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The development of the animal model of diabetic retinopathy by the control of the retina-specific VEGF expression

通过控制视网膜特异性VEGF表达建立糖尿病视网膜病变动物模型

基本信息

批准号：
12671714
负责人：
OKAMOTO Naoyuki
金额：
$ 2.18万
依托单位：
Kitasato University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671714/
关键词：
gene expression vascular endothelial growth factor VEGF Diabetic retinopathy Neovascularization Animal model Transgenic mouse Rhodopsin 糖尿病網膜病

项目摘要

Transgenic mice with vascular endothelial growth factor (VEGF) driven by the rhodopsin promoter (rho/VEGF mice) develop neovascularization that originates from the deep capillary bed of the retina and grows into the subretinal space. In rho/VEGF mice, VEGF expression in photoreceptors begins between postnatal days 5 and 7, the period when the deep capillary bed is developing. An important question is whether or not the developmental stage of the deep capillary bed is critical for occurrence of neovascularization. Also, although rho/VEGF mice are extremely useful for the study of ocular neovascularization, there are some applications for which the early onset of VEGF expression is a disadvantage. In this study, we used the reverse tetracycline transactivator (rtTA) inducible promoter system coupled to the promoter to control the time of onset of VEGF transgene expression in photoreceptors. In the absence of doxycycline, adult double-transgenic rho/rtTA-TRE/VEGF mice showed little VEGF t … More ransgene expression and no phenotype. The addition of doxycycline to the drinking water resulted in prominent transgene expression and evidence of neovascularization within 3 to 4 days. Like rho/VEGF mice, the neovascularization originated from the deep capillary bed of the retina, but it was more extensive and caused outer retinal folds followed by total retinal detachment. Real-time polymerase chain reaction and enzyme-linked immunosorbent assay demonstrated that the mice with inducible expression of VEGF that developed retinal detachment had much higher ocular levels of VEGF mRNA and protein compared to rho/VEGF mice that manifest a much milder phenotype. These data demonstrate that regardless of developmental stage of the vascular bed, increased expression of VEGF in the retina is sufficient to cause neovascularization, and high levels of expression cause severe neovascularization and traction retinal detachment. Mice with inducible expression of VEGF in the retina provide a valuable new model of ocular neovascularization including diabetic retinopathy. Less

具有由视紫红质启动子驱动的血管内皮生长因子（VEGF）的转基因小鼠（rho/VEGF小鼠）产生源自视网膜深毛细血管床并生长到视网膜下腔的新血管形成。在rho/VEGF小鼠中，光感受器中的VEGF表达开始于出生后第5天至第7天，此时深毛细血管床正在发育。一个重要的问题是深毛细血管床的发育阶段是否是新生血管发生的关键。此外，尽管rho/VEGF小鼠对于眼部新生血管形成的研究非常有用，但是对于某些应用，VEGF表达的早期发作是不利的。在这项研究中，我们使用的反向四环素反式激活因子（rtTA）诱导型启动子系统耦合到启动子控制的时间开始的VEGF转基因表达的感光细胞。在没有强力霉素的情况下，成年双转基因rho/rtTA-TRE/VEGF小鼠显示很少的VEGF表达。 ...更多信息转基因表达和无表型。在饮用水中添加强力霉素导致显著的转基因表达和3至4天内的新血管形成的证据。与rho/VEGF小鼠一样，新血管形成起源于视网膜的深毛细血管床，但它更广泛，并引起外视网膜褶皱，随后发生完全视网膜脱离。实时聚合酶链反应和酶联免疫吸附试验表明，与表现出更温和的表型的rho/VEGF小鼠相比，具有可诱导VEGF表达的小鼠发展为视网膜脱离，具有更高的VEGF mRNA和蛋白质的眼部水平。这些数据表明，无论血管床的发育阶段如何，视网膜中VEGF表达的增加足以引起新生血管形成，并且高水平的表达引起严重的新生血管形成和牵引性视网膜脱离。在视网膜中具有可诱导的VEGF表达的小鼠提供了包括糖尿病视网膜病变在内的眼部新生血管形成的有价值的新模型。少