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: 10213058
• 负责人: KAUSTABH GHOSH
• 金额: $ 38.91万
• 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/10213058
• 关键词: Affect; Anti-Inflammatory Agents; Aorta; Arteries; Biochemical; Blindness; Blood Vessels; Blood capillaries; Cardiovascular system; Cell Adhesion; Cell Culture Techniques; Chronic; Clinical; Collagen; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Retinopathy; Diabetic mouse; Disease; Endothelial Cells; Endothelium; Enzymes; Exhibits; Eye diseases; Future; Genetic; Goals; Inflammation; Intercellular adhesion molecule 1; Knock-out; Lesion; Leukocytes; Leukostasis; Link; Mechanics; Mediating; Monomeric GTP-Binding Proteins; Mus; NF-kappa B; Pathogenesis; Pharmacology; Play; Protein-Lysine 6-Oxidase; Research; Retina; Role; Signal Transduction; Testing; Up-Regulation; Work; Yang; aging population; base; clinical development; crosslink; cytokine; experience; innovation; mechanotransduction; mouse model; overexpression; prevent; retina blood vessel structure; rho; rho GTP-Binding Proteins; vascular inflammation

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 糖尿病性视网膜病（DR）是糖尿病的主要盲目的微血管并发症 以及工人年龄人群视力丧失的主要原因。尽管目前的临床疗法 旨在解决DR的高级阶段，人们认识到更有效的博士管理 可以通过在早期解决该疾病来实现。糖尿病引起的视网膜炎症是 与DR的发病机理密切相关。视网膜内皮激活（ICAM-1表达）戏剧 在炎症中起主要作用，因为仅抑制ICAM-1会阻止视网膜毛细血管白细胞增多 高度过敏性和与DR相关的变性。但是恰恰是视网膜内皮细胞 （EC）在糖尿病中被激活不正确。由于糖尿病一直很强烈 与主动脉和动脉的刚度增加有关，患有慢性炎症，我们 当被问及糖尿病是否也导致视网膜毛细血管变硬，如果是的话，是否增加了 毛细血管刚度促进糖尿病的视网膜炎症。我们的初步数据显示了视网膜 糖尿病小鼠中的毛细血管比正常小鼠的毛细血管明显更硬，这与正常小鼠相关的毛细血管 赖氨酸氧化酶（LOX）表达增加。药理学抑制LOX依赖性毛细管 僵硬的单独阻断视网膜内皮ICAM-1与糖尿病相关。我们的初步研究 还表明，糖尿病中视网膜炎症的僵硬依赖性控制是由 机械敏感和促炎的小GTPase Rho及其下游效应岩石，它是 在糖尿病小鼠的视网膜毛细血管和HG处理的视网膜EC培养物中明显上调。基于 这些观察结果，我们假设糖尿病导致视网膜毛细血管的LOX依赖性僵硬 并提高了Rho/Rock，反过来促进了NF-KB介导的内皮ICAM-1表达和 与早期DR相关的视网膜炎症。该提议的目的是发现链接 在糖尿病，视网膜毛细血管刚度，内皮机械转导和视网膜炎症之间。 为了实现这一目标，我们将追求以下特定目标。目标1：充分检查 LOX对视网膜毛细管僵硬依赖性炎症的药理和遗传抑制 早期DR的血管病变；目标2：确定糖尿病诱导的生化的程度 视网膜的变化有助于LOX依赖性视网膜毛细管僵硬。和目标3：描绘 毛细管僵硬依赖性视网膜炎症的机械转导机制 糖尿病。