Role of Retinal Capillary Stiffness in Diabetic Retinopathy

视网膜毛细血管僵硬在糖尿病视网膜病变中的作用

• 批准号: 10161547
• 负责人: KAUSTABH GHOSH
• 金额: $ 23.24万
• 依托单位: DOHENY EYE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10161547
• 关键词: Role; Retinal; Capillary; Stiffness; Diabetic

PROJECT ABSTRACT Diabetic retinopathy (DR) is a major, potentially blinding, microvascular complication of diabetes and the leading cause of vision loss in the working-age population. Although current clinical therapies aim to resolve the advanced stages of DR, there is a recognition that more effective DR management can be achieved by tackling the disease at the early stage. Diabetes-induced retinal inflammation is strongly implicated in the pathogenesis of DR. Retinal endothelial activation (ICAM-1 expression) plays a major role in inflammation because inhibiting ICAM-1 alone blocks retinal capillary leukostasis, hyperpermeability, and degeneration associated with DR. But precisely how retinal endothelial cells (ECs) become activated in diabetes is not properly understood. Since diabetes has been strongly associated with increased stiffness of the aorta and arteries, which undergo chronic inflammation, we asked whether diabetes also leads to stiffening of retinal capillaries and, if so, whether the increased capillary stiffness promotes retinal inflammation in diabetes. Our preliminary data has revealed that retinal capillaries in diabetic mice are significantly stiffer than those in normal mice, which correlates with increased lysyl oxidase (LOX) expression. Pharmacological inhibition of LOX-dependent capillary stiffening alone blocks retinal endothelial ICAM-1 associated with diabetes. Our preliminary studies have also revealed that this stiffness-dependent control of retinal inflammation in diabetes is mediated by the mechanosensitive and proinflammatory small GTPase Rho and its downstream effector ROCK, which is markedly upregulated in retinal capillaries of diabetic mice and HG-treated retinal EC cultures. Based on these observations, we hypothesize that diabetes leads to LOX-dependent stiffening of retinal capillaries and elevated Rho/ROCK that, in turn, promotes NF-kB-mediated endothelial ICAM-1 expression and retinal inflammation associated with early DR. The objective of this proposal is to uncover the link between diabetes, retinal capillary stiffness, endothelial mechanotransduction, and retinal inflammation. To achieve this goal, we will pursue the following specific aims. Aim 1: To fully examine the effects of pharmacologic and genetic inhibition of LOX on retinal capillary stiffening-dependent inflammation and vascular lesions of early DR; Aim 2: To determine the extent to which diabetes-induced biochemical changes in the retina contribute to LOX-dependent retinal capillary stiffening; and Aim 3: To delineate the mechanotransduction mechanism underlying capillary stiffening-dependent retinal inflammation in diabetes.

项目摘要 糖尿病视网膜病变(DR)是糖尿病的一种主要的、潜在致盲的微血管并发症 也是劳动年龄人口失明的主要原因。尽管目前的临床治疗方法 目的为了解决晚期DR，人们认识到更有效的DR管理 可以通过在早期阶段处理这种疾病来实现。糖尿病引起的视网膜炎症是 视网膜内皮细胞活化(ICAM-1表达)在DR发病机制中的重要作用 在炎症中起主要作用，因为单靠抑制ICAM-1就能阻断视网膜毛细血管的白细胞停滞， 高通透性，与DR相关的退变，但视网膜内皮细胞究竟是如何 (ECS)在糖尿病中被激活还没有被正确地理解。因为糖尿病一直很严重 伴随着主动脉和动脉僵硬的增加，这会经历慢性炎症，我们 问糖尿病是否也会导致视网膜毛细血管僵硬，如果是，是否会增加 毛细血管僵硬可促进糖尿病患者的视网膜炎症。我们的初步数据显示视网膜 糖尿病小鼠的毛细血管明显比正常小鼠的毛细血管僵硬，这与 赖氨酰氧化酶(LOX)表达增加。低氧依赖毛细血管的药理抑制作用 单独硬化可阻断与糖尿病相关的视网膜内皮细胞ICAM-1。我们的初步研究已经 还揭示了糖尿病患者视网膜炎症的这种僵硬依赖的控制是由 机械敏感和促炎的小GTP酶Rho及其下游效应石，即 糖尿病小鼠和HG处理的视网膜EC培养的视网膜毛细血管显著上调。基于 这些观察结果，我们假设糖尿病导致依赖LOX的视网膜毛细血管僵硬 和Rho/ROCK升高，进而促进NF-kB介导的内皮ICAM-1表达和 与早期DR相关的视网膜炎症这项建议的目的是揭示这种联系 糖尿病、视网膜毛细血管僵硬、内皮细胞机械转导和视网膜炎症之间的关系。 为实现这一目标，我们将追求以下具体目标。目标1：全面检查以下项目的影响 LOX对视网膜毛细血管硬化性炎症的药理和遗传抑制作用 早期DR的血管病变；目标2：确定糖尿病诱导的生化反应的程度 视网膜的变化有助于依赖LOX的视网膜毛细血管硬化；目标3：描绘 毛细血管硬化性视网膜炎症的机械传导机制 糖尿病。