Mechanisms of Retinal Vascular Permeability in Diabetes

描述（由申请人提供）：糖尿病视网膜病变是视力损害的主要原因，并可因高血压而加重。视力损害是由于视网膜血管通透性增加和黄斑水肿。该项目的总体目标是了解糖尿病和高血压如何相互作用损害视力。具体目标是确定化学（VEGF，血管紧张素II）和物理因素（增加静水压力）增加视网膜血管通透性的机制。在这个项目的最初四年中，研究人员已经表明，VEGF和糖尿病改变内皮紧密连接蛋白的表达和磷酸化，同时增加血视网膜屏障（BRB）的渗透性。初步研究表明，VEGF，血管紧张素II和高血糖损害内皮细胞的信号通路紧密连接。此外，实验性高血压对内皮细胞施加物理力。该项目将研究VEGF、血管紧张素II和压力增加BRB通透性的信号转导途径。一般假设提出，糖尿病和高血压损害血视网膜屏障的完整性通过影响内皮紧密连接蛋白。三个具体目标将验证这一假设：首先，确定VEGF调节紧密连接蛋白磷酸化和视网膜血管通透性的机制；第二，确定跨壁静水压力升高损害BRB完整性的机制；第三，探讨高血压加速糖尿病大鼠血视网膜屏障破坏的机制。将使用细胞培养、离体和体内模型相结合的方法。本研究的基本原理是了解BRB调控的分子机制将为糖尿病和其他视网膜血管疾病的血管通透性和视力丧失的控制提供更好的手段。

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.