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Oxidative Stress, VEGF and Retinopathy

氧化应激、VEGF 和视网膜病变

基本信息

批准号：
6745536
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
项目类别：
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

项目摘要

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.

血管内皮生长因子(VEGF)等生长因子被认为在糖尿病长期并发症的发生中发挥作用，包括增殖性和非增殖性糖尿病视网膜病变。视网膜中有多种细胞表达血管内皮生长因子，包括Muller细胞和视网膜色素上皮(RPE)细胞。5名糖尿病视网膜病变患者的玻璃体样本中的血管内皮生长因子水平升高。这项建议将侧重于糖尿病视网膜病变中血管内皮生长因子表达增强的机制，重点是RPE细胞。具体地说，本研究的目的是验证一种假说，即糖尿病及其晚期糖基化终产物(AGE)中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的表达。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(4HNE)上，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。其具体目的是：1)证实MEG、4HNE及其AGE可改变RPE细胞内氧化还原状态，导致RPE细胞内VEGF表达上调。2)探讨MEG、4HNE及其AGE改变血管内皮生长因子表达的机制。3)评估抗氧化剂策略以对抗MEG、4HNE及其年龄的影响。醛(氧化)应激模型强调了在糖尿病视网膜病变的病因中，除葡萄糖外，羰基化合物的作用。它提供了一个可测试的模型，将高血糖-氧化应激-生长因子-糖尿病视网膜病变联系起来。