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: 7138069
• 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/7138069
• 关键词: aging; angiogenesis; cytokine; diabetic retinopathy; enzyme inhibitors; 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 circulation; retina degeneration; retina detachment; retina disorder; retinal pigment epithelium; tissue /cell culture; transforming growth factors; uvea disorder; vascular endothelial growth factors

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 a 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 focused 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 proliferative vitreoretinopathy (PVR) associated with retinal detachments, 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. However, the sources and production of TGF-b by retinal resident cells were not clearly known. We have examined the role of various cytokines and other mediators in the regulation of the expression of TGF-b by RPE. Our results demonstrated a differential role for interferon (IFN)-g, which enhanced TGF-b1 but inhibited TGF-b2 production. Interestingly, other inflammatory mediators such as tumor necrosis factor (TNF)-alpha and interleukin-1 enhanced the secretion of both TGF-b1 and TGF-b2. These observations were corroborated by mRNA analyses by Real-time and conventional RT-PCR methods. The contrasting effects of IFN-g on TGF-b1 and TGF-b2 sheds new light on the possible differential actions of TGF-b1 and TGF-b2 in the pathophysiology of retinal diseases. Further studies are in progress to evaluate the potential role of TGF-b1 and TGF-b2 and their receptors in the retinal diseases. We are evaluating the role and expression of Interferon-beta, which plays a vital role as an antiviral, anti-inflammatory agent, in the retinal and choroidal diseases. There is increasing evidence that Interferon-beta prevents blood-tissue barrier by preserving vascular cell functions. In human choroidal fibroblast cells (HCHF), IFN-gamma induced secretion of IFN-beta, which was enhanced significantly by the synergistic action of TNF-alpha. Human RPE cells did not secrete IFN-beta by IFN-gamma and TNF-alpha treatment. Interleukins and growth factors had no effects on IFN-beta production by both HCHF and RPE cells. Real-time and conventional RT-PCR methods showed enhanced expression of IFN-beta mRNA in IFN-gamma and TNF-alpha treated HCHF. IFN-beta produced by choroidal cells may act to protect the integrity of the choroidal vasculature and blood-retinal barrier during inflammatory conditions.

视网膜色素上皮（RPE）是存在于视网膜和脉络膜之间的单层细胞，对视网膜的正常功能至关重要。视网膜的许多炎症、感染性疾病和其他疾病都与视网膜的变性和/或功能障碍有关。我们已经开发了一个人类RPE细胞培养系统，并以此为模型来研究RPE在视网膜疾病病理生理中的各种作用。我们将注意力集中在转化生长因子- β (TGF-b)上，因为TGF-b参与了视网膜疾病的增殖性、炎症性和感染性病因。在年龄相关性黄斑变性（ARMD）和与视网膜脱离相关的增殖性玻璃体视网膜病变（PVR）中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-b在玻璃体、视网膜和RPE中的表达升高与视网膜纤维化和CNV密切相关。然而，视网膜常驻细胞TGF-b的来源和产生尚不清楚。我们已经研究了各种细胞因子和其他介质在RPE调节TGF-b表达中的作用。我们的研究结果表明干扰素(IFN)-g具有不同的作用，它可以增强TGF-b1，但抑制TGF-b2的产生。有趣的是，其他炎症介质如肿瘤坏死因子(TNF)- α和白细胞介素-1均能促进TGF-b1和TGF-b2的分泌。这些观察结果通过Real-time和常规RT-PCR方法的mRNA分析得到证实。IFN-g对TGF-b1和TGF-b2的影响对比揭示了TGF-b1和TGF-b2在视网膜疾病病理生理中的可能差异作用。进一步的研究正在评估TGF-b1和TGF-b2及其受体在视网膜疾病中的潜在作用。