Dyslipidemia and Diabetic Retinopathy

血脂异常和糖尿病视网膜病变

基本信息

批准号：
10659205
负责人：
Julia V Busik
金额：
$ 39.09万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10659205
关键词：
Acylation Animal Model Apoptosis Apoptotic Binding 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 Length Linoleic Acids Mediating Metabolic Metabolism Pathogenesis Patients Permeability 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 pharmacologic preservation prevent protective effect retinal damage therapeutic evaluation therapeutic target therapeutically effective

项目摘要

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.

使用药物治疗的最新进展极大地扩展了糖尿病治疗方案视网膜病。玻璃体内抗VEGF免疫疗法已被证明有效解决两者新生血管性糖尿病性视网膜病（DR）和糖尿病黄斑水肿（DME）（1-5）。大临床但是，研究表明，大约40％的患者对抗VEGF治疗没有反应（1-3）长期使用后，反VEGF的撤回会导致反弹效应症状恶化。重要的是，抗VEGF治疗是针对晚期的疾病的阶段，当完全逆转残留损害是困难的时。那是一个概念和确定新目标的技术突破和治愈这种并发症的策略是最重要的。视网膜的独特代谢需求和高度专业化的结构和功能决定支持残留代谢的复杂监管途径，同时保持自主权在血视网膜屏障（BRB）（6）后面。这种错综复杂的平衡在糖尿病患者中丧失环境（7-9）。这种失调的一个重要例子是表盘的转移受保护的，非常长的链（VLC）神经酰胺（C≥26）的鞘脂的鞘脂。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是由酸鞘磷脂酶（ASM）（10-14）产生的。 VLC神经酰胺的生产涉及延伸很长的链脂肪酸蛋白4 （ELOVL4）介导的VLC饱和脂肪酸的合成，然后将其掺入神经酰胺通过神经酰胺合酶的作用（CERS）（15）。我们以前已经证明，ASM已更新（10），而Elovl4是糖尿病视网膜中下调（19）。 ASM的下调或ELOVL4的上调在细胞培养和动物模型（10，20）。我们假设Ceramide Rheostat表盘从SC到VLC的转移神经酰胺将改善糖尿病性视网膜病的结果：1）防止SC 神经酰胺介导的促炎和促凋亡变化，而2）维持 VLC-Ceramide屏障功能。