Dietary control of angiogenesis in retinopathy models

描述（由申请人提供）：治疗视网膜新生血管（NV）的社会成本很高，不治疗视网膜病变的经济和人力成本甚至更高。我们必须制定有效的廉价干预措施。虽然视网膜血管疾病的特点是血脂异常，有有限的研究脂质代谢的视网膜病变。我们发现了一个深刻的有益影响的高？三比一？6多不饱和脂肪酸（PUFA）饮食对氧诱导性视网膜病变（OIR）视网膜NV的影响;我们建议定义所涉及的特定代谢物和酶。视网膜病变的特征是炎症，影响视网膜血管和神经元。脂质调节炎症并影响血管生成和神经保护。有效的促炎症和促血管生成介质是从？6-PUFA通过环氧合酶（考克斯）和脂氧合酶（LOX）。相同的酶代谢？3-PUFA转化为抗炎、抗血管生成、神经保护介质。这是至关重要的，以了解这些主要的脂质代谢途径的具体贡献，并确定代谢产物传达各自的影响？3、？6-PUFA对视网膜病变的影响。然后，可以使用所鉴定的酶的抑制剂或活化剂来特异性地诱导或增强用免疫抑制剂观察到的有益效果。3-PUFA充足饮食。第三种主要的PUFA代谢途径，细胞色素P450（Cyp 450）与血管舒张和炎症有关。对CYP 450知之甚少？6或？3 PUFA代谢产物对视网膜病变NV或神经保护的影响。调节Cyp 450的药物正在进行高血压的临床试验。我们假设具体？3、？6 PUFA代谢产物，从考克斯，LOX和Cyp 450酶促加工，介导OIR和糖尿病视网膜病变的血管和神经元的稳态。使用COX 1，2，LOX 5，12/15 KO小鼠和Cyp 450内皮特异性转基因小鼠？6或？3 PUFA饮食在OIR中，我们将（i）测试特定脂质酶的损失是否抑制或增强？三比一？6 PUFA对NV的保护作用，用脂质组学鉴定生物活性代谢物，并通过鉴定脂质受体（AIM I，II）确定它们改变视网膜病变严重程度的机制;以及（ii）确定脂质衍生途径如何影响OIR和糖尿病视网膜病变中的神经血管串扰，血管损失和再生（AIM III）。总结：这些研究将确定视网膜病变：i）的相对重要性？三比一？饮食中的6种PUFA（是吃吗？PUFA（鱼）比不吃好吗？6多不饱和脂肪酸（肉）？）ii）产生主要生物活性PUFA代谢物的酶途径的积极和消极贡献（如果阿司匹林（一种考克斯抑制剂）或齐留通（一种LOX抑制剂）或Cyp 450相互作用药物阻断有益代谢物的产生，那么吃鱼是否无效？是否有任何代谢物是疾病风险增加或减少的生物标志物？）（三）影响？三分之一？6多不饱和脂肪酸对OIR和糖尿病视网膜神经元的影响（可以吗？3 PUFA代谢产物预防糖尿病神经元丢失？）。尽管血脂异常与眼血管疾病的进展密切相关，但在这一领域对脂质生物化学的研究还不够充分。膳食脂质可能是安全、有效和廉价的治疗选择。 公共卫生相关性：我们将研究饮食脂质、加工酶和生物活性脂质代谢物在增殖性视网膜病变发病机制中的作用;与糖尿病、ROP和AMD具有与脂质失调相关并受脂质代谢物影响的炎症成分的事实形成鲜明对比的是，在这一领域几乎没有做过任何工作。我们以前已经发现了一个深刻的有益影响高？三比一？6多不饱和脂肪酸（PUFA）饮食对氧诱导视网膜病变（OIR）视网膜新生血管的影响。由于PUFA组织水平取决于口服摄入量，（？3-PUFA在美国饮食中含量低），调整饮食脂质是预防视网膜病变的一种引人注目的方法。

DESCRIPTION (provided by applicant): The cost to society of treating retinal neovascularization (NV) is high, and the economic and human cost of not treating retinopathy is even higher. We must develop effective inexpensive interventions. Although retinal vascular disease is characterized by dyslipidemia, there is limited research on lipid metabolism in retinopathy. We found a profound beneficial effect of a high ?3 vs. ?6 polyunsaturated fatty acid (PUFA) diet on retinal NV in oxygen-induced retinopathy (OIR); we propose to define the specific metabolites and enzymes involved. Retinopathy is characterized by inflammation and affects both retinal vessels and neurons. Lipids modulate inflammation and influence angiogenesis and neuroprotection. Potent pro-inflammatory and pro-angiogenic mediators are metabolized from ?6-PUFAs via cyclooxygenase (COX) and lipoxygenase (LOX). The same enzymes metabolize ?3-PUFAs 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 metabolites that convey the respective effects of ?3 and ?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 ?3-PUFA replete diet. A third major PUFA metabolizing pathway, cytochrome P450s (Cyp450s) are implicated in vasodilation and inflammation. Little is known of CYP450 ?6 or ?3PUFA metabolite influence on NV or neuroprotection in retinopathy. Drugs modulating Cyp450s are in clinical trials for hypertension. We hypothesize that specific ?3 and ?6 PUFA metabolites, processed enzymatically from COX, LOX and Cyp450, mediate both vascular and neuronal homeostasis in OIR and diabetic retinopathy. Using COX1,2, LOX5,12/15 KO mice and Cyp450 endothelial specific trangenics on ?6 or ?3 PUFA diets in OIR we will (i) test if loss of a specific lipid enzyme suppresses or enhances the ?3 vs. ?6 PUFA protective effect on NV, identify the bioactive metabolites with lipidomics and the mechanisms by which they alter the severity of retinopathy with identification of lipid receptors (AIM I, II); and (ii) determine how lipid-derived pathways affect neurovascular crosstalk, vessel loss and regrowth in OIR and diabetic retinopathy (AIM III). SUMMARY: These studies will determine for retinopathy: i) the relative importance of ?3 vs. ?6 PUFA in diet (is eating ?3PUFA (fish) better than not eating ?6 PUFA (meat)?) ii) the positive and negative contributions of enzymatic pathway(s) that produce the major bioactive PUFA metabolites (does aspirin, a COX inhibitor or Zileuton, a LOX inhibitor, or a Cyp450 interactive drug negate eating fish if it blocks production of a beneficial metabolite? Is any metabolite a biomarker of increased or reduced disease risk?) iii) the effects of ?3/?6 PUFA on retinal neurons in OIR and diabetes (can an ?3 PUFA metabolite prevent neuron loss in diabetes?). Lipid biochemistry has been inadequately explored in this area although dyslipidemia is closely associated with progression of ocular vascular diseases. Dietary lipids may be safe, potent, and inexpensive treatment options. PUBLIC HEALTH RELEVANCE: We will examine the role of dietary lipids, processing enzymes and bioactive lipid metabolites in the pathogenesis of proliferative retinopathies; little work has been done in this area in stark contrast to the fact that diabetes, ROP and AMD have inflammatory components linked to lipid dysregulation and affected by lipid metabolites. We have previously found a profound beneficial effect of a high ?3 vs. ?6 polyunsaturated fatty acid (PUFA) diet on retinal neovascularization in oxygen-induced retinopathy (OIR). As PUFA tissue level is dependent on oral intake, (?3-PUFA is low in US diets), adjusting dietary lipids is a compelling way to prevent retinopathy.