Mechanisms of Retinal Vascular Permeability in Diabetes

摘要 糖尿病仍然是世界范围内失明的主要原因， 来自世界卫生组织的数据显示，超过4.22亿成年人患有糖尿病， 发病率持续上升。根据国家眼科研究所的数据， 40岁及以上患有糖尿病，8.2%患有威胁视力的视网膜病变。 黄斑水肿仍然与视力丧失密切相关，目前的治疗集中在 预防促进水肿的细胞因子驱动的血管通透性变化的机制。 我们以前的研究从根本上帮助我们理解了 血管内皮生长因子（VEGF）诱导视网膜血管生成的机制 磁导率有效的抗VEGF治疗的发展是一个受欢迎的补充 糖尿病视网膜病变的治疗，但这种方法仍然不足， 需要治疗。在当前的应用中，我们现在专注于理解 血视网膜屏障再生研究已经确定了一个必要的作用，诺林在形成 血视网膜屏障在这里，我们探讨了诺林恢复血管的令人兴奋的潜力， VEGF诱导的损伤后的屏障特性。这些研究有望揭示 这两种关键的细胞因子相互作用以控制视网膜血管屏障特性。此外，本发明还 初步数据揭示了Norrin信号分子的完全新颖的相互作用， 凌乱的（DVL），直接结合紧密连接蛋白。这些蛋白质相互作用的作用 将在分子水平上阐明norrin信号传导和紧密连接生物学， 了解Norrin对屏障恢复的作用机制。我们预计，这一提议将 提供了关于健康和糖尿病中血-视网膜屏障调节的新信息， 将提供一个框架，从中开发潜在的新的治疗选择，以治疗 黄斑水肿

ABSTRACT Diabetes mellitus remains a leading cause of blindness world-wide and epidemiological data from the World Health Organization reveal over 422 million adults live with diabetes and the rate of disease onset continues to rise. According to the National Eye Institute 10.2 million US adults 40 years and older have diabetes mellitus, and 8.2% with vision threatening retinopathy. Macular edema remains closely linked to loss of vision and current therapies focus on mechanisms to prevent cytokine driven changes in vascular permeability that promote edema. Our previous research has fundamentally contributed to understanding the molecular mechanisms that lead to vascular endothelial growth factor (VEGF) induced retinal vessel permeability. The development of effective anti-VEGF therapies has been a welcome addition for the treatment of diabetic retinopathy, but this approach remains insufficient and new therapies are needed. In the current application we now focus on understanding the process of blood-retinal barrier regeneration. Research has identified a required role for norrin in formation of the blood-retinal barrier. Here, we explore the exciting potential for norrin to restore vascular barrier properties after VEGF-induced injury. The studies promise to shed new light on how these two critical cytokines interact to control retinal vessel barrier properties. Further, preliminary data reveal completely novel interactions of the norrin signaling molecule, disheveled (DVL), binding directly to tight junction proteins. The role of these protein interactions on norrin signaling and tight junction biology will be elucidated at a molecular level in order to understand the mechanisms of norrin action on barrier restoration. We expect this proposal will provide novel information on regulation of the blood-retinal barrier in health and in diabetes and will provide a framework from which to develop potential new therapeutic options to treat macular edema.