Mechanisms of Retinal Vascular Permeability in Diabetes

描述(申请人提供)：糖尿病视网膜病变是视力受损的主要原因，高血压会加重。视力障碍是由于视网膜血管通透性增加和黄斑水肿造成的。这个项目的总体目标是了解糖尿病和高血压是如何相互作用损害视力的。其具体目标是确定化学因素(血管内皮生长因子、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。在该项目的最初四年中，研究人员表明，血管内皮生长因子和糖尿病改变了内皮紧密连接蛋白的表达和磷酸化，并伴随着血-视网膜屏障(BRB)通透性的增加。初步研究表明，血管内皮细胞生长因子、血管紧张素II和高血糖会损害内皮细胞紧密连接的信号通路。此外，实验性高血压对血管内皮细胞施加物理作用力。该项目将研究血管内皮生长因子、血管紧张素II和压力增加BRB通透性的信号转导途径。一般的假设是糖尿病和高血压通过影响内皮紧密连接蛋白来损害血-视网膜屏障的完整性。三个特定的目标将检验这一假说：第一，确定血管内皮生长因子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。将采用细胞培养、体外和体内模型相结合的方式。这项研究的基本原理是，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损失提供更好的手段。

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.