Compound 49b prevents retinal endothelial cell apoptosis in type 2 diabetes

化合物 49b 预防 2 型糖尿病视网膜内皮细胞凋亡

• 批准号: 8440655
• 负责人: Jena J Steinle
• 金额: --
• 依托单位: MEMPHIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440655
• 关键词: Adrenergic Agents; Adrenergic Agonists; Adrenergic Receptor; Adverse effects; Agreement; Apoptosis; Apoptotic; Blindness; Blood Vessels; Blood capillaries; Cardiovascular system; Cell Death; Cells; Chronic; Cleaved cell; Clinical Trials; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Dose; Drug Kinetics; Endothelial Cells; Eye; Eyedrops; Ganglion Cell Layer; General Population; Goals; Health; Homeostasis; Human; IGFBP3 gene; In Vitro; Insulin; Insulin-Like Growth Factor Binding Protein 3; Intervention; Isoproterenol; Measures; Modeling; Movement; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Oxygen; Pathology; Pharmaceutical Preparations; Pharmacological Treatment; Prevention; Property; Proteins; Rat-1; Rattus; Receptor Signaling; Reporting; Retina; Retinal; Retinal Diseases; Role; Signal Transduction; Staging; Streptozocin; Structure; Testing; Topical application; Toxicology; Vascular Endothelial Growth Factors; Veterans; adrenergic; base; capillary; caspase-3; diabetic; diabetic patient; diabetic rat; glycemic control; improved; in vivo; laser photocoagulation; novel; prevent; public health relevance; receptor binding; type I diabetic

DESCRIPTION (provided by applicant): Diabetic retinopathy remains the fifth leading cause of preventable blindness worldwide and an increasing problem for veterans. Interventions to prevent progression of diabetic retinopathy are limited to improved glycemic control (a challenging goal for all diabetic patients) and to laser photocoagulation (available only for advanced stages of retinopathy). We and others have reported that adrenergic signaling is lost in the diabetic retina, suggesting that development of novel agents to restore autonomic homeostasis is necessary. Unfortunately, currently available adrenergic agents are associated with adverse systemic or non-specific effects. These problems inspired our group to synthesize compound 49b, a novel and selective -adrenergic receptor agonist, as a potential paradigm shift in the prevention of diabetic retinopathy. Our preliminary data suggest that compound 49b prevents the formation of degenerate capillaries, which involves degenerate capillary formation, which are the hallmark pathology noted in the diabetic retinal vasculature. In addition to preventing degenerate capillaries in vivo, compound 49b prevents the cleavage of caspase 3, a well- established marker of apoptosis, in retinal endothelial cells (REC) in vitro, suggesting that Compound 49b can decrease apoptosis. In the oxygen-induced model of retinopathy, others have associated increased levels of insulin-like growth factor binding protein-3 (IGFBP-3) with protection from REC apoptosis. Furthermore, using the streptozotocin-induced diabetic rat model, we observed that chronic insulin deficiency reduced IGFBP-3 protein levels in whole retinal lysates, but topical application of compound 49b to the eye restored retinal IGFBP-3 to its control level in these insulin- deficient rats. Thu, we hypothesize that compound 49b prevents the critical vascular damage underlying diabetic retinopathy in part by restoring IGFBP-3 levels in retinal endothelial cells. This project focuses on a deeper understanding of the mechanisms underlying this protective action in a type II rat model, which will expedite movement of this novel drug into human clinical trials.

描述（由申请人提供）： 糖尿病性视网膜病仍然是全球可预防失明的第五个主要原因，这对于退伍军人来说是一个越来越多的问题。预防糖尿病性视网膜病的干预措施仅限于改善血糖控制（所有糖尿病患者的挑战性目标）和激光光凝（仅用于视网膜病的晚期阶段）。我们和其他人报告说，在糖尿病性视网膜中丧失了肾上腺素能信号，这表明需要开发新型药物以恢复自主神经稳态。不幸的是，当前可用的肾上腺素能剂与不良全身或非特异性作用有关。这些问题启发了我们小组合成一种新型和选择性的肾上腺素能受体激动剂，作为预防糖尿病性视网膜病的潜在范式转移。 我们的初步数据表明，化合物49b阻止了退化毛细血管的形成，涉及退化的毛细血管形成，这是糖尿病性视网膜脉管系统中指出的标志性病理。除了在体内预防毛细血管外，化合物49b还防止了视网膜内皮细胞（REC）在体外的caspase 3的裂解（caspase 3），这是一种良好的细胞凋亡标志物（REC），这表明化合物49b可以降低细胞凋亡。在视网膜病变的氧诱导的模型中，其他人则与防止凋亡相关的胰岛素样生长因子结合蛋白-3（IGFBP-3）的水平增加了REC凋亡。此外，使用链霉菌素诱导的糖尿病大鼠模型，我们观察到，慢性胰岛素缺乏症在整个视网膜裂解物中降低了IGFBP-3蛋白水平，但在这些胰岛素缺乏的大鼠中，化合物49b在眼睛恢复的视网膜IGFBP-3中的局部应用在其控制水平上降低了IGFBP-3蛋白水平。 THU，我们假设化合物49B可以通过恢复视网膜内皮细胞中的IGFBP-3水平来阻止糖尿病性视网膜病变的关键血管损伤。这个项目集中在 深入了解II型大鼠模型中这种保护作用的机制，这将加快这种新药物的运动进入人类临床试验。