Mechanisms of Retinal Vascular Permeability in Diabetes

摘要 糖尿病仍然是世界范围内致盲的主要原因和流行病学数据 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，糖尿病的发病率 疾病的发病率继续上升。根据国家眼科研究所的数据，有1020万美国成年人 40岁及以上有糖尿病，8.2%有视力威胁的视网膜病变。 黄斑水肿仍然与视力丧失密切相关，目前的治疗重点是 防止细胞因子引起促进水肿的血管通透性变化的机制。 我们之前的研究从根本上有助于理解分子 血管内皮生长因子(VEGF)诱导视网膜血管形成的机制 渗透性。有效的抗血管内皮生长因子疗法的发展是一个受欢迎的补充。 用于治疗糖尿病视网膜病变，但这种方法仍然存在不足和新的 治疗是必要的。在当前的应用中，我们现在重点了解以下过程 血-视网膜屏障再生。研究已经确定了Norrin在形成中所需的角色 血-视网膜屏障。在这里，我们探索去甲肾上腺素重建血管的令人兴奋的潜力 血管内皮生长因子诱导损伤后的屏障特性。这些研究有望为我们揭示 这两个关键的细胞因子相互作用，控制视网膜血管屏障的特性。此外， 初步数据揭示了Norrin信号分子的全新相互作用， 蓬乱的(DVL)，直接与紧密连接蛋白结合。这些蛋白质相互作用的作用 关于Norrin信号和紧密连接生物学的研究将在分子水平上阐明，以便 了解去甲肾上腺素在屏障修复中的作用机制。我们预计这项提议将 提供有关健康和糖尿病患者血-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方案 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.