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: 6826681
• 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/6826681
• 关键词: aging; angiogenesis; chorioretinitis; cytokine; diabetic retinopathy; enzyme inhibitors; eye infections; gene expression; growth factor receptors; human tissue; inflammation; macular degeneration; mitogen activated protein kinase; necrosis; platelet derived growth factor; polymerase chain reaction; proliferative vitreoretinopathy; receptor expression; 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 other 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 (CNV), 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 CNV. Platelet derived growth factors (PDGF) are known to be associated with retinal proliferative and angiogenic disorders such as proliferative vitreoretinopathy (PVR) and age realted macular degeneration (ARMD). PDGF promotes proliferation and migration of fibroblasts, pericytes, smooth muscle, glial and RPE cells. Our studies indicated that TGF-b is a potent inducer of PDGF-AA and PDGF-AB in RPE cells while choroidal fibroblasts(CHF) do not produce PDGF. Receptors for PDGF are highly expressed on CHF but not on RPE. Human recombinant PDGF-isoforms (AA, AB, BB) significantly enhanced CHF proliferation, elongation and migration. In contrast no significant effects on RPE proliferation and migration were observed. These results show that PDGF secreted by RPE cells (stimulated by TGF-b) act on nearby connective tissue cells (fibroblasts) and possibly on vascular pericytes and smooth muscle cells. Consequent promotion of proliferation and migration of these target cells results in the pathogenesis of PVR and CNV in ARMD. Regulation of the expression of PDGF in RPE by TGF-b strongly suggests an important role for TGF-b in neovascularization associated with retinal disorders such as PVR and ARMD.

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、感染性和其它疾病与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（CNV）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CNV密切相关。已知血小板衍生生长因子（PDGF）与视网膜增殖性和血管生成性疾病如增殖性玻璃体视网膜病变（PVR）和年龄相关性黄斑变性（ARMD）相关。PDGF促进成纤维细胞、周细胞、平滑肌、神经胶质和RPE细胞的增殖和迁移。我们的研究表明，TGF-β是RPE细胞中PDGF-AA和PDGF-AB的有效诱导剂，而脉络膜成纤维细胞（CHF）不产生PDGF。PDGF受体在CHF上高度表达，但在RPE上不表达。人重组PDGF亚型（AA，AB，BB）显着增强CHF的增殖，延长和迁移。相反，没有观察到对RPE增殖和迁移的显著影响。这些结果表明，由RPE细胞分泌的PDGF（由TGF-β刺激）作用于附近的结缔组织细胞（成纤维细胞），并可能作用于血管周细胞和平滑肌细胞。这些靶细胞的增殖和迁移促进了ARMD中PVR和CNV的发病。TGF-β对RPE中PDGF表达的调节强烈提示TGF-β在与视网膜疾病如PVR和ARMD相关的新生血管形成中起重要作用。