Dyslipidemia and Diabetic Retinopathy

血脂异常和糖尿病视网膜病变

• 批准号: 10478284
• 负责人: Julia V Busik
• 金额: $ 37.92万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10478284
• 关键词: Acylation; Animal Model; Apoptosis; Apoptotic; Blood Preservation; Blood Vessels; Blood-Retinal Barrier; CYP1A2 gene; Cell Culture Techniques; Cells; Ceramides; Clinical Research; Complex; Complication; Complications of Diabetes Mellitus; Cytochrome P450; Diabetes Mellitus; Diabetic Retinopathy; Disease; Down-Regulation; Dyslipidemias; Endothelium; Environment; Enzymes; Equilibrium; Exhibits; Family; Health; Hydroxylation; Immunotherapy; Inflammation; Inflammatory; Lead; Length; Linoleic Acids; Mediating; Metabolic; Metabolism; Pathogenesis; Patients; Permeability; Pharmacology; Pharmacotherapy; Phospholipase; Production; Proteins; Regulatory Pathway; Retina; Role; Saturated Fatty Acids; Specificity; Sphingolipids; Sphingomyelins; Structure; Symptoms; Testing; Tight Junctions; Time; Tissues; Transacylase; Up-Regulation; Very Long Chain Fatty Acid; Volatile Fatty Acids; Withdrawal; acid sphingomyelinase; bevacizumab; combat; diabetic; dihydroceramide desaturase; improved outcome; macular edema; neovascular; novel; preservation; prevent; protective effect; retinal damage; therapeutic evaluation; therapeutic target; therapeutically effective

Recent advances using pharmacotherapy greatly expand treatment options for diabetic retinopathy. Intravitreal anti-VEGF immunotherapy has proven to be effective in resolving both neovascular diabetic retinopathy (DR) and diabetic macular edema (DME)(1-5). Large clinical studies, however, reveal that about 40% of patients do not respond to anti-VEGF therapy(1-3) and the withdrawal of anti-VEGF after the long-term use can lead to rebound effects with worsening of the symptoms. Importantly, anti-VEGF treatments are directed at the very late stage in the disease, when full reversal of retinal damage is difficult. Thus, a conceptual and technical breakthrough to identify novel targets and a strategy to cure this complication is paramount. Unique metabolic demands and highly specialized structure and function of the retina dictate complex regulatory pathways to support retinal metabolism while preserving autonomy behind the blood-retinal barrier (BRB)(6). This intricate balance is lost in a diabetic environment(7-9). An important example of such dysregulation is the shift in the dial of sphingolipid rheostat from protective, pro-barrier very long chain (VLC) ceramides (C≥26) to pro-inflammatory and pro-apoptotic Short Chain (SC) ceramides (C≤24). SC ceramides in the retina are mainly produced from sphingomyelins by acid sphingomyelinase (ASM) (10-14). Production of VLC ceramides involves Elongation of very long chain fatty acids protein 4 (ELOVL4)-mediated synthesis of VLC saturated fatty acids that are then incorporated into ceramides by the action of ceramide synthases (CerS)(15). We have previously demonstrated that ASM is highly upregulated(10) and ELOVL4 is downregulated(19) in the diabetic retina. Downregulation of ASM or upregulation of ELOVL4 were protective against diabetes-induced retinal vascular degeneration in cell culture and animal models(10, 20). We hypothesize that the shift in the ceramide rheostat dial from SC to VLC ceramides will improve the outcome of diabetic retinopathy by: 1) preventing SC ceramide-mediated pro-inflammatory and pro-apoptotic changes while 2) maintaining VLC-ceramide barrier function.

药物治疗的最新进展大大扩展了糖尿病的治疗选择 视网膜病变玻璃体内抗VEGF免疫治疗已被证明是有效的解决这两个问题 新生血管性糖尿病视网膜病变（DR）和糖尿病黄斑水肿（DME）（1-5）。大型临床 然而，研究表明，约40%的患者对抗VEGF治疗无反应（1-3） 长期使用后停用抗VEGF可导致反跳效应， 症状恶化。重要的是，抗VEGF治疗针对非常晚期的 在疾病的阶段，当视网膜损伤的完全逆转是困难的。因此，一个概念和 确定新靶点的技术突破和治愈这种并发症的策略， 至高无上。 独特的代谢需求和高度专业化的结构和视网膜的功能 控制复杂的调节途径，以支持视网膜代谢，同时保持自主性 血视网膜屏障（BRB）（6）。糖尿病患者失去了这种复杂的平衡 环境（7-9）。这种失调的一个重要例子是， 鞘脂变阻器，从保护性、亲屏障极长链（VLC）神经酰胺（C≥26）到 促炎和促凋亡短链（SC）神经酰胺（C≤24）。SC神经酰胺 视网膜主要通过酸性鞘磷脂酶（ASM）由鞘磷脂产生（10-14）。 VLC神经酰胺的生产涉及极长链脂肪酸蛋白4的延伸 （NH 4VL 4）介导的VLC饱和脂肪酸的合成，然后将其掺入到 通过神经酰胺酶（CerS）的作用产生神经酰胺（15）。 我们以前已经证明ASM是高度上调的（10），而HPVL 4是高度上调的（12）。 在糖尿病视网膜中下调（19）。ASM的下调或HPVL 4的上调 在细胞培养中对糖尿病诱导的视网膜血管变性具有保护作用， 动物模型（10，20）。 我们假设神经酰胺变阻器刻度盘从SC到VLC的变化 神经酰胺将通过以下方式改善糖尿病视网膜病变的结果：1）预防SC 神经酰胺介导的促炎症和促凋亡变化，同时2）维持 VLC-神经酰胺屏障功能。