Lipidmetabolism in retinal neovascular disease with emphasize on diabetic retinopathy and age related macular degeneration: role of polyunsuturated fatty acids (PUFA) as therapeutic intervention.

视网膜新生血管疾病中的脂质代谢，重点是糖尿病性视网膜病变和年龄相关性黄斑变性：多不饱和脂肪酸（PUFA）作为治疗干预的作用。

• 批准号: 269524004
• 负责人: Dr. Raffael Liegl
• 金额: --
• 依托单位: Department of Ophthalmology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/269524004?language=en
• 关键词: Lipidmetabolism; retinal; neovascular; disease; emphasize

Retinal neovascularization (NV) is a major cause of blindness. The cost to society of treating NV with current drugs or ablation therapy is high, stressing our health care system. Yet the economic and human cost of not treating retinopathy is even higher. It is critical to assess effective inexpensive interventions to reduce this disease burden. Although age-related macular degeneration and diabetic retinopathy are characterized by dyslipidemia, little research has been done in lipid metabolism in retinal vascular disease; it is essential to develop this field. This group has previously found a profound beneficial effect of a high omega3 (w-3) vs. omega6 (w-6) polyunsaturated fatty acid (PUFA) diet on retinal NV in oxygen-induced retinopathy (OIR). As PUFA tissue level is dependent on oral intake, (w-3-PUFA is low in european and US diets), adjusting dietary lipids is a compelling way to prevent retinopathy. Retinopathy affects both retinal vessels and neurons and is characterized in part by inflammation. Lipids modulate inflammation and influence angiogenesis and neuroprotection. Potent pro-inflammatory and pro-angiogenic mediators are metabolized from w-6-PUFAs via cyclooxygenase (COX) and lipoxygenase (LOX). Via the same pathways, w-3-PUFAs are metabolized into anti-inflammatory, anti-angiogenic, neuroprotective mediators. It is critical to understand the specific contributions of each of these major lipid metabolizing pathways and identify the exact metabolites that convey the respective effects of w-3 and w-6-PUFAs on retinopathy. Inhibitors or activators of the identified enzymes can then be used to specifically induce or enhance the beneficial effects observed with an w-3-PUFA replete diet. A third major newly discovered family of PUFA metabolizing enzymes, cytochrome P450s (Cyp450s) are independent of COX and LOX and implicated in vasodilation, angiogenesis and inflammation. Little is known about CYP450 w-6- and even less of CYP450 w-3PUFA metabolites with respect to NV or neuroprotection in retinopathy. This area must be explored. Based on our prior work and new preliminary results:We hypothesize that specific w-3 and w-6 PUFA metabolites, processed enzymatically from COX, LOX and Cyp450, mediate both vascular and neuronal homeostasis in OIR and diabetic retinopathy.The proposed experiments will test this hypothesis and identify the specific lipid pathways, their metabolites and the mechanisms by which they alter the severity of retinopathy.

视网膜新生血管（NV）是致盲的主要原因。用目前的药物或消融疗法治疗NV的社会成本很高，给我们的卫生保健系统带来了压力。然而，不治疗视网膜病变的经济和人力成本甚至更高。至关重要的是评估有效的廉价干预措施，以减少这种疾病的负担。虽然年龄相关性黄斑变性和糖尿病视网膜病变的特点是血脂异常，很少有研究已经做了视网膜血管疾病的脂质代谢，这是必要的，以发展这一领域。该小组先前已经发现高ω 3（w-3）与ω 6（w-6）多不饱和脂肪酸（PUFA）饮食对氧诱导的视网膜病变（OIR）中的视网膜NV具有深远的有益作用。由于PUFA组织水平取决于口服摄入量（欧洲和美国饮食中w-3-PUFA较低），因此调整饮食脂质是预防视网膜病变的一种引人注目的方法。视网膜病变影响视网膜血管和神经元，并且部分特征在于炎症。脂质调节炎症并影响血管生成和神经保护。有效的促炎和促血管生成介质通过环氧合酶（考克斯）和脂氧合酶（LOX）从w-6-PUFA代谢。通过相同的途径，w-3-PUFA被代谢成抗炎、抗血管生成、神经保护介质。了解这些主要脂质代谢途径中的每一种的具体贡献并确定传达w-3和w-6-PUFA对视网膜病变的各自作用的确切代谢物是至关重要的。然后可以使用所鉴定的酶的抑制剂或激活剂来特异性地诱导或增强用w-3-PUFA充满饮食观察到的有益效果。新发现的PUFA代谢酶的第三个主要家族，细胞色素P450（Cyp 450）不依赖于考克斯和LOX，并且涉及血管舒张、血管生成和炎症。关于CYP 450 w-6-和CYP 450 w-3 PUFA代谢物在视网膜病变中的NV或神经保护作用知之甚少。必须探索这一领域。 基于我们先前的工作和新的初步结果：我们假设，特定的w-3和w-6多不饱和脂肪酸代谢产物，酶促加工的考克斯，LOX和Cyp 450，调解血管和神经元的稳态OIR和糖尿病视网膜病变，拟议的实验将验证这一假设，并确定特定的脂质途径，其代谢产物和它们改变视网膜病变的严重程度的机制。