Oxidative Stress, VEGF and Retinopathy

氧化应激、VEGF 和视网膜病变

• 批准号: 6620288
• 负责人: DAVID L VANDER JAGT
• 金额: $ 15万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620288
• 关键词: NAD(H) phosphate; RNase protection assay; aldehydes; ascorbate; diabetic retinopathy; disease /disorder etiology; enzyme linked immunosorbent assay; flow cytometry; free radicals; gene expression; glutathione; glycation; high performance liquid chromatography; human tissue; ketones; mass spectrometry; messenger RNA; northern blottings; nuclear magnetic resonance spectroscopy; oxidation reduction reaction; oxidative stress; retinal pigment epithelium; tissue /cell culture; tocopherols; vascular endothelial growth factors; western blottings

Growth factors such as vascular endothelial growth factor (VEGF) have been suggested to play a role in the development of long-term diabetic complications including both proliferative and non-proliferative diabetic retinopathy. VEGF is expressed by a number of cell types in the retina including Muller cells and retinal pigmented epithelial (RPE) cells. VEGF levels are elevated in vitreous body samples from five subjects with diabetic retinopathy. This proposal will focus on the mechanism of enhanced VEGF expression in diabetic retinopathy, with emphasis on RPE cells. Specifically, the objective of this study is to test the hypothesis that reactive endogenous aldehydes that are elevated in diabetes and their advanced Glycation Endproducts (AGE) up-regulate expression of VEGF in RPE cells through alterations of intracellular redox status. The proposed studies will focus on the ketoaldehyde methylglyoxal (MeG) and the alpha-beta unsaturated aldehyde 4- hydroxynonenal (4HNE) to test the hypothesis. We designate this the Aldehyde (Oxidative) Stress Model of Diabetic Complications. The Specific Aims are: 1) To demonstrate that MeG, 4HNE and their AGE can alter intracellular redox status, resulting in up-regulation of VEGF expression in RPE cells. 2) To elucidate the mechanisms by which MeG, 4HNE and their AGE alter expression of VEGF. 3) To evaluate anti-oxidant strategies for countering the effects of MeG, 4HNE and their AGE. The Aldehyde (Oxidative) Stress Model emphasizes the role of carbonyl compounds in addition to glucose in the etiology of diabetic retinopathy. It provides a testable model that connects hyperglycemia-> oxidative stress-> growth factors-> diabetic retinopathy.

生长因子如血管内皮生长因子（VEGF）已被认为在包括增殖性和非增殖性糖尿病视网膜病变的长期糖尿病并发症的发展中起作用。VEGF由视网膜中的许多细胞类型表达，包括Muller细胞和视网膜色素上皮（RPE）细胞。VEGF水平升高的玻璃体样品从五个受试者糖尿病视网膜病变。该建议将集中于糖尿病视网膜病变中VEGF表达增强的机制，重点是RPE细胞。具体而言，本研究的目的是检验糖尿病及其晚期糖基化终产物（AGE）升高的反应性内源性醛通过改变细胞内氧化还原状态上调RPE细胞中VEGF表达的假设。拟议的研究将集中在酮醛甲基乙二醛（MeG）和α-β不饱和醛4-羟基壬烯醛（4 HNE），以检验这一假设。我们将其命名为糖尿病并发症的醛（氧化）应激模型。具体目标是：1）证明MeG、4 HNE及其AGE可改变RPE细胞内氧化还原状态，导致VEGF表达上调。2)探讨MeG、4 HNE及其AGE改变VEGF表达的机制。3)评价对抗MeG、4 HNE及其AGE作用的抗氧化策略。醛（氧化）应激模型强调了羰基化合物在糖尿病视网膜病变病因学中的作用。它提供了一个可测试的模型，连接高血糖->氧化应激->生长因子->糖尿病视网膜病变。