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: 8666524
• 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/8666524
• 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）： 糖尿病视网膜病变仍然是全球可预防失明的第五大原因，也是退伍军人面临的一个日益严重的问题。预防糖尿病视网膜病变进展的干预措施仅限于改善血糖控制（对所有糖尿病患者来说都是一个具有挑战性的目标）和激光光凝（仅适用于晚期视网膜病变）。我们和其他人已经报道了肾上腺素能信号在糖尿病视网膜中丢失，这表明开发新的药物来恢复自主稳态是必要的。不幸的是，目前可用的肾上腺素能药物与不良全身或非特异性作用相关。这些问题启发了我们的小组合成化合物49 b，一种新型的选择性肾上腺素能受体激动剂，作为预防糖尿病视网膜病变的潜在范式转变。 我们的初步数据表明，化合物49 b防止退化毛细血管的形成，其涉及退化毛细血管形成，这是糖尿病视网膜血管系统中注意到的标志性病理。除了在体内防止毛细血管退化之外，化合物49 b在体外防止视网膜内皮细胞（REC）中的半胱天冬酶3（一种已确立的细胞凋亡标志物）的切割，表明化合物49 b可以减少细胞凋亡。在氧诱导的视网膜病变模型中，其他人将胰岛素样生长因子结合蛋白-3（IGFBP-3）水平的增加与REC凋亡的保护作用联系起来。此外，使用链脲佐菌素诱导的糖尿病大鼠模型，我们观察到慢性胰岛素缺乏降低了全视网膜裂解物中的IGFBP-3蛋白水平，但在这些胰岛素缺乏的大鼠中，将化合物49 b局部应用于眼睛使视网膜IGFBP-3恢复至其对照水平。因此，我们假设化合物49 b部分地通过恢复视网膜内皮细胞中的IGFBP-3水平来预防糖尿病视网膜病变潜在的严重血管损伤。该项目重点 在II型大鼠模型中更深入地了解这种保护作用的机制，这将加速这种新药进入人体临床试验。