed to evaluate the effectiveness of the targeted therapeutic drug.

[0089] In one specific embodiment, the disease model or disease model carrier is subjected to a targeted therapy, and the disease model or disease model carrier subjected to the targeted therapy and the disease model or disease model carrier not subjected to the targeted therapy are administered or not administered the above-mentioned drugs, and the progression of inflammation in multiple groups is observed to evaluate the effectiveness of the small molecule drug.

[0090] The chemical drugs of the present invention include β-lactam antibiotics (including penicillins, cephalosporins, thienamycins, monobactams, β-lactamase inhibitors, methoxypenicillins, etc.), aminoglycoside antibiotics (including streptomycin, gentamicin, kanamycin, tobramycin, amikacin, neomycin, ribostamycin, micronomycin, astromycin, etc.), tetracycline antibiotics (including tetracycline, oxytetracycline, chlortetracycline, and doxycycline, etc.), chloramphenicol antibiotics (including chloramphenicol, thiamphenicol, etc.), macrolide antibiotics (including erythromycin, leucomycin, erythromycin estolate, acetylspiramycin, midecamycin, josamycin, azithromy ... isin, etc.), glycopeptide antibiotics (including vancomycin, norvancomycin, teicoplanin, etc.), quinolone antibiotics (including norfloxacin, ofloxacin, ciprofloxacin, pefloxacin, gatifloxacin), nitroimidazole antibiotics (including metronidazole, tinidazole, ornidazole, etc.), rifamycin antibiotics (including rifampicin, etc.), echinocandin antibiotics, polyene antibiotics, pyrimidine antibiotics, arylamine antibiotics, azole antibiotics, other antibiotics (fosfomycin, capreomycin, cycloserine, lincomycin, clindamycin, mitomycin, actinomycin D, bleomycin, adriamycin, isoniazid, pyrazinamide, cyclosporine, etc.).

[0091] The biological drug of the present invention is an antibacterial peptide, and the antibacterial peptide is one or more selected from insect antibacterial peptides, such as lepidopteran antibacterial peptides, dipteran antibacterial peptides, coleopteran antibacterial peptides, dragonfly antibacterial peptides, hymenopteran antibacterial peptides, silkworm antibacterial peptides, etc.; mammalian antibacterial peptides, such as porcine antibacterial peptides, ovine antibacterial peptides, bovine antibacterial peptides, human antibacterial peptides, etc.; amphibian antibacterial peptides: magainin, etc.; antibacterial peptides derived from fish, mollusks, and crustaceans: ostrich antibacterial peptides, catfish antibacterial peptides, mussel antibacterial peptides, shrimp antibacterial peptides, etc.; plant antibacterial peptides: thionin, etc.; and bacterial antibacterial peptides: bacitracin, gramicidin, polymyxin, nisin, etc.

[0092] The natural medicines of the present invention are one or more selected from Astragalus Root, Coptis Root, Angelica Root, Chinese Chip, White Root, Chinese Bamboo Root, Turmeric, Fritillaria Root, Coix Seed, Chinese Herb, Calcine Dancient Ink, Salvia Officinalis, Purple Root, Chinese Herb, Chinese Golden Root, Chinese Golden Root, Chinese Golden Root, Chinese Golden Root, Chinese Bamboo ...

[0093] The drug according to the present invention may be an oral drug, an injection drug or an external drug, and the external drug includes a drug for mucosal administration, preferably an eye drop drug.

[0094] The dosage form of the drug of the present invention may be a solution, tablet, pill, capsule, injection liquid, powder, powder for injection, patch, coating agent or preparation for mucosal administration, and the preparation for mucosal administration is preferably eye drops, eye ointment or eye spray, etc. [Brief description of the drawings]

[0095] [Figure 1] Genotype and phenotype of Crb1rd8 / rd8(rd8)-SPF mice. Figure 1A shows the genotype gel electrophoresis of Crb1rd8 / rd8(rd8) mice and Crb1wt / wt (C57BL / J, abbreviated as "wt") mice. Figure 1B shows representative fundus photographs of Rd8-SPF mice and WT-SPF mice, and typical white spots were observed on the inferior nasal side of the retina in Rd8-SPF mice. Figure 1C shows H&E staining to detect pathological changes in both eyes of Rd8-SPF mice at E18. [Diagram 2] Potential mechanisms of retinal abnormalities and retinopathy in Rd8-SPF mice. Figure 2A shows H&E staining to detect pathological changes in both eyes of Rd8-SPF mice and WT-SPF mice at E18, P12 (before eye opening), P15 (after eye opening), and 8 weeks (8W). Rd8 mice showed typical retinal abnormalities, including progressive retinal hypoplasia (wrinkles and haloes) and degeneration, whereas WT mice showed normal retinal structure. Figure 2B shows statistical data on the presence or absence of ocular damage in Rd8-SPF mice and WT-SPF mice at E18, P12, P15, and 8W. Typical lesions were seen in all retinas of Rd8 mice at P12, P15, and 8W, but none were seen in WT-SPF mice. WT-SPF, n=6 per group at E18, P12, P15, 8W, and Rd8-SPF, n=32 at E18, n=6 at P12, and n=8 at P15. Figure 2C is a volcano plot analysis of DEGs in the upper (nonlesional) and lower (lesional) regions of the retina in Rd8 mice. Slamf1 (signaling lymphocyte activation molecule family member 1) and Ncf4 (neutrophil cytoplasmic factor) are the two genes with the highest fold proliferation in retinopathy in Rd8-SPF mice. Figure 2D is an IPA functional analysis of DEGs. Figure 2E shows that immunofluorescence staining revealed a large number of IBA1+ microglia (red) in the retinal lesions of Rd8 mice. [Diagram 3]RNA-seq analysis comparing gene expression profiles in the upper and lower regions of the retina of Rd8-SPF mice. Figure 3A shows the graphs of the upper (nonlesional) and lower (lesional) regions of Rd8-SPF mice. Figure 3B shows that the expression of Rd8-SPF mice had at least two-fold differences between the upper and lower regions of the retina (P<0.05) as a result of RNA-seq analysis. Figure 3C shows the expression patterns of 179 DEGs in the upper and lower regions of the retina of Rd8-SPF mice and WT-SPF mice. [Figure 4] Identification of bacteria in the retinal lesions of Rd8-SPF mice. Of these, Figure 4A is a principal coordinate analysis (PCoA) showing that the bacterial composition in the retinal tissues of Rd8 mice is significantly different from that of WT mice. Figure 4B is the identification of microbial species composition in the upper (S) and lower (I) tissues of the retina of Rd8 mice by metagenomic sequencing analysis (n = 4). Figure 4C is the fluorescent in situ hybridization detection of retinal bacterial 16srDNA and vanco-bodipy in Rd8-SPF mice and WT-SPF mice (4 weeks old). Figure 4D is the bacterial distribution in the retinal lesions of Rd8 mice by transmission electron microscopy (TEM) (the positive control is E. coli). [Diagram 5] Disruption of retinal adherens junctions in Rd8-SPF mice. Figure 5A shows immunofluorescence staining of CRB1 (red) in the retinas of Rd8-SPF mice and WT-SPF mice, where BM is Bruch's membrane, CC is choriocapillary membrane, and BL is basement membrane. Figure 5B shows transmission electron microscopy observation of the adherens junctions in the outer membrane of the retina of Rd8-SPF mice and WT-SPF mice, where the red arrows indicate adherens junctions, AJ is adherens junctions, OLM is outer membrane, ONL is outer nuclear layer, and IS is inner membrane. Figure 5C shows the results of transmission electron microscopy observation of the adherens lysis of the basal layer, distortion of the choriocapillary basal layer, and disruption of the collagen layer in the retinal pigment epithelium (RPE) of Rd8-SPF mice, where CC is choriocapillary membrane, CH is choroid, and BL is basement membrane. FIG. 5D shows the results of statistical analysis of the thickness of Bruch's membrane in Rd8-SPF mice and WT-SPF mice, ****P<0.0001. [Figure 6A] Transmission electron microscopy (TEM) of adherens junctions (AJs) in the outer membrane (OLM) and outer nuclear layer (ONL) of Rd8-SPF mice. [Figure 6B] The thickness of Bruch's membrane in Rd8-SPF mice and WT-SPF mice was shown by transmission electron microscopy (TEM). [Figure 7] Colonic epithelial barrier dysfunction and associated inflammation in Rd8-SPF mice. Among them, Figure 7A shows the relative abundance of Rd8 reticuloendothelial bacteria in different sites of the gastrointestinal tract in Rd8 and WT mice (n=5). Figure 7B-D shows immunofluorescence staining of CRB1 protein (B), phalloidin (C) and occludin (D) in colonic cells of Rd8-SPF mice and WT-SPF mice. Figure 7E is a statistical analysis of the relative intensity of occludin in Rd8-SPF mice and WT-SPF mice. Figure 7F is a Western blot detection of claudin 1 expression in colonic epithelial cells of Rd8-SPF mice and WT-SPF mice. Figure 7G is a statistical analysis of the relative intensity of claudin 1 in Rd8-SPF mice and WT-SPF mice. Figure 7H is the adherens junctions and tight junctions between colonic epithelia of Rd8-SPF mice and WT-SPF mice observed by transmission electron microscopy. Figure 7I-L are statistical analyses of the number of epithelial microvilli (I), microvilli length (J), microvilli width (K), and total number of intact adherens junctions (L) in Rd8-SPF and WT-SPF mice. Figure 7M-N are comparisons of the mRNA expression levels of Tnfa, Il1b, Il12a, (M), and mucin 2 (N) in Rd8-SPF and WT-SPF mice. [Figure 8]Microbial species composition of the microbiota in different sites of the gastrointestinal tract of Rd8-SPF mice. Among them, Figure 8A-F are the principal coordinate analysis (PCoA) of the microbial species composition of the gastrointestinal samples including stomach (Figure 8A), jejunum (Figure 8B), ileum (Figure 8C), cecum (Figure 8D), colon (Figure 8E) and rectum (Figure 8F) of WT mice (n=5) and Rd8 mice (n=5) based on the Bray-Curtis distance. Figure 8G compares the relative abundance of Akkermansia muciniphila in the cecum (H), colon (I) and rectum (J) of Rd8 mice and WT mice by grouping the microbial composition (H-J) of the lower gastrointestinal tract (cecum, colon and rectum) of Rd8 mice and WT mice by PCoA. Data are shown as mean ± SEM, *P<0.05. [Figure 9] Tight junctions and adherens junctions in the cecum of Rd8 mice. Among them, Figure 9A is immunofluorescence staining of CRB1 protein (green) in cecal enterocytes of Rd8-SPF mice and WT-SPF mice. Figure 9B is immunofluorescence staining of occludin (red) in cecal enterocytes of Rd8-SPF mice and WT-SPF mice. Figure 9C is statistical analysis of the relative intensity of occludin in Rd8-SPF mice and WT-SPF mice, *P<0.05. Figure 9D is Western blot detection of claudin 1 expression in the cecum of Rd8-SPF mice and WT-SPF mice. Figure 9E is statistical analysis of the relative intensity of claudin 1 in Rd8-SPF mice and WT-SPF mice, NS represents not significant. Figure 9F is transmission electron microscopy, normal tight junctions and adherens junctions were observed in the epithelial barrier of the cecum, MV is microbubbles, MC is mitochondria. [Figure 10] Figure 10A shows transmission electron microscopy of adherens junctions (AJs) between colonic epithelium and tight junctions (TJs) in Rd8-SPF and WT-SPF mice, where MVs are microbubbles and MCs are mitochondria. Figure 10B shows the frequency of fluorescent + bacteria / cells in peripheral blood of Rd8 and WT mice by flow cytometry. [Figure 11]Disruption of intestinal epithelial barrier function in Rd8-SPF mice. Among them, Figure 11A shows that serum fluorescence intensity was significantly higher in Rd8 mice than in WT mice by intestinal FICT-dextran permeability assay, ***P<0.001. Figure 11B compares the percentage of fluorescent+ bacteria / cells in peripheral blood of Rd8 mice and WT mice using fecal microbiota transplantation method with vanco-bodipy labeling, *P<0.05. Figure 11C-D shows that vanco-bodipy+ bacteria were detected in retinopathy of Rd8 mice by both fluorescence microscopy (C) and immunofluorescence staining (D). Figure 11F-G shows the comparison of colon length, serum bacterial 16srrNA (F) and bacterial LPS (G) levels between Rd8 mice and WT mice 13 days after DSS administration, ****P<0.0001. Figure 11H is the daily monitoring of body weight of Rd8 (n=20) and WT (n=19) mice treated with 2.5% DSS. Figure 11I is the Kaplan-Meier curve of Rd8 (n=20) and WT (n=19) mice treated with 2.5% DSS. [Figure 12]Retinal phenotypes of Rd8 GF mice and Rd8 GF SPF mice. Of these, Figure 12A shows representative fundus images of Rd8-SPF mice and Rd8 GF mice at 4 weeks, 8 weeks, 12 weeks, and 16 weeks. Figure 12B shows histological observations of the retinas of both eyes of Rd8-GF mice at E18, P12, P15, and 8W. Figure 12C shows fluorescent in situ hybridization staining of bacterial 16srDNA and vanco-bodipy in the retinas of Rd8-GF mice. Figure 12D shows immunofluorescence staining of IBA1 (red) in the retinas of Rd8-SPF mice, Rd8 GF mice, and WT-SPF mice. Figure 12E shows the percentage of IBA1+ microglia in the ONL of Rd8-SPF, Rd8 GF, and WT-SPF mice, ***P<0.001, NS represents not significant. Figure 12F shows immunofluorescence staining of retinal ZO-1 (red) and phalloidin (green) proteins in Rd8-SPF, Rd8-GF, and WT-SPF mice. Figure 12G shows H&E staining to detect P15 and 8W retinopathy in Rd8-GF mice (Rd8-GF-SPF mice) reared in a postnatal SPF environment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0096] The technical solutions in the examples of the present invention are described below clearly and completely. In the examples described below, the modeling method of rearing Crb1 gene mutant mice in an SPF environment was used alone, and the presence of local inflammatory reactions in the retina and the presence of bacteria at the lesion site were verified to determine that the retina model was infected with bacteria. Further, the following experiment verified that the bacteria were from the intestine. This specific example does not exclude other modeling methods, such as rearing in an environment with more complex microbiological conditions, or administering microorganisms derived from the intestine or the same microorganisms as the intestinal microorganisms to the ocular tissue, thereby directly or indirectly contacting the ocular tissue with the above-mentioned microorganisms.

[0097] It is clear that the described embodiments are only a part of the embodiments of the present invention, and are not all of them. All other embodiments that can be obtained by those skilled in the art based on the embodiments of the present invention without requiring creative efforts are included in the protection scope of the present invention.

[0098] 1. Mouse C57BL / 6N mice carrying the Rd8 mutation (Crb1 rd8 / Rd8 , named "Rd8 mice.") and C57BL / 6J mice (Crb1 wt / wt , named “wt mice.”) were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. and treated under specific pathogen-free (SPF) conditions in the animal facility of Zhongshan Ophthalmology Center. Germ-free (GF) RD8 mice were generated from female RD8 mouse embryos in the animal facility of the First Affiliated Hospital of Sun Yat-sen University. GF mice were maintained under germ-free conditions, and fecal samples were tested weekly for microorganisms and parasites by the facility staff to ensure the sterility of the GF units. The genotypes of the mice were determined as described above (Mattapallil et al., 2012). The Crb1 genotypes of the two mouse strains were confirmed (Figure 4A). All animal experiments were approved by the Animal Care and Use Committee of Zhongshan Ophthalmology Center and conformed to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.

[0099] 2. Method 2.1 Grouping Mice were killed by cervical dislocation, and eyes were enucleated and fixed in 4% paraformaldehyde (PFA) in phosphate-buffered saline (PBS) at 4°C for 24 h. Samples were washed three times in PBS, dehydrated in a series of alcohols and twice in xylene, then embedded in paraffin wax and serially sliced ​​at 10 μm using a microtome (RM 223; Leica, Wetzlar, Hesse-Darmstadt, Germany). Sections were stained with hematoxylin and eosin (H&E). H&E images were acquired with an Imager.Z2 (Zeiss).

[0100] Eyeballs were enucleated and placed in 4% PFA at room temperature for 5 min, after which the eye cups were dissected and fixed for 45 min, colon tissue was excised and fixed in 4% PFA at room temperature for 4 h, then washed with PBS, and the isolated eye cups and colon were cryoprotected by infiltration in 30% sucrose overnight, embedded in OCT compound (Cat. 4583; SAKURA, USA), and stored at -80°C until slicing. Sections were cut at 12 μm for all immunostaining purposes.

[0101] Tissue sections were blocked with 10% donkey serum / PBST (0.1% tritonx-100 / PBS) for 30 min and then incubated with primary antibodies overnight at 4°C. After washing with PBST, sections were incubated with fluorescent dye-conjugated secondary antibodies and mounted with Fluoromount-G (Southern Biotech, Birmingham, AL, USA). Phalloidin (A12379; Thermo-Fisher) staining was performed using the same immunohistochemical method, except that the secondary antibodies were omitted. The ApoTome (Zeiss) was equipped with a Zeiss confocal microscope (Zeiss LSM880; Zeiss, Oberkochen, Germany) and an Imager.Z2. The main antibodies used in this study were anti-Crb1 (PA5-66373, ThermoFisher; 1:50), anti-Iba1 (ab178846, Abcam; 1:500), anti-ZO-1 (61-7300, ThermoFisher; 1:500), anti-Occludin (OC-3F10, Invitrogen; 1:200), and AlexaFluor 488 phalloidin (A12379, ThermoFisher; 1:500).

[0102] 2.2 Fundus photography Mice were anesthetized and pupils were dilated. Hydroxypropyl methylcellulose eye drops were periodically instilled to keep the cornea moist. Mouse fundus photographs were taken with a Micron IV mouse fundus camera (Phoenix Research Laboratories, Inc., Pleasanton, CA, USA).

[0103] 2.3 RNA-seq analysis of the upper and lower retina Total RNA was analyzed using MasterPure TM Total DNA and RNA were extracted from the upper and lower retina using a total DNA / RNA purification kit (epicentre). RNA concentration was measured using the Qbit-RNA-HS Analysis Kit. TM Sequencing libraries were prepared using a Total RNA seq (H / M / R) Library Preparation Kit (Vazyme, China) according to the standard protocol provided by the manufacturer, and sequenced on an MGISEQ 2000RS platform.

[0104] The original measurements were first assessed for quality control by FastQC (v0.11.8) and cutadapt (v1.15). The clean measurements were aligned to the mouse genome (mm10) using HISAT2 (v2.1.0). Gene expression data were imported into the DESeq2 package in R software (v3.6.1) to perform differential expression analysis. Differentially expressed genes (DEGs) were imported into Intelligent Pathway Analysis (IPA) to perform functional enrichment analysis.

[0105] 2.4 Metagenomic sequence analysis Collect retinal samples and perform MasterPure TM DNA was extracted using the Intact DNA and RNA Purification Kit (epicentre). The contents of the stomach, jejunum, ileum, cecum, colon, and rectum were collected, and DNA was extracted using the QIAamp PowerFecal DNA kit (QIAGEN). After measuring the concentration, DNA was extracted from the VAHTS according to the standardized protocol provided by the manufacturer. TMDNA sequencing libraries were prepared using the MGI Universal DNA Library Preparation Kit (Vazyme, China). Metagenomic sequencing analysis was performed using MGISEQ-2000RS. Original measurements were filtered for quality control by Trimmomatic (v0.36) and PRINSEQ (v0.20.4). Mouse reads were removed using KneadData (v0.6.1) (https: / / bitbucket.org / biobakery / kneaddata). Kraken2 (v2.0.9) was used to map non-mouse cleared reads to a pre-built MiniKraken database. Classification results were screened at a confidence level of 0.20. Negative blank controls were processed together with the samples. All biological species present in the negative blank control group were removed.

[0106] 2.5 FITC-dextran in vivo intestinal permeability assay To evaluate the barrier function, an in vivo permeability assay was performed using the FITC-labeled dextran method. Food and water were removed overnight, and 8-week-old mice were orally administered 50 mg of FITC-labeled dextran (FD-70; Sigma-Aldrich) per 100 g (body weight). Serum was collected 5 h after administration, and the fluorescence intensity (excitation, 492 nm; emission, 525 nm) of each sample was measured.

[0107] 2.6 Flow cytometry WT and Rd8 mice were fasted overnight and intragastrically administered 1x109E of E. coli (engineered to stably express RFP). Six hours after intragastric administration, mice were euthanized and 400μL of peripheral blood was gently pipetted into a tube containing 4mL of ACK lysis buffer (Gibco, USA) and incubated at RT for 3–5min. After centrifugation at 300xg for 5min, cells were fixed and permeabilized (Cytofix / perm solution, BD Biosciences, USA) and analyzed by flow cytometry (MACSQuant Analyzer 10, Miltenyi Biotec, Germany).

[0108] 2.7 Electron microscope structure preparation Immediately after euthanasia, the colon and eyeballs were collected and fixed in phosphate-buffered glutaraldehyde-formaldehyde solution for 1 h at room temperature. The colon was cut into 2 mm blocks. The anterior segment was excised and the posterior segment was cut into 2 mm × 2 mm blocks. The excised tissues were left in fresh fixative for 12 h, then fixed in 1% osmium tetroxide, dehydrated, and embedded in Epon resin. Regions of interest were prescreened on micrometer-thick sections stained with toluidine blue under a light microscope. Ultrasound images at 80 nm were then collected and restained with uranyl acetate and lead citrate. The sonicated sections were observed under a transmission electron microscope.

[0109] 2.8 Fluorescence in situ hybridization (FISH) The following oligonucleotide probe was used in this study: EUB338, 5'-GCTGCCTCCGTAG-GAGT-3' (Amann et al., 1990). The 5' end of the probe contains a single primary amino group to which tetramethylrhodamine isothiocyanate is covalently attached. The dye-oligonucleotide conjugate (100 μM) was stored at -20°C.

[0110] The temporarily fixed retinal sections were rinsed three times with DEPC-treated PBS, treated with 0.2% Triton X-100 / DEPC-treated PBS, hybridized with the probe (500 nM) at 37°C overnight, and mounted with Fluoromount-G.

[0111] 2.9 Detection of gene expression levels in colonic tissues by real-time quantitative PCR Fresh mouse colon tissues (~1 cm) were snap frozen in liquid nitrogen, pulverized, and then lysed in RNA extraction lysis buffer. Total RNA was then purified using the Qiagen RNeasy Plus kit and reverse transcribed into cDNA using the Takara PrimeScript RT kit and gDNA eraser. The expression levels of the corresponding genes were detected by qPCR. The data were normalized to β-actin.

[0112] 2.10 Quantitative measurement of 16SrRNA gene levels in plasma by QPCR After treatment with 2.5% DSS for 13 days, plasma was isolated from whole blood of WT and Rd8 mice. Approximately 50 μL of plasma was taken and purified using a MasterPure TM Total nucleic acids were isolated using a Complete DNA and RNA Purification Kit (epicentre, USA). Precipitated nucleic acids were dissolved in 20 μL of nuclease-free water. qPCR analysis (ChamQ-SYBR-Color-qPCR-Master-Mix, Vazyme, China) was performed using a LightCycler 96 system (Roche, USA). Because the DNA concentration of all samples was extremely low, the same volume of each sample was used as template (4 μL in 20 μL). Total bacterial abundance was measured using the following universal 16S rRNA gene primers: 27F 5'-AGAGTTTGATCCTGGCTCAG-3', 534R 5'-GCATTACCGCGGCTGCTGG-3'.

[0113] 2.11 Enzyme-linked immunosorbent assay (ELISA) Each sample was directly assayed in 100 μL of plasma. The LPS concentration in plasma was measured by an enzyme-linked immunosorbent kit (SEB526Ge; Cloud-Clone Corp., USA).

[0114] 2.12 Colonization of fluorescent vanco-bodipy-labeled gut bacteria in Rd8 mice Fresh fecal samples were collected in 50 ml conical tubes containing sterile 1x PBS and spun until homogenized. The contents were filtered through a 0.22 μm filter (Millipore) to remove fecal debris, and the gut microbiota was centrifuged and then incubated with vanco-bodipy for 30 min at RT. Vanco-bodipy-labeled gut bacteria were diluted to 1x10 in PBS. 8 cfu / mouse was administered intragastrically. 24 hours after intragastric administration, retinal sections were taken and observed.

[0115] 2.13 Experimental study of dextran sulfate sodium (DSS)-induced colitis Enteritis was induced in mice by chronic oral administration of 2.5% DSS (MW 36000-50000d, Yeasen, China) via drinking water. Body weight was monitored daily from day 0 to day 13, and mice were killed on day 13 to measure colon length. For survival analysis, mice were given 2.5% DSS ad libitum in drinking water for 43 days and mice were monitored for mortality every 24 hours for 43 days.

[0116] 2.14 Depletion of gut symbionts A broad-spectrum antibiotic mixture of ampicillin (A; 1 g / L; Sigma), metronidazole (M; 1 g / L; Sigma), neomycin (N; 1 g / L; Sigma), and vancomycin (V; 500 mg / L; Sigma (AMNV)) was administered in drinking water to pregnant female mice and continued to be administered to the pups after weaning. Control mice were placed in a conventional apparatus on the same rack. EXAMPLES

[0117] Example 1 Model Construction We observed the retinal microenvironment characteristics of Crb1rd8 / rd8 (rd8) mice and Crb1wt / wt (C57BL / J, named "wt") mice (Figure 1A). When we observed the phenotype of Rd8 mice raised in a specific pathogen-free environment (Rd8-SPF), fundus examination revealed a white spot on the infranasal side of the inferior eye (Figure 1B), and all typical retinal symptoms were observed, including progressive retinal dysplasia (wrinkles and haloes) and histological degeneration of the retina (H&E staining) (Figure 2A). As a result, 7 out of 32 Rd8 mice developed mild retinal dysplasia (E18) before birth (Figure 2A and Figure 2B). Furthermore, all abnormalities at E18 occurred unilaterally (Figure 2A and Figure 1C). On the other hand, typical lesions such as retinal wrinkles and haloes were observed in the retinas of all Rd8 mice at P12 (before eye opening), P15 (after eye opening), and 8 weeks of age (8W), but not in any WT-SPF mice (Figures 2A and 2B). These data indicate that retinal abnormalities in Rd8 mice already occur at fetal stage E18, and that the intraocular environment determines the retinal phenotype under the genetic influence of the Crb1 mutation.

[0118] Example 2 Detection of intralesional pathogen presence and associated local immune response in the retina of model-established mice (Rd8-SPF) To compare gene expression profiles in the superior (without lesion) and inferior (with lesion) regions of Rd8-SPF mice, we performed transcriptome analysis using RNA-seq technology (Figure 3A). After removing genes with differential expression patterns (2-fold change, P<0.05) between the superior and inferior retinal regions of WT-SPF mice, we found 179 DEGs (DEGs) with at least 2-fold difference in expression (P<0.05) between the superior and inferior retinal regions of Rd8-SPF mice (Figure 3B and Figure 2C). In Rd8-SPF mice, most of these 179 DEGs were highly expressed in the defective inferior hemisegment (Figure 3C). Functional analysis of these DEGs using the Ingenuity Pathway analysis (IPA) tool showed that genes involved in bacterial and viral recognition were significantly enriched in all DEGs highly expressed in retinopathy in Rd8-SPF mice (Figure 2D). Importantly, the top two genes with the highest multiplicative increase in the lesion, Ncf4 and Slamf1, were both regulators of the phagocyte antimicrobial response. This data suggests the presence of intralesional pathogens and associated local immune responses in Rd8 retinas, and these results, combined with the enriched expression of genes with proinflammatory functions (Figure 2D) and the infiltration of IBA1+ microglia into the retinal lesion area (Figure 2E).

[0119] Example 3 Detection of the presence of bacteria in retinal lesions in model mice Metagenomic analysis was performed on retinal tissues from WT-SPF mice (n = 5, 4 weeks old) and Rd8-SPF mice (n = 4, 4 weeks old). The analysis showed that the bacterial DNA content was extremely low in the retinas of WT and Rd8 mice, and no viral or fungal DNA was detected after all quality control and decontamination processes. However, as shown in Figure 4A, principal coordinate analysis (PCoA) showed that there were significant differences in the bacterial composition of the retinas of WT-SPF and Rd8-SPF mice. Importantly, further metagenomic analysis of the upper and lower regions of the retina of Rd8-SPF (n=4, 4 weeks old) mice revealed that seven bacteria were significantly enriched in the lower region of the retina, including Anaerostipes hadrus, Bifidobacterium pseudocatenulatum, Megamonas funiformis, Nitrosomonas Is79A3, Oscillibacter, Tatumella sp.TA1, and Thiobacillus denitrificans (Figure 4B). To directly observe the presence of bacteria in the retinal lesions, Rd8-SPF mice (4 weeks old) were stained by fluorescent in situ hybridization (FISH) and vanco-bodipy staining, especially for the cell walls of gram-positive bacteria. As shown in Figure 4C, bacteria were only detected in the lesion area, but not in the normal retinal area. The presence of bacteria within the lesion area was further confirmed using transmission electron microscopy (TEM) (Figure 4D). This data demonstrated that bacteria were found in the retinal lesion area of ​​Rd8-SPF mice.

[0120] Example 5. Demonstration that the main defect in the retina of Rd8-SPF mice is the outer blood-retinal barrier Immunofluorescence staining data confirmed that CRB1 protein expression was reduced or absent in the outer membrane of Rd8 retinas (Figure 5A). Data also confirmed weak expression of CRB1 protein in Bruch's membrane (Figure 5A). Transmission electron microscopy revealed disruption of adherens junctions in the outer membrane at the lesion site of the retina in Rd8-SPF mice, which was associated with the outward shift of the outer nuclear layer (Figure 5B and Figure 6A). Transmission electron microscopy also revealed dissolution of adherens junctions in the retinal pigment epithelium (RPE) basement membrane and distortion of the choriocapillary basement membrane and disruption of the collagen layer between them in Rd8-SPF retinas, none of which were seen in WT-SPF mice (Figure 5C and Figure 6B). This correlated with the rupture of Bruch's membrane and the marked reduction in the thickness of Bruch's membrane in Rd8-SPF mice (Figure 5C, Figure 6B, Figure 5D). In contrast, transmission electron microscopy revealed no changes in the tight junctions between retinal capillary endothelial cells and retinal pigment epithelial cells, suggesting that the primary defect in the retinas of Rd8-SPF mice is the outer blood-retinal barrier, rather than the inner blood-retinal barrier.

[0121] Example 6 Metagenomic analysis of the microbiota at the site of intestinal obstruction All seven bacteria found in the Rd8 retina (Fig. 4B) were previously all gastrointestinal (GI) bacteria. Therefore, we performed metagenomic analysis of the microbiota in different sites of the GI tract (including stomach, jejunum, ileum, cecum, colon, and rectum) of WT-SPF mice (n = 5) and Rd8-SPF mice (n = 5) (Fig. 8A-F). The microbial composition in the lower GI tract of Rd8-SPF mice was significantly different from that of WT-SPF mice (Fig. 8G). Akkermansia mucinphila was identified as the most distinct bacterial species in the WT and Rd8 gut microbiota in the cecum (Fig. 8H), colon (Fig. 8I), and rectum (Fig. 8J), but was not traced in the Rd8 retina (Fig. 4B). Indeed, all seven bacteria in the Rd8 retina were detected in the lower GI tract of WT and Rd8 mice, with the highest bacterial abundance in the cecum (Fig. 7A). However, they were hardly detected in the upper gastrointestinal tract of Rd8 mice.These data suggest that these retinal bacteria are present in the gastrointestinal microbiota of Rd8-SPF mice but not in WT-SPF mice.

[0122] Immunofluorescence staining confirmed the expression of CRB1 protein in cecal enterocytes of wild-type mice, but its expression was significantly reduced in Rd8 mice (Figure 9A). Here, the expression of occludin (Figure 9B-C) was significantly lost in the cecum of Rd8 mice, and the expression of claudin-1 (Figure 9D-E) was not evident. Furthermore, transmission electron microscopy observed normal tight junctions and adherens junctions in the cecal epithelial barrier (Figure 9F).

[0123] Example 7 Examining the Presence of Barrier Defects in the Colon of Rd8 Mice Similar to the results in the cecum, CRB1 protein was significantly expressed at the apical and basal surfaces of colonic epithelial cells (Figure 7B). Loss of CRB1 protein was associated with a significant reduction in the expression of phalloidin (Figure 7C) and occludin (Figure 7D and Figure 4E), but not claudin 1 (Figure 7F and Figure 4G) proteins. Importantly, using transmission electron microscopy, we observed that most cells lacked localized adherens junctions between colonic epithelia, whereas tight junctions appeared normal in Rd8 mice (Figure 7H and Figure S6A). In addition to altered junctions, mitochondrial vacuolization was observed in the colonic epithelium of Rd8 mice. Although the number of epithelial microvilli was unchanged (Figure 7I), microvilli in Rd8 mice became longer (Figure 7J) and thinner (Figure 7K), and the total number of intact adherens junctions was significantly reduced compared to WT mice (Figure 7L). The changes in junction and microvilli ultrastructure were also accompanied by a significant increase in the expression of Il12a in the colonic wall ( Fig. 7M ), but no changes in the expression of Tnfa, Il1b, and mucin 2 ( Fig. 7N ). Together, these data suggest that Rd8 mice have colonic epithelial barrier dysfunction and associated inflammation in the colonic wall.

[0124] Example 8 We investigated whether intestinal epithelial barrier dysfunction leads to altered intestinal permeability and microbial translocation to the peripheral bloodstream and retinal tissue in Rd8 mice. Intestinal FICT-dextran permeability was measured in WT and Rd8 mice. As shown in Figure 11A, the fluorescence in the peripheral blood of Rd8 mice was significantly increased 5 h after FICT-dextran administration compared with the blood fluorescence intensity of WT mice. Furthermore, using the Vancompy-labeled fecal microbiota transplantation assay, a significant increase in fluorescent+ bacteria / cells was observed in the peripheral blood of Rd8 mice 24 h after fecal transplantation compared with WT mice (Figures 10B and 11B). Importantly, the presence of Vancomopy+ bacteria was detectable in the retinal lesions of Rd8 mice (Figure 11C), but not in the WT retinal lesions (data not shown), which was further confirmed by immunofluorescence staining of retinal tissues of Rd8 mice (Figure 11D). These data suggest that enhanced intestinal permeability to polysaccharide molecules and bacterial cells leads to the translocation of bacteria from the intestinal lumen to the bloodstream and retinal lesions.

[0125] Example 9: Experiment on the response of Rd8 to intestinal stress when intestinal permeability is increased Exposure of WT and Rd8 mice to 1.5% dextran sulfate sodium (DSS) in drinking water caused mild colitis in WT mice. Thirteen days after DSS treatment, colon length in Rd8 mice was significantly shorter than that in wild-type mice (Figure S1E). Bacteria in the blood of Rd8 mice were more abundant than those in the blood of wild-type mice, as indicated by serum bacterial 16S rRNA (Figure S1F) and bacterial LPS (Figure S1G) levels.

[0126] Example 10. Reversal effect of bacteria on the retinal phenotype of Rd8 mice In the retinas of Rd8 mice, bacteria were detected within the lesions caused by the disruption of the outer blood-retinal barrier and the gut-epithelial barrier, but it is unclear whether these bacteria are the cause or the result of retinal degeneration in Rd8 mice. Therefore, Rd8 mice were re-isolated under germ-free (GF) conditions and tested for changes in retinal degeneration phenotype. As shown in Figure 12A, the retinopathy (white spots) seen in Rd8-SPF mice was hardly observed in germ-free Rd8 (Rd8 GF) mice. Retinal histology of Rd8-GF mice showed the absence of the typical lesions seen in Rd8-SPF mice (Figure 2A and Figure 1C), and normally developing retinal tissue (Figure 12B) was observed, demonstrating the absence of retinal degeneration in Rd8-GF mice. The absence of retinal bacteria in Rd8GF mice (Figure ​(Figure12C) 12C) correlates with the dramatic reduction in microglia in the retinal outer nuclear layer (ONL) (Figure12D and 12E) in Rd8GF mice, whereas ZO-1 and phalloidin staining showed outer membrane destruction (Figure12F) as seen in both Rd8-SPF and Rd8GF mice. Furthermore, rearing Rd8GF mice in an SPF environment after birth (Rd8GF SPF mice) recurred retinopathy (Figure12G). These data support that retinal degeneration in Rd8 mice is bacteria-dependent.

[0127] The above-mentioned embodiments are only used to explain the technical solutions of the present invention, and are not limited thereto. Although the present invention has been described in detail with reference to the above-mentioned embodiments, those skilled in the art should understand that it is still possible to make modifications to the technical solutions recorded in the above-mentioned embodiments, or to make equivalent replacements to part or all of the technical features therein, and such modifications or replacements do not cause the corresponding technical solutions to depart from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for constructing an eye disease model or model carrier, comprising infecting the eye disease model or model carrier with a microorganism.

2. 2. The method of claim 1, wherein the infecting includes direct contact with the microorganism or indirect contact with the microorganism, wherein the indirect contact with the microorganism is characterized by the presence of a retinal barrier between the eye and the microorganism.

3. 3. The method of claim 2, wherein the microorganisms are derived from or identical to the intestinal bacteria of the same individual.

4. 4. The method of claim 3, wherein the eye disease comprises retinal degeneration, preferably the retinal degeneration is a progressive retinal degeneration, more preferably the retinal degeneration is an inherited retinal degeneration.

5. 5. The method of claim 4, wherein the eye disease comprises an ocular inflammation, preferably wherein the ocular inflammation comprises retinitis.

6. 6. The method according to claim 5, characterized in that the model is a non-human animal, preferably a monkey, a dog, a chimpanzee, a rat or a mouse.

7. 7. The method of claim 6, wherein the model carrier is selected from a cell, a tissue or an organ, the tissue or organ being derived from a non-human animal, the cells being derived from a primary cell or cell line of a human or non-human animal, and the tissue or organ being derived from an ocular tissue or organ derived from a non-human animal or obtained by growth of human stem cells.

8. The method of claim 7, wherein the model or model carrier has a pathogenic mutation in an eye gene, and preferably the eye gene in which the pathogenic mutation has occurred includes a mutation in one or more of the following genes: ABCA4, ABCC6, ABCC9, ACBD5, ACO2, ACO2, ACTG1, ADGRV1, AHI1, AIPL1, ALMS1, AMY2B, APC, ARFGEF1, ARL13B, ARL6, ARMC9, ATOH7, B9D1, BAG3, BBS1, BBS2, BBS5, BEST. 1, C2CD3, CA4, CABP4, CACNA1F, CBS, CC2D2A, CDH23, CDH23, CDHR1, CEMIP2, CEP104, CEP250, CEP290, CEP290, CEP41, CEP78, CERKL, CFAP410, CFAP418, C HM, CLCC1, CLCN7, CLN3, CLN5, CLN8, CLRN1, CLRN1, CNGA1, CNGA1, CNGA3, CN GB1, CNGB3, CNNM4, COL11A1, COL11A2, COL18A1, COL2A1, COL4A1, COL9A1, CO L9A2, CP, CP, CPLANE1, CRB1, ERCC4, CSPP1, CTNNA1, CYP4V2, DHDDS, DYNC2H 1, DYNC2I1, DYNC2I2, ENPP1, ERCC4, EVC2, EYS, EYS, F5, FAM161A, FBN1, FKRP , FKTN, FLG, FLVCR1, FOXE3, FUZ, GLB1, GMPPB, GNAT1, GRK1, GRM6, GUCA1A, G UCA1B, GUCY2D, HADHA, HGSNAT, HPS3, HPS5, IDH3B, IFT122, IFT140, IFT140, IFT43, IFT52, IFT74, IFT80, IFT80, IFT81, IFT88, IKBKG, IMPDH1, IMPG2, I NPP5E, INTU, IQCB1, IQCE, IREB2, KCNJ13, KCNQ1, KCNV2, KIAA0586, KIAA075 3, KIF7, KIZ, KIZ-AS1, KLHL7, KRIT1, LBR, LCA5, LOC101927157, LOC111365 204, LRP2, LRP5, MAK, MAPKAPK3, MATK, MCOLN1, MERTK, MKS1, MPDZ, MT-ATP6,MT-CO3, MT-TE, MT-TL1, MTHFR, MUTYH, MYO7A, MYO7A, NMNAT1, NPHP1, NR2E3, OCA2, OTX2, PANK2, PAX6, PCAR E, PCDH15, PDE6A, PDE6B, PDE6B, PDE6D, PEX1, PEX1, PEX12, PEX26, PEX6, PHF3, PITPNM3, PKD2, PLA2G5, POC 5, POMT1, PRCD, PRDM13, PROM1, PRPF3, PRPF31, PRPF8, PRPH2, RAD51C, RBP3, RBP4, RD3, RDH12, RDH5, RGR, R GR, RHO, RIMS1, RLBP1, ROM1, RP1, RP1L1, RP2, RPE65, RPE65, RPGR, RPGRIP1, RPGRIP1L, RS1, SACS, SAG, SCA PER, SDCCAG8, SIX6, SLC19A1, SLC22A5, SLC26A4, SLC2A9, SLTM, SNRNP200, SPAG17, SPATA7, SPG11, TFAP2A , TGFB2, TGFBR2, TMEM107, TMEM237, TMEM67, TOGARAM1, TOPORS, TPP1, TRAF3IP1, TREX1, TRIM59-IFT80, TS PAN12, TTC21B, TTC21B, TTC8, TULP1, USH1C, USH2A, USH2A, USH2A, USH2A, USH2A-AS1, VAC14, VCAN, VCAN, VCAN-AS1, VHL, VPS13B, WDR19, WDR19, WDR35, WDR73, YARS1, ZFYVE26, ZFYVE26, ZNF408, or a combination of two or more thereof.

9. The method of claim 8, wherein the CRB1 gene of the model or model carrier contains one or more of the following mutations: c. 107C>G, c. 111delT, c. 135C>G, c. 257_258dupTG, c. 258C>T, c. 428_432delGATTC, c. 430T>G, c. 470G>C, c. 481dupG, c. 482C>T, c. 584G>T, c. 613_619del, c. 717_718insG, c. 750T>G, c. 915T>A, c. 929G>A, c. 936T>G, c. 998G>A, c. 1084C>T, c. 1125C>G, c. 1148G>A, c. 1208C>G, c. 1269C>A, c. 1298A>G, c. 1313G>A, c. 1438T>C, c. 1438T>G, c. 1576C>T, c. 1604T>C, c. 1690G>T, c. 1733T>A, c. 1750G>T, c. 1760G>A, c. 1834T>C, c. 1963delC, c. 2025G>T, c. 2042G>A, c. 2128G>C, c. 2129C>T, c. 2185_2186insAlu, c. 2219C>T, c. 2222T>C, c. 2234C>T, c. 2245_2247del 3bp (TCA), c. 2258T>C, c. 2290C>T, and c. 2365_2367del AAT, in-frame deletion, c. 2401A>T, c. 2438_2439ins>100A, c. 2441_2442del, c. 2465G>A, c. 2479G>T, c. 2506C>A, c. 2509G>C, c. 2536G>A, c. 2548_2551delGGCT, c. 2548G>A, c. 2555T>C, c. 2611_2613insT, c. 2671T>G, c. 2676delG, c. 2681A>G, c. 2688T>A, c. 2816G>A, c. 2843G>A, c. 2853dupT, c. 2884_2886delTTA, c. 2957A>T, c. 2966T>C, c. 2983G>T, c. 3002A>T, c. 3008T>C, c. 3035T>C, c. 3037C>T, c. 3074G>A, c. 3074G>T, c. 3122T>C, c. 3212T>C, c. 3296C>A, c. 3299T>C, c. 3299T>G, c. 3307G>A / C, c. 3320T>C, c. 3320T>G,c.3331G>T、c.3343_3352del、c.3347delT、c.3343_3352del、c.3347delT、c.3427delT、c.3482A>G、c.3493T>C、c.3655T>G、c.3541T>C、c.3542dupG、c.3593A>G、c.3613G>A、c.3653G>T、c.3659_3660delinsA、c.3664C>T、c.3668G>C、c.3676G>T、c.3713_3716dup、c.3879G>A、c.3914C>T、c.3949A>C、c.3961T>A、c.3988delG、c.3988G>T、c.3995G>T、c.3996C>A、c.3997G>T、c.4094C>A、c.4121_4130del、c.4142C>T、c.4148G>A、c.2128+2T>G、c.2842+5G>A、c.3878+1G>T、c.4005+1G>A、c.4005+2T>G、c.4006-2A>G、c.4006-1G>T、c.619G>A、c.614T>C、c.1472A>T、c.1903T>C、c.2809G>A、c.3103C>T、c.4082G>A、c.4060G>A、c.866C>T、c.1463T>C、c.2035C>G、c.2306_2307GC>AG、c.2306G>A、c.2714G>A、c.2875G>A、c.3992G>A。、

10. 10. The method of claim 9, wherein the CRB1 gene of the model or model carrier comprises the Rd8 mutation.

11. The method according to claim 10, wherein the mutation is a homozygous mutation or a heterozygous mutation.

12. 12. The method according to claim 11, wherein the genetic mutation of the model or model carrier is congenital or acquired by genetic recombination manipulation.

13. 13. The method of claim 12, wherein the disease model has colonic epithelial barrier dysfunction and / or associated inflammation of the colon wall.

14. The microorganism is one or a combination of two or more of bacteria, archaea, protists, fungi, or viruses. Preferably, the microorganism is a bacterium, and the bacterium is selected from the group consisting of Anaerostipes, Bifidobacterium, Megamonas, Nitrosomonas, Oscillibacter, Tatumella, and Thiobacillus. sp.), Clostridium, Acinetobacter, Streptococcus, Mannheimia, Fibrobacter, Prevotella, Campylobacter, Acinetobacter, Actinomyces, Hymenobacter, Escherichia, Tissierella, Klebsiella, Porphyromonas, Azospirillum, Aquimarina , Achromobacter, Acidithiobacillus, Burkholderia, Marinobacter, Treponema, Actinosporangium, Vibrio, The method according to claim 13, characterized in that the bacterium is one or more selected from the group consisting of the genus Ruminococcus, Methanobrevibacter, Shigella, the genus Frankia, the genus Anaeroplasma, and the genus Coprococcus.

15. The bacteria include Anaerostipes hadrus, Bifidobacterium pseudocatenulatum, Nitrosomonas sp. Is79A3, Oscillibacter valericigenes, Tatumella sp. TA1, Megamonas funiformis, Thiobacillus denitrificans, and the like. denitrificans), Clostridium tetani, Clostridium perfringens, Clostridium botulinum, Acinetobacter calcoaceticus, Acinetobacter ruvofii, Acinetobacter baumannii, Acinetobacter haemolyticus, Acinetobacter junii, Acinetobacter johnsonii, Streptococcus pyogenes, Streptococcus hemolyticus, Fibrobacter succinogenes, Fibrobacter intestinalis, Porphyromonas asaccharolytica, Porphyromonas endodontalis, Porphyromonas gingibicanis, Campylobacter jejuni, Campylobacter coli, Campylobacter lari, Campylobacter upsaliensis, Campylobacter concisus, Campylobacter fetus, Actinomyces isla erii, Actinomyces naeslundii, Actinomyces odontolyticus, Actinomyces viscosus, Actinomyces nouii, Escherichia coli, Escherichia bullatae, Escherichia fergussoni, Escherichia hermannii, Escherichia vulneris, Tisserella praeacuta, Klebsiella pneumoniae, Klebsiella ozaenae, Azos Pillium brasilense, Achromobacter, Thiobacillus denitrificans, Thiobacillus ferrooxidans, Thiobacillus thiooxidans, Thiobacillus neapolitanus, Burkholderia, Mycobacterium marinum, Treponema pallidum, Treponema hyodysenteriae, Vibrio metschnikoffii, Ruminococcus albus, Ruminococcus flavefaciens,Methanobrevibacter ruminantium, Shigella dysenteriae, Shigella flexneri, Shigella boydii, Shigella sonnei, Frankia, Coprococcus oitactus, Streptomyces albus, Pseudomonas mendocina, Micrococcus sedentarius, Alicycliphilus denitrificans, Achromobacter xylosoxidans, Sphingomonas, Mycobacterium abscessus, Arthrobacter aurescens, Prevotella, Sinorhizobium medicae, Acidigenic yeast, Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter calcoaceticus, Comamonas testosteroni, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter koseri, Diadobacter fermentans, Serratia marcescens, Sphingomonas wittichii, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia pickettii, Lactobacillus crispatus, Burkholderia, Lactobacillus delbrueckii, Meiothermus sylvanus silvanus (D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium auricum, and Finegoldia magna.

16. A model carrier for an eye disease, wherein the eye disease is caused by infecting the model carrier with a microorganism, preferably the model carrier is selected from cells, tissues or organs, more preferably the cells are derived from primary cells or cell lines of a human or non-human animal, and the tissue or organ is derived from an eye tissue or organ derived from a non-human animal or obtained by growing human stem cells.

17. The eye disease model carrier of claim 16, wherein the eye disease includes retinal degeneration, preferably the retinal degeneration is progressive retinal degeneration, more preferably the retinal degeneration is hereditary retinal degeneration.

18. The eye disease model carrier according to claim 17, wherein the eye disease comprises ocular inflammation, and preferably the ocular inflammation comprises retinitis.

19. The eye disease model carrier according to claim 18, wherein the microorganisms are derived from or identical to the intestinal bacteria of the same individual.

20. The eye disease model carrier according to claim 19, characterized in that the model carrier has mutations in one or more of the following genes: ABCA4, ABCC6, ABCC9, ACBD5, ACO2, ACO2, ACTG1, ADGRV1, AHI1, AIPL1, ALMS1, AMY2B, APC, ARFGEF1, ARL13B, ARL13B, ARL6, ARMC9, ATOH7, B9D1, BAG3, BBS1, BBS1, BBS2, BBS5, BEST1, C2CD3, CA4, CABP4, CACNA1F, CBS, CC2D2A, C DH23, CDH23, CDHR1, CEMIP2, CEP104, CEP250, CEP290, CEP290, CEP41, CEP7 8, CERKL, CFAP410, CFAP418, CHM, CLCC1, CLCN7, CLN3, CLN5, CLN8, CLRN1, CL RN1, CNGA1, CNGA1, CNGA3, CNGB1, CNGB3, CNNM4, COL11A1, COL11A2, COL18A 1, COL2A1, COL4A1, COL9A1, COL9A2, CP, CP, CPLANE1, CRB1, ERCC4, CSPP1, CT NNA1, CYP4V2, DHDDS, DYNC2H1, DYNC2I1, DYNC2I2, ENPP1, ERCC4, EVC2, EYS , EYS, F5, FAM161A, FBN1, FKRP, FKTN, FLG, FLVCR1, FOXE3, FUZ, GLB1, GMPPB, GNAT1, GRK1, GRM6, GUCA1A, GUCA1B, GUCY2D, HADHA, HGSNAT, HPS3, HPS5, ID H3B, IFT122, IFT140, IFT140, IFT43, IFT52, IFT74, IFT80, IFT80, IFT81, IF T88, IKBKG, IMPDH1, IMPG2, INPP5E, INTU, IQCB1, IQCE, IREB2, KCNJ13, KCN Q1, KCNV2, KIAA0586, KIAA0753, KIF7, KIZ, KIZ-AS1, KLHL7, KRIT1, LBR, LCA 5, LOC101927157, LOC111365204, LRP2, LRP5, MAK, MAPKAPK3, MATK, MCOLN1 , MERTK, MKS1, MPDZ, MT-ATP6, MT-CO3, MT-TE, MT-TL1, MTHFR, MUTYH, MYO7A,MYO7A, NMNAT1, NPHP1, NR2E3, OCA2, OTX2, PANK2, PAX6, PCARE, PCDH15, PDE6A, PDE6B, PDE6B, PDE6D, PEX1, PEX1, PEX12, PEX26, PEX6, PHF3, PITPNM3, PKD2, PLA2G5, POC5, POMT1, PRCD, PRDM13, PROM1, PR PF3, PRPF31, PRPF8, PRPH2, RAD51C, RBP3, RBP4, RD3, RDH12, RDH5, RGR, RGR, RHO, RIMS1, RLBP1, ROM1 , RP1, RP1L1, RP2, RPE65, RPE65, RPGR, RPGRIP1, RPGRIP1L, RS1, SACS, SAG, SCAPER, SDCCAG8, SIX6, SL C19A1, SLC22A5, SLC26A4, SLC2A9, SLTM, SNRNP200, SPAG17, SPATA7, SPG11, TFAP2A, TGFB2, TGFBR2, TMEM107, TMEM237, TMEM67, TOGARAM1, TOPORS, TPP1, TRAF3IP1, TREX1, TRIM59-IFT80, TSPAN12, TTC 21B, TTC21B, TTC8, TULP1, USH1C, USH2A, USH2A, USH2A, USH2A, USH2A-AS1, VAC14, VCAN, VCAN, VCAN-AS1, VHL, VPS13B, WDR19, WDR19, WDR35, WDR73, YARS1, ZFYVE26, ZFYVE26, ZNF408, or a combination of two or more thereof.

21. The CRB1 gene mutation of the model carrier according to claim 20 is characterized by including one or more of the following mutations: c.107C>G, c.111delT, c.135C>G, c.257_258dupTG, c.258C>T, c.428_432delGATTC, c.430T>G, c.470G>C, c.481dupG, c.482C>T, c.584G>T, c.613_619del, c.717_718insG, c.750T>G, c.915T>A, c.929G>A, c.936T>G, c.998G>A, c.1084C>T, c.1125C>G, c.1148G>A, c.1208C>G, c.1269C>A, c.1298A>G, c.1313G>A, c.1438T>C, c.1438T>G, c.1576C>T, c.1604T>C, c.1690G>T, c.1733T>A, c.1750G>T, c.1760G>A, c.1834T>C, c.1963delC, c.2025G>T, c.2042G>A, c.2128G>C, c.2129C>T, c.2185_2186insAlu, c.2219C>T, c.2222T>C, c.2234C>T, c.2245_2247del 3bp (TCA), c.2258T>C, c.2290C>T, c.2365_2367del AAT, in-frame deletion, c.2401A>T, c.2438_2439ins>100A, c.2441_2442del, c.2465G>A, c.2479G>T, c.2506C>A, c.2509G>C, c.2536G>A, c.2548_2551delGGCT, c.2548G>A, c.2555T>C, c.2611_2613insT, c.2671T>G, c.2676delG, c.2681A>G, c.2688T>A, c.2816G>A, c.2843G>A, c.2853dupT, c.2884_2886delTTA, c.2957A>T, c.2966T>C, c.2983G>T, c.3002A>T, c.3008T>C, c.3035T>C, c.3037C>T, c.3074G>A, c.3074G>T, c.3122T>C, c.3212T>C, c.3296C>A, c.3299T>C, c.3299T>G, c.3307G>A / C, c.3320T>C, c.3320T>Gc.3331G>T、c.3343_3352del、c.3347delT、c.3343_3352del、c.3347delT、c.3427delT、c.3482A>G、c.3493T>C、c.3655T>G、c.3541T>C、c.3542dupG、c.3593A>G、c.3613G>A、c.3653G>T、c.3659_3660delinsA、c.3664C>T、c.3668G>C、c.3676G>T、c.3713_3716dup、c.3879G>A、c.3914C>T、c.3949A>C、c.3961T>A、c.3988delG、c.3988G>T、c.3995G>T、c.3996C>A、c.3997G>T、c.4094C>A、c.4121_4130del、c.4142C>T、c.4148G>A、c.2128+2T>G、c.2842+5G>A、c.3878+1G>T、c.4005+1G>A、c.4005+2T>G、c.4006-2A>G、c.4006-1G>T、c.619G>A、c.614T>C、c.1472A>T、c.1903T>C、c.2809G>A、c.3103C>T、c.4082G>A、c.4060G>A、c.866C>T、c.1463T>C、c.2035C>G、c.2306_2307GC>AG、c.2306G>A、c.2714G>A、c.2875G>A、c.3992G>A。、

22. The eye disease model carrier according to claim 21, wherein the mutation in the CRB1 gene of the model carrier is an Rd8 mutation.

23. The eye disease model carrier according to claim 22, wherein the mutation is a homozygous mutation or a heterozygous mutation.

24. The eye disease model carrier according to claim 23, wherein the mutation is congenital or acquired later by genetic recombination manipulation.

25. The eye disease model carrier of claim 24, wherein the non-human animal has colonic epithelial barrier dysfunction and / or associated inflammation of the colon wall.

26. The microorganism is one or a combination of two or more of bacteria, archaea, protists, fungi, or viruses. Preferably, the microorganism is a bacterium, and the bacterium is selected from the group consisting of Anaerostipes, Bifidobacterium, Megamonas, Nitrosomonas, Oscillibacter, Tatumella, and Thiobacillus. sp.), Clostridium, Acinetobacter, Streptococcus, Mannheimia, Fibrobacter, Prevotella, Campylobacter, Actinobacter, Actinomyces, Hymenobacter, Escherichia, Tissierella, Klebsiella, Porphyromonas, Azospira, Aquimarina, Achromobacter, Achromobacter, Acidithiobacillus, Burkholderia, Marinobacter, Treponema, Actinosporangium, Vibrio, Ruminococcus The eye disease model carrier according to claim 25, characterized in that it is one or more selected from the group consisting of Ruminococcus, Methanobrevibacter, Shigella, Frankia, Anaeroplasma, and Coprococcus.

27. The bacteria include Anaerostipes hadrus, Bifidobacterium pseudocatenulatum, Nitrosomonas sp. Is79A3, Oscillibacter valericigenes, Tatumella sp. TA1, Megamonas funiformis, Thiobacillus denitrificans, and the like. denitrificans), Clostridium tetani, Clostridium perfringens, Clostridium botulinum, Acinetobacter calcoaceticus, Acinetobacter ruvofii, Acinetobacter baumannii, Acinetobacter haemolyticus, Acinetobacter junii, Acinetobacter johnsonii, Streptococcus pyogenes, Streptococcus hemolyticus, Fibrobacter succinogenes, Fibrobacter intestinalis, Porphyromonas asaccharolytica, Porphyromonas endodontalis, Porphyromonas gingibicanis, Campylobacter jejuni, Campylobacter coli, Campylobacter lari, Campylobacter upsaliensis, Campylobacter concisus, Campylobacter fetus, Actinomyces isla erii, Actinomyces naeslundii, Actinomyces odontolyticus, Actinomyces viscosus, Actinomyces nouii, Escherichia coli, Escherichia bullatae, Escherichia fergussoni, Escherichia hermannii, Escherichia vulneris, Tisserella praeacuta, Klebsiella pneumoniae, Klebsiella ozaenae, Azos Pillium brasilense, Achromobacter, Thiobacillus denitrificans, Thiobacillus ferrooxidans, Thiobacillus thiooxidans, Thiobacillus neapolitanus, Burkholderia, Mycobacterium marinum, Treponema pallidum, Treponema hyodysenteriae, Vibrio metschnikoffii, Ruminococcus albus, Ruminococcus flavefaciens,Methanobrevibacter ruminantium, Shigella dysenteriae, Shigella flexneri, Shigella boydii, Shigella sonnei, Frankia, Coprococcus oitactus, Streptomyces albus, Pseudomonas mendocina, Micrococcus sedentarius, Alicycliphilus denitrificans, Achromobacter xylosoxidans, Sphingomonas, Mycobacterium abscessus, Arthrobacter aurescens, Prevotella, Sinorhizobium medicae, Acidigenic yeast, Staphylococcus epidermidis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus haemolyticus, Pseudomonas putida, Stenotrophomonas maltophilia, Bacillus cereus, Bacillus megaterium, Lactobacillus reuteri, Gardnerella vaginalis, Enterococcus faecium, Cytophaga hutchinsonii, Bacillus licheniformis, Xanthomonas oryzae, Acinetobacter baumannii, Acinetobacter calcoaceticus, Comamonas testosteroni, Mycobacterium kansasii, Bacillus thuringiensis, Citrobacter koseri, Diadobacter fermentans, Serratia marcescens, Sphingomonas wittichii, Klebsiella pneumoniae, Pseudomonas fluorescens, Ralstonia pickettii, Lactobacillus crispatus, Burkholderia, Lactobacillus delbrueckii, Meiothermus sylvanus silvanus (D), Escherichia coli, Micrococcus luteus, Bacillus subtilis, Corynebacterium auricum, and Finegoldia magna.

28. The eye disease model carrier according to any one of claims 16 to 27, characterized in that the eye disease model carrier is obtained according to the method according to any one of claims 1 to 15.

29. The eye disease model carrier according to any one of claims 16 to 27, characterized in that the eye disease model carrier is derived from an eye disease model constructed by the method according to any one of claims 1 to 15.

30. Use of the method according to any one of claims 1 to 15, an eye disease model prepared by the method according to any one of claims 1 to 15, or an eye disease model carrier according to any one of claims 16 to 27 for screening of targeted therapeutic drugs for eye diseases.

31. 31. The use according to claim 30, wherein the targeted therapy targets a gene associated with an eye disease.

32. 32. The use according to claim 31, characterized in that the gene associated with an eye disease is one or a combination of two or more of the following genes: ABCA4, ABCC6, ABCC9, ACBD5, ACO2, ACO2, ACTG1, ADGRV1, AHI1, AIPL1, ALMS1, AMY2B, APC, ARFGEF1, ARL13B, ARL13B, ARL6, ARMC9, ATOH7, B9D1, BAG3, BBS1, BBS1, BBS2, BBS5, BEST1, C2CD3, CA4, CABP4, CACNA1F, CBS, CC2D2A, C DH23, CDH23, CDHR1, CEMIP2, CEP104, CEP250, CEP290, CEP290, CEP41, CEP7 8, CERKL, CFAP410, CFAP418, CHM, CLCC1, CLCN7, CLN3, CLN5, CLN8, CLRN1, CL RN1, CNGA1, CNGA1, CNGA3, CNGB1, CNGB3, CNNM4, COL11A1, COL11A2, COL18A 1, COL2A1, COL4A1, COL9A1, COL9A2, CP, CP, CPLANE1, CRB1, ERCC4, CSPP1, CT NNA1, CYP4V2, DHDDS, DYNC2H1, DYNC2I1, DYNC2I2, ENPP1, ERCC4, EVC2, EYS , EYS, F5, FAM161A, FBN1, FKRP, FKTN, FLG, FLVCR1, FOXE3, FUZ, GLB1, GMPPB, GNAT1, GRK1, GRM6, GUCA1A, GUCA1B, GUCY2D, HADHA, HGSNAT, HPS3, HPS5, ID H3B, IFT122, IFT140, IFT140, IFT43, IFT52, IFT74, IFT80, IFT80, IFT81, IF T88, IKBKG, IMPDH1, IMPG2, INPP5E, INTU, IQCB1, IQCE, IREB2, KCNJ13, KCN Q1, KCNV2, KIAA0586, KIAA0753, KIF7, KIZ, KIZ-AS1, KLHL7, KRIT1, LBR, LCA 5, LOC101927157, LOC111365204, LRP2, LRP5, MAK, MAPKAPK3, MATK, MCOLN1 , MERTK, MKS1, MPDZ, MT-ATP6, MT-CO3, MT-TE, MT-TL1, MTHFR, MUTYH, MYO7A,<h2 style=";text-align:left;direction:ltr">MYO7A、NMNAT1、NPHP1、N R2E3、OCA2、OTX2、PANK2 、PAX6、PCARE、PCDH15、P DE6A、PDE6B、PDE6B、PDE 6D、PEX1、PEX1、PEX12、P EX26、PEX6、PHF3、PITPNM 3、PKD2、PLA2G5、POC5、P OMT1、PRCD、PRDM13、PRO M1、PRPF3、PRPF31、PRPF 8、PRPH2、RAD51C、RBP3、R BP4、RD3、RDH12、RDH5、R GR、RGR、RHO、RIMS1、RLBP 1、ROM1、RP1、RP1L1、RP2 、RPE65、RPE65、RPGR、RPG RIP1、RPGRIP1L、RS1、SA CS、SAG、SCAPER、SDCCAG 8、SIX6、SLC19A1、SLC22 A5、SLC26A4、SLC2A9、SLT M、SNRNP200、SPAG17、SP ATA7、SPG11、TFAP2A、TGF B2、TGFBR2、TMEM107、TMEM237、TMEM67、TOGARAM1 、TOPORS、TPP1、TRAF3IP 1、TREX1、TRIM59-IFT80 、TSPAN12、TTC21B、TTC2 1B、TTC8、TULP1、USH1C、U SH2A、USH2A、USH2A、USH 2A、USH2A-AS1、VAC14、VC AN、VCAN、VCAN-AS1、VHL 、VPS13B、WDR19、WDR19、W DR35、WDR73、YARS1、ZFY VE26、ZFYVE26、ZNF408。、

33. The use according to claim 32, wherein the targeted therapy targets one or more of the following mutations in the CRB1 gene: c.257_258dupTG, c.258C>T, c.428_432delGATTC, c.430T>G, c.470G>C, c.481dupG, c.482C>T, c.584G>T, c.613_619del, c.717_718insG, c.750T>G, c.915T>A, c.929G>A, c.936T>G, c.998G>A, c.1084C>T, c.1125C>G, c.1148G>A, c.1208C>G, c.1269C>A, c.1298A>G, c.1313G>A, c.1438T>C, c.1438T>G, c.1576C>T, c.1604T>C, c.1690G>T, c.1733T>A, c.1750G>T, c.1760G>A, c.1834T>C, c.1963delC, c.2025G>T, c.2042G>A, c.2128G>C, c.2129C>T, c.2185_2186insAlu, c.2219C>T, c.2222T>C, c.2234C>T, c.2245_2247del 3bp (TCA), c.2258T>C, c.2290C>T, c.2365_2367del AAT, in-frame deletion, c.2401A>T, c.2438_2439ins>100A, c.2441_2442del, c.2465G>A, c.2479G>T, c.2506C>A, c.2509G>C, c.2536G>A, c.2548_2551delGGCT, c.2548G>A, c.2555T>C, c.2611_2613insT, c.2671T>G, c.2676delG, c.2681A>G, c.2688T>A, c.2816G>A, c.2843G>A, c.2853dupT, c.2884_2886delTTA, c.2957A>T, c.2966T>C, c.2983G>T, c.3002A>T, c.3008T>C, c.3035T>C, c.3037C>T, c.3074G>A, c.3074G>T, c.3122T>C, c.3212T>C, c.3296C>A, c.3299T>C, c.3299T>G, c.3307G>A / C, c.3320T>C, c.3320T>G, c.3331G>T, c.3343_3352del, c.3347delT,c.3343_3352del、c.3347delT、c.3427delT、c.3482A>G、c.3493T>C、c.3655T>G、c.3541T>C、c.3542dupG、c.3593A>G、c.3613G>A、c.3653G>T、c.3659_3660delinsA、c.3664C>T、c.3668G>C、c.3676G>T、c.3713_3716dup、c.3879G>A、c.3914C>T、c.3949A>C、c.3961T>A、c.3988delG、c.3988G>T、c.3995G>T、c.3996C>A、c.3997G>T、c.4094C>A、c.4121_4130del、c.4142C>T、c.4148G>A、c.2128+2T>G、c.2842+5G>A、c.3878+1G>T、c.4005+1G>A、c.4005+2T>G、c.4006-2A>G、c.4006-1G>T、c.619G>A、c.614T>C、c.1472A>T、c.1903T>C、c.2809G>A、c.3103C>T、c.4082G>A、c.4060G>A、c.866C>T、c.1463T>C、c.2035C>G、c.2306_2307GC>AG、c.2306G>A、c.2714G>A、c.2875G>A、c.3992G>A。、

34. wherein the targeted therapeutic agent is modified cells, protein, ABCA4、ABCC6、ABCC9、ACBD5、ACO2、ACO2、ACTG1、ADGRV1、AHI1、AIPL1、ALMS1、AMY2B、APC、ARFGEF1、ARL13B、ARL13B、ARL6、ARMC9、ATOH7、B9D1、BAG3、BBS1、BBS1、BBS2、BBS5、BEST1、C2CD3、CA4、CABP4、CACNA1F、CBS、CC2D2A、CDH23、CDH23、CDHR1、CEMIP2、CEP104、CEP250、CEP290、CEP290、CEP41、CEP78、CERKL、CFAP410、CFAP418、CHM、CLCC1、CLCN7、CLN3、CLN5、CLN8、CLRN1、CLRN1、CNGA1、CNGA1、CNGA3、CNGB1、CNGB3、CNNM4、COL11A1、COL11A2、COL18A1、COL2A1、COL4A1、COL9A1、COL9A2、CP、CP、CPLANE1、CRB1、ERCC4、CSPP1、CTNNA1、CYP4V2、DHDDS、DYNC2H1、DYNC2I1、DYNC2I2、ENPP1、ERCC4、EVC2、EYS、EYS、F5、FAM161A、FBN1、FKRP、FKTN、FLG、FLVCR1、FOXE3、FUZ、GLB1、GMPPB、GNAT1、GRK1、GRM6、GUCA1A、GUCA1B、GUCY2D、HADHA、HGSNAT、HPS3、HPS5、IDH3B、IFT122、IFT140、IFT140、IFT43、IFT52、IFT74、IFT80、IFT80、IFT81、IFT88、IKBKG、IMPDH1、IMPG2、INPP5E、INTU、IQCB1、IQCE、IREB2、KCNJ13、KCNQ1、KCNV2、KIAA0586、KIAA0753、KIF7、KIZ、KIZ-AS1、KLHL7、KRIT1、LBR、LCA5、LOC101927157、LOC111365204、LRP2、LRP5、MAK、MAPKAPK3、MATK、MCOLN1、MERTK、MKS1、MPDZ、MT-ATP6、MT-CO3、MT-TE、MT-TL1、MTHFR、MUTYH、MYO7A、MYO7A、NMNAT1、NPHP1、NR2E3、OCA2、OTX2、PANK2、PAX6、PCARE、PCDH15、PDE6A、Target the gene of PDE6B, PDE6B, PDE6D, PEX1, PEX1, PEX12, PEX26, PEX6, PHF3, PITPNM3, PKD2, PLA2G5, POC5, POMT1, PRCD, PRDM13, PROM1, PRPF3, PRPF31, PRPF8, PRPH2, RAD51C, RBP3, RBP4, RD3, RDH12, RDH5, RGR, RGR, RHO, RIMS1, RLBP1, ROM1, RP1, RP1L1, RP2, RPE65, RPE65, RPGR, RPGRIP1, RPGRIP1L, RS1, SACS, SAG, SCAPER, SDCCAG8, SIX6, SLC19A1, SLC22A5, SLC26A4, SLC2A9, SLTM, SNRNP200, SPAG17, SPATA7, SPG11, TFAP2A, TGFB2, TGFBR2, TMEM107, TMEM237, TMEM67, TOGARAM1, TOPORS, TPP1, TRAF3IP1, TREX1, TRIM59 - IFT80, TSPAN12, TTC21B, TTC21B, TTC8, TULP1, USH1C, USH2A, USH2A, USH2A, USH2A, USH2A - AS1, VAC14, VCAN, VCAN, VCAN - AS1, VHL, VPS13B, WDR19, WDR19, WDR35, WDR73, YARS1, ZFYVE26, ZFYVE26 or ZNF408, or c.257_258dupTG, c.258C>T, c.428_432delGATTC, c.430T>G, c.470G>C, c.481dupG, c.482C>T, c.584G>T, c.613_619del, c.717_718insG, c.750T>G, c.915T>A, c.929G>A, c.936T>G, c.998G>A, c.1084C>T, c.1125C>G, c.1148G>A, c.1208C>G, c.1269C>A, c.1298A>G, c.1313G>A, c.1438T>C, c.1438T>G, c.1576C>T, c.1604T>C, c.1690G>T, c.1733T>A, c.1750G>T, c.1760G>A, c.1834T>C, c.1963delC, c.2025G>T, c.2042G>A, c.2128G>C, c.2129C>T, c.2185_2186insAlu, c.2219C>T,c.2222T>C, c.2234C>T, c.2245_2247del 3bp (TCA), c.2258T>C, c.2290C>T, c.2365_2367del AAT, in-frame deletion, c.2401A>T, c.2438_2439ins>100A, c.2441_2442del, c.2465G>A, c.2479G>T, c.2506C>A, c.2509G>C, c.2536G>A, c.2548_2551delGGCT, c.2548G>A, c.2555T>C, c.2611_2613insT, c.2671T>G, c.2676delG, c.2681A>G, c.2688T>A, c.2816G>A, c.2843G>A, c.2853dupT, c.2884_2886delTTA, c.2957A>T, c.2966T>C, c.2983G>T, c.3002A>T, c.3008T>C, c.3035T>C, c.3037C>T, c.3074G>A, c.3074G>T, c.3122T>C, c.3212T>C, c.3296C>A, c.3299T>C, c.3299T>G, c.3307G>A / C, c.3320T>C, c.3320T>G, c.3331G>T, c.3343_3352del, c.3347delT, c.3343_3352del, c.3347delT, c.3427delT, c.3482A>G, c.3493T>C, c.3655T>G, c.3541T>C, c.3542dupG, c.3593A>G, c.3613G>A, c.3653G>T, c.3659_3660delinsA, c.3664C>T, c.3668G>C, c.3676G>T, c.3713_3716dup, c.3879G>A, c.3914C>T, c.3949A>C, c.3961T>A, c.3988delG, c.3988G>T, c.3995G>T, c.3996C>A, c.3997G>T, c.4094C>A, c.4121_4130del, c.4142C>T, c.4148G>A, c.2128+2T>G, c.2842+5G>A, c.3878+1G>T, c.4005+1G>A, c.4005+2T>G, c.4006-2A>G, c.4006-1G>T, c.619G>A, c.614T>C, c.1472A>T, c.1903T>C, c.2809G>A, c.3103C>T,RNAs targeting the mutation sites c. 4082G>A, c. 4060G>A, c. 866C>T, c. 1463T>C, c. 2035C>G, c. 2306_2307GC>AG, c. 2306G>A, c. 2714G>A, c. 2875G>A or c. 3992G>A, and / or ABCA4、ABCC6、ABCC9、ACBD5、ACO2、ACO2、ACTG1、ADGRV1、AHI1、AIPL1、ALMS1、AMY2B、APC、ARFGEF1、ARL13B、ARL13B、ARL6、ARMC9、ATOH7、B9D1、BAG3、BBS1、BBS1、BBS2、BBS5、BEST1、C2CD3、CA4、CABP4、CACNA1F、CBS、CC2D2A、CDH23、CDH23、CDHR1、CEMIP2、CEP104、CEP250、CEP290、CEP290、CEP41、CEP78、CERKL、CFAP410、CFAP418、CHM、CLCC1、CLCN7、CLN3、CLN5、CLN8、CLRN1、CLRN1、CNGA1、CNGA1、CNGA3、CNGB1、CNGB3、CNNM4、COL11A1、COL11A2、COL18A1、COL2A1、COL4A1、COL9A1、COL9A2、CP、CP、CPLANE1、CRB1、ERCC4、CSPP1、CTNNA1、CYP4V2、DHDDS、DYNC2H1、DYNC2I1、DYNC2I2、ENPP1、ERCC4、EVC2、EYS、EYS、F5、FAM161A、FBN1、FKRP、FKTN、FLG、FLVCR1、FOXE3、FUZ、GLB1、GMPPB、GNAT1、GRK1、GRM6、GUCA1A、GUCA1B、GUCY2D、HADHA、HGSNAT、HPS3、HPS5、IDH3B、IFT122、IFT140、IFT140、IFT43、IFT52、IFT74、IFT80、IFT80、IFT81、IFT88、IKBKG、IMPDH1、IMPG2、INPP5E、INTU、IQCB1、IQCE、IREB2、KCNJ13、KCNQ1、KCNV2、KIAA0586、KIAA0753、KIF7、KIZ、KIZ-AS1、KLHL7、KRIT1、LBR、LCA5、LOC101927157、LOC111365204、LRP2、LRP5、MAK、MAPKAPK3、MATK、MCOLN1、MERTK、MKS1、MPDZ、MT-ATP6、MT-CO3、MT-TE、MT-TL1、MTHFR、MUTYH、MYO7A、MYO7A、NMNAT1、NPHP1、NR2E3、OCA2、OTX2、PANK2、PAX6、PCARE、PCDH15、PDE6A、Target the genes of PDE6B, PDE6B, PDE6D, PEX1, PEX1, PEX12, PEX26, PEX6, PHF3, PITPNM3, PKD2, PLA2G5, POC5, POMT1, PRCD, PRDM13, PROM1, PRPF3, PRPF31, PRPF8, PRPH2, RAD51C, RBP3, RBP4, RD3, RDH12, RDH5, RGR, RGR, RHO, RIMS1, RLBP1, ROM1, RP1, RP1L1, RP2, RPE65, RPE65, RPGR, RPGRIP1, RPGRIP1L, RS1, SACS, SAG, SCAPER, SDCCAG8, SIX6, SLC19A1, SLC22A5, SLC26A4, SLC2A9, SLTM, SNRNP200, SPAG17, SPATA7, SPG11, TFAP2A, TGFB2, TGFBR2, TMEM107, TMEM237, TMEM67, TOGARAM1, TOPORS, TPP1, TRAF3IP1, TREX1, TRIM59 - IFT80, TSPAN12, TTC21B, TTC21B, TTC8, TULP1, USH1C, USH2A, USH2A, USH2A, USH2A, USH2A - AS1, VAC14, VCAN, VCAN, VCAN - AS1, VHL, VPS13B, WDR19, WDR19, WDR35, WDR73, YARS1, ZFYVE26, ZFYVE26 or ZNF408, or c.257_258dupTG, c.258C>T, c.428_432delGATTTC, c.430T>G, c.470G>C, c.481dupG, c.482C>T, c.584G>T, c.613_619del, c.717_718insG, c.750T>G, c.915T>A, c.929G>A, c.936T>G, c.998G>A, c.1084C>T, c.1125C>G, c.1148G>A, c.1208C>G, c.1269C>A, c.1298A>G, c.1313G>A, c.1438T>C, c.1438T>G, c.1576C>T, c.1604T>C, c.1690G>T, c.1733T>A, c.1750G>T, c.1760G>A, c.1834T>C, c.1963delC, c.2025G>T, c.2042G>A, c.2128G>C, c.2129C>T, c.2185_2186insAlu, c.2219C>T,c.2222T>C, c.2234C>T, c.2245_2247del 3bp (TCA), c.2258T>C, c.2290C>T, c.2365_2367del AAT, in-frame deletion, c.2401A>T, c.2438_2439ins>100A, c.2441_2442del, c.2465G>A, c.2479G>T, c.2506C>A, c.2509G>C, c.2536G>A, c.2548_2551delGGCT, c.2548G>A, c.2555T>C, c.2611_2613insT, c.2671T>G, c.2676delG, c.2681A>G, c.2688T>A, c.2816G>A, c.2843G>A, c.2853dupT, c.2884_2886delTTA, c.2957A>T, c.2966T>C, c.2983G>T, c.3002A>T, c.3008T>C, c.3035T>C, c.3037C>T, c.3074G>A, c.3074G>T, c.3122T>C, c.3212T>C, c.3296C>A, c.3299T>C, c.3299T>G, c.3307G>A / C, c.3320T>C, c.3320T>G, c.3331G>T, c.3343_3352del, c.3347delT, c.3343_3352del, c.3347delT, c.3427delT, c.3482A>G, c.3493T>C, c.3655T>G, c.3541T>C, c.3542dupG, c.3593A>G, c.3613G>A, c.3653G>T, c.3659_3660delinsA, c.3664C>T, c.3668G>C, c.3676G>T, c.3713_3716dup, c.3879G>A, c.3914C>T, c.3949A>C, c.3961T>A, c.3988delG, c.3988G>T, c.3995G>T, c.3996C>A, c.3997G>T, c.4094C>A, c.4121_4130del, c.4142C>T, c.4148G>A, c.2128+2T>G, c.2842+5G>A, c.3878+1G>T, c.4005+1G>A, c.4005+2T>G, c.4006-2A>G, c.4006-1G>T, c.619G>A, c.614T>C, c.1472A>T, c.1903T>C, c.2809G>A, c.3103C>T,The use according to claim 32, characterized in that it comprises DNA targeting the mutation site of c. 4082G>A, c. 4060G>A, c. 866C>T, c. 1463T>C, c. 2035C>G, c. 2306_2307GC>AG, c. 2306G>A, c. 2714G>A, c. 2875G>A or c. 3992G>A.

35. Use of the method according to any one of claims 1 to 15, an eye disease model prepared by the method according to any one of claims 1 to 15, or an eye disease model carrier according to any one of claims 16 to 27 in research on eye diseases.

36. Use of the method according to any one of claims 1 to 15, the eye disease model prepared by the method according to any one of claims 1 to 15, or the eye disease model carrier according to any one of claims 16 to 27 for screening drugs related to eye diseases, wherein the drugs include one or a combination of two or more of small molecule drugs, chemical drugs, polymer drugs, biological drugs or natural drugs (e.g., Chinese herbal medicines or Chinese herbal medicine extracts), cellular drugs, RNA drugs, and DNA drugs.

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