Role Of Retinal Pigment Epithelium In Retinal Disorders

视网膜色素上皮在视网膜疾病中的作用

• 批准号: 6681744
• 负责人: CHANDRASEK N NAGINENI
• 金额: --
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6681744
• 关键词: Toxoplasma gondii; aging; angiogenesis; antiinflammatory agents; chorioretinitis; cytokine; diabetic retinopathy; enzyme inhibitors; eye infections; gene expression; human tissue; inflammation; macular degeneration; messenger RNA; mitogen activated protein kinase; necrosis; ocular toxoplasmosis; polymerase chain reaction; protozoal infection; retina disorder; retinal pigment epithelium; tissue /cell culture; transforming growth factors; uveitis; vascular endothelial growth factors; vision disorders

Retinal pigment epithelium (RPE), a single layer of cells present between the retina and choroid in the eye, is vital for the normal functioning of the retina. Many of the inflammatory, infectious and hereditary diseases of the retina are associated with the degeneration and /or dysfunction of the RPE. We have developed human RPE cell culture system and have used this as a model to investigate the various roles of RPE in the pathophysiology of retinal disorders. We have focussed our attention on Transforming Growth factor-beta (TGF-b), since TGF-b is involved in retinal disorders of proliferative, inflammatory and infectious etiology. Retinal and Choroidal neovascularization (NV), observed during age related macular degeneration (ARMD) and diabetic retinopathy, are the leading causes of visual impairment. Elevated expression of TGF-b in vitreous, retina and RPE has been closely correlated with the retinal fibrosis and choroidal neovascularization. Since vascular endothelial growth factor (VEGF) is associated with NV, we have examined the role of RPE in VEGF expression. TGF-b is found to be the potent inducer of VEGF secretion by RPE. Effects of TGF-b are specific since other related growth factors had no effects, and TGF-b effects are neutralized by TGF-b receptor II antibody. RT-PCR analyses indicated the expression of 121,165 and 189 aa isoforms of VEGF mRNA, which are up regulated by TGF-b. By using specific inhibitors of mitogen activated protein kinases and Northern blot analyses, we found that TGF-b activate VEGF transcription through MAPK and smad pathways. Regulation of the expression of VEGF in RPE by TGF-b strongly suggests an important role for TGF-b in neovascularization associated with retinal disorders.

视网膜色素上皮（RPE）是存在于眼睛中的视网膜和脉络膜之间的单层细胞，对于视网膜的正常功能至关重要。视网膜的许多炎性、感染性和遗传性疾病与RPE的变性和/或功能障碍有关。我们已经开发了人RPE细胞培养系统，并以此为模型来研究RPE在视网膜疾病的病理生理学中的各种作用。我们将注意力集中在转化生长因子-β（TGF-β）上，因为TGF-β参与增殖性、炎症性和感染性病因的视网膜疾病。在年龄相关性黄斑变性（ARMD）和糖尿病视网膜病变期间观察到的视网膜和脉络膜新生血管（NV）是视力损害的主要原因。TGF-β在玻璃体、视网膜和RPE中的高表达与视网膜纤维化和脉络膜新生血管形成密切相关。由于血管内皮生长因子（VEGF）与NV相关，我们研究了RPE在VEGF表达中的作用。发现TGF-β是RPE分泌VEGF的有效诱导剂。TGF-β的作用是特异性的，因为其他相关的生长因子没有作用，TGF-β的作用被TGF-β受体II抗体中和。RT-PCR分析显示VEGF mRNA的121、165和189个氨基酸异构体的表达，这些异构体的表达受TGF-β上调。通过丝裂原活化蛋白激酶特异性抑制剂和北方印迹分析，我们发现TGF-β通过MAPK和smad途径激活VEGF的转录。TGF-β对RPE中VEGF表达的调节强烈表明TGF-β在与视网膜疾病相关的新生血管形成中起重要作用。