Mechanisms of Retinal Vascular Permeability in Diabetes

糖尿病视网膜血管通透性的机制

基本信息

批准号：
7220571
负责人：
David Antonetti
金额：
$ 32.49万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-09-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7220571
关键词：
Address Angiotensin II Angiotensin II Receptor Biological Assay Blindness Blood-Retinal Barrier Calcium Channel Cell membrane Chemicals Complementary DNA Condition Cultured Cells Data Development Diabetes Mellitus Diabetic Retinopathy Dominant-Negative Mutation Endothelial Cells Endothelium Goals Hormonal Hydrostatic Pressure Hyperglycemia Hypertension Hypotension Impairment In Vitro Inbred SHR Rats Lead Localized Measures Modeling Molecular Patients Permeability Phosphorylation Property Protein Kinase C Proteins Rate Rattus Receptor Activation Regulation Research Research Personnel Retinal Risk Factors Role Serine/Threonine Phosphorylation Signal Pathway Signal Transduction Signal Transduction Pathway Starling (law)Testing Tight Junctions Transfection Vascular Diseases Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Vascular Permeabilities Vision Water Western Blotting base diabetic diabetic rat human NOS3 protein immunocytochemistry improved in vivo in vivo Model insight instrument macular edema monolayer novel occludin pressure protein expression solute

项目摘要

DESCRIPTION (provided by applicant): Diabetic retinopathy is a leading cause of vision impairment and is exacerbated by hypertension. Vision impairment results from increased retinal vascular permeability and macular edema. The overall goal of this project is to understand how diabetes and hypertension interact to impair vision. The specific objectives are to identify the mechanisms by which chemical (VEGF, angiotensin II) and physical factors (increased hydrostatic pressure) increase retinal vascular permeability. In the initial four years of this project the investigators have shown that VEGF and diabetes alter the expression and phosphorylation of endothelial tight junction proteins concomitant with increased blood-retinal barrier (BRB) permeability. Preliminary studies demonstrate that VEGF, angiotensin II and hyperglycemia impair endothelial cell signaling pathways to tight junctions. In addition, experimental hypertension exerts physical forces on endothelium. The project will investigate the signal transduction pathways by which VEGF, angiotensin II and pressure forces increase BRB permeability. The general hypothesis is proposed that diabetes and hypertension impair blood-retinal barrier integrity via effects on endothelial tight junction proteins. Three specific aims will test the hypothesis: first, to determine the mechanism by which VEGF regulates tight junction protein phosphorylation and retinal vascular permeability; second, to determine the mechanism by which elevated transmural hydrostatic pressure impairs BRB integrity; and third, to investigate the mechanism by which hypertension accelerates blood-retinal barrier breakdown in diabetic rats. A combination of cell culture, ex vivo and in vivo models will be used. The rationale for this research is that understanding the molecular mechanisms of BRB regulation will provide improved means to control vascular permeability and vision loss in diabetes and other retinal vascular diseases.

描述（由申请人提供）：糖尿病性视网膜病是视力障碍的主要原因，并因高血压而加剧。视觉障碍是由于视网膜血管渗透性和黄斑水肿的增加而导致的。该项目的总体目标是了解糖尿病和高血压如何相互作用以损害视力。具体目标是确定化学（VEGF，血管紧张素II）和物理因素（静水压力升高）的机制增加视网膜血管渗透性。在该项目的最初四年中，研究人员表明，VEGF和糖尿病会改变内皮紧密连接蛋白随着血液 - 视网膜屏障（BRB）渗透性的增加的表达和磷酸化。初步研究表明，VEGF，血管紧张素II和高血糖会损害紧密连接的内皮细胞信号通路。此外，实验性高血压会在内皮上施加物理力。该项目将研究VEGF，血管紧张素II和压力力增加BRB渗透性的信号转导途径。人们提出了一般假设，即通过对内皮紧密连接蛋白的影响而损害血屏性屏障完整性。三个具体目的将检验假设：首先，确定VEGF调节紧密连接蛋白磷酸化和视网膜血管渗透性的机制；其次，确定升高的透射式静水压力会损害BRB完整性的机制；第三，为了研究高血压加速糖尿病大鼠血液视网膜屏障的机制。将使用细胞培养，体内和体内模型的组合。这项研究的理由是，了解BRB调节的分子机制将为控制糖尿病和其他视网膜血管疾病的血管通透性和视力丧失提供改进的方法。