Compound 49b Prevents Retinal Endothelial Cell Death Through IGFBP-3 Levels

化合物 49b 通过 IGFBP-3 水平预防视网膜内皮细胞死亡

• 批准号: 8982368
• 负责人: Jena J Steinle
• 金额: $ 26.36万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8982368
• 关键词: Compound; 49b; Prevents; Retinal; Endothelial

DESCRIPTION (provided by applicant): Diabetic retinopathy remains the fifth leading cause of preventable blindness worldwide. Interventions to prevent progression of diabetic retinopathy are limited to improved glycemic control (a challenging goal for all diabetic patients) and to lase 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. Thus, 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.

描述（由申请人提供）：糖尿病视网膜病变仍然是全世界可预防性失明的第五大原因。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）和激光光凝术（仅适用于晚期视网膜病变）。我们和其他人已经报道，糖尿病视网膜中肾上腺素信号传导丢失，这表明有必要开发新的药物来恢复自主神经稳态。不幸的是，目前可用的肾上腺素能药物与不良的全身或非特异性作用相关。这些问题激发我们的团队合成化合物 49b，一种新型选择性β-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 49b 可以防止退化毛细血管的形成，退化毛细血管的形成涉及退化毛细血管的形成，这是糖尿病视网膜脉管系统中注意到的标志性病理学。除了在体内防止毛细血管退化外，化合物 49b 还可在体外视网膜内皮细胞 (REC) 中防止 Caspase 3（一种公认的细胞凋亡标志物）的裂解，表明化合物 49b 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) 水平的升高与 REC 细胞凋亡的保护联系起来。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整个视网膜裂解物中的 IGFBP-3 蛋白水平，但在这些胰岛素缺乏大鼠中局部施用化合物 49b 使视网膜 IGFBP-3 恢复至其对照水平。因此，我们 假设化合物 49b 部分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的严重血管损伤。该项目的重点是更深入地了解这种保护行动的机制。