ROLE OF HORMONES AND POLYOLS IN DIABETIC EYE DISEASE

激素和多元醇在糖尿病眼病中的作用

• 批准号: 3263006
• 负责人: JOSEPH R WILLIAMSON
• 金额: $ 28.86万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-01 至 1994-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3263006
• 关键词: acyl coA; acyltransferase; adenosinetriphosphatase; albumins; aldehyde reductase; cardiovascular disorder; carnitine; diabetic ophthalmopathy; disease /disorder model; drug related diabetes mellitus; electron microscopy; fatty acid metabolism; glucose metabolism; glucose transport; hypertension; laboratory rat; long chain fatty acid; mass spectrometry; nicotinate; oxidation reduction reaction; oxidoreductase inhibitor; palmitates; pathologic process; potassium channel; radionuclides; rubidium; sex hormones; sodium channel; sorbinil; sorbitol; streptozotocin; vascular endothelium permeability

The major objective of the experiments outlined in this application is to elucidate the pathogenesis of glucose/diabetes-induced vascular dysfunction linked to increased metabolism of glucose via the sorbitol pathway. The general hypothesis to be tested is that diabetes-induced vascular dysfunction is mediated by metabolic imbalances resulting from increased flux of glucose via the sorbitol pathway. The specific aims of the proposed experiments are to: 1) assess the role of accumulation of long-chain fatty acyl esters (i.e., palmitoylcarnitine and palmitoyl CoA) in mediating sorbitol pathway-linked vascular dysfunction, 2) elucidate the nature of sex steroid-modulation of sorbitol pathway metabolism and vascular dysfunction, 3) test the hypothesis that vascular dysfunction caused by increased sorbitol pathway metabolism increases the susceptibility of the vasculature to injury by risk factors independent of diabetes (i.e., hypertension), and 4) test the hypothesis that a combination of pharmacologic agents which correct different metabolic imbalances resulting from increased sorbitol pathway metabolism should be more efficacious than any one of these pharmacologica agents alone in preventing vascular dysfunction caused by chronic diabetes. These questions and hypotheses will be investigated in animals with streptozotocin-induced diabetes as well as in in vitro studies of tissues removed from diabetic and nondiabetic animals. The impact of selected pharmacologic agents on diabetes-induced vascular dysfunction, i.e., increased blood flow (assessed by use of radiolabeled microspheres) and vascular permeation by radiolabeled albumin will be assessed in the eyes, peripheral nerve, and aorta prior to removal of tissues from these animals for assessment of the effects of pharmacologic agents on diabetes-induced changes in tissue levels of metabolites of interest.

本应用程序中概述的实验的主要目的是 阐明葡萄糖/糖尿病诱导的血管的发病机理 功能障碍与山梨糖醇的葡萄糖代谢增加有关 路径。 要测试的一般假设是糖尿病诱导的 血管功能障碍是由由 葡萄糖通过山梨糖醇途径的通量增加。 具体目标 提出的实验是：1）评估积累的作用 长链脂肪酰基酯（即棕榈酰钙和棕榈酸酯 COA）在介导山梨糖醇途径连接的血管功能障碍中，2） 阐明山梨糖醇途径的性类固醇调节的性质 代谢和血管功能障碍，3）检验以下假设。 山梨糖醇途径增加代谢引起的血管功能障碍 增加脉管系统因风险受伤的敏感性 与糖尿病无关的因素（即高血压），4）测试 假设有正确的药理学剂的组合 山梨糖醇途径增加的不同代谢失衡 新陈代谢应该比其中任何一种更有效 仅在防止由 慢性糖尿病。 这些问题和假设将被调查 在具有链球菌素诱导的糖尿病以及体外的动物中 从糖尿病和非糖尿病动物中去除的组织的研究。 这 选定的药理学对糖尿病诱导的血管的影响 功能障碍，即增加血液流量（通过使用放射性标记评估 微球）和放射标记白蛋白的血管渗透将是 在去除之前，在眼睛，周围神经和主动脉中进行评估 这些动物的组织以评估 糖尿病诱导的组织水平变化的药理学剂 感兴趣的代谢产物。