权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

药物治疗的最新进展极大地扩大了糖尿病的治疗选择视网膜病变。玻璃体内抗血管内皮生长因子免疫疗法已被证明在解决这两个问题上是有效的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，大约40%的患者对抗血管内皮生长因子治疗没有反应(1-3)。而长期使用后停用抗血管内皮生长因子可导致反弹效应。症状的恶化。重要的是，抗血管内皮生长因子治疗针对的是非常晚的在疾病的发展阶段，视网膜损伤很难完全逆转。因此，一个概念性和识别新目标的技术突破和治疗这种并发症的策略是派拉蒙。视网膜独特的新陈代谢需求和高度专业化的结构和功能口述复杂的调控途径以支持视网膜新陈代谢，同时保持自主性血-视网膜屏障(BRB)后面(6)。糖尿病患者失去了这种错综复杂的平衡。环境(7-9)。这种失调的一个重要例子是鞘磷脂变阻器从保护性的、支持屏障的超长链神经酰胺(C≥26)到促炎症和促凋亡短链(SC)神经酰胺(C≤24)。干细胞中的神经酰胺视网膜主要由酸性鞘磷脂酶(ASM)产生(10-14)。 VLC神经酰胺的生产涉及超长链脂肪酸蛋白4的延伸 (ELOVL4)介导的VLC饱和脂肪酸的合成神经酰胺合成酶(CERs)的作用(15)。我们之前已经证明ASM高度上调(10)，ELOVL4是糖尿病视网膜表达下调(19)。ASM下调或ELOVL4上调在细胞培养和培养中对糖尿病引起的视网膜血管变性具有保护作用动物模型(10只，20只)。我们假设神经酰胺变阻器的转盘从SC到VLC 神经酰胺将通过以下方式改善糖尿病视网膜病变的预后：1)预防SC 神经酰胺介导的促炎和促凋亡变化 VLC-神经酰胺屏障功能。