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(NV)是导致失明的主要原因。用目前的药物或消融疗法治疗NV的社会成本很高，给我们的医疗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。评估有效而廉价的干预措施以减轻这一疾病的负担至关重要。尽管老年性黄斑变性和糖尿病视网膜病变以血脂异常为特征，但对视网膜血管疾病的脂代谢研究较少，有必要发展这一领域。该小组此前发现，高omega3(w-3)与omega6(w-6)多不饱和脂肪酸(PUFA)饮食对氧诱导视网膜病变(OIR)患者的视网膜NV有深远的有益影响。由于多不饱和脂肪酸的组织水平取决于口服摄入量(w-3-PUFA在欧洲和美国的饮食中很低)，调整饮食血脂是预防视网膜病变的一个引人注目的方法。视网膜病变同时影响视网膜血管和神经元，部分以炎症为特征。脂质调节炎症，影响血管生成和神经保护。强大的促炎和促血管生成介质是由w-6-PUFAs通过环氧合酶(COX)和脂氧合酶(LOX)代谢而来的。通过相同的途径，w-3-PUFAs被代谢成抗炎、抗血管生成和神经保护的介质。了解这些主要脂质代谢途径的具体作用，并确定w-3和w-6-PUFAs在视网膜病变中各自作用的确切代谢物是至关重要的。所确定的酶的抑制剂或激活剂然后可用于特定地诱导或增强在w-3-PUFA完全饮食中观察到的有益效果。第三个新发现的多不饱和脂肪酸代谢酶家族是细胞色素P450(Cyp450)，它独立于COX和LOX，参与血管扩张、血管生成和炎症。关于视网膜病变中的NV或神经保护作用，对CYP450 w-6-代谢产物知之甚少，对其代谢产物更是知之甚少。必须探索这一领域。基于我们以前的工作和新的初步结果：我们假设，在OIR和糖尿病视网膜病变中，特定的w-3和w-6多不饱和脂肪酸代谢产物由COX、LOX和CYP450经酶处理后，介导了血管和神经元的动态平衡。拟议的实验将验证这一假说，并确定特定的脂质途径、代谢产物以及它们改变视网膜病变严重程度的机制。

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.