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。我们必须制定有效而廉价的干预措施。虽然视网膜血管疾病以血脂异常为特征，但对视网膜病变的脂质代谢研究有限。我们发现了一种深刻的有益效果？3 vs. ？6多不饱和脂肪酸（PUFA）饮食对氧致视网膜病变（OIR）视网膜NV的影响我们建议确定具体的代谢物和酶的参与。视网膜病变的特点是炎症，影响视网膜血管和神经元。脂质调节炎症，影响血管生成和神经保护。有效的促炎和促血管生成介质是从？6-PUFAs通过环氧合酶（COX）和脂氧合酶（LOX）。同样的酶代谢？3-PUFAs转化为抗炎、抗血管生成、神经保护介质。了解这些主要脂质代谢途径的具体贡献，并确定传递各自影响的代谢物是至关重要的。3和？6-PUFAs对视网膜病变的影响。所鉴定酶的抑制剂或激活剂可用于特异性诱导或增强an ？富含3-PUFA的饮食。第三种主要的PUFA代谢途径是细胞色素p450 (cyp450)，它与血管舒张和炎症有关。对CYP450知之甚少？6还是？pufa代谢物对视网膜病变NV或神经保护的影响。调节cyp450的药物正处于高血压的临床试验中。我们假设具体的？3和？从COX、LOX和Cyp450酶促加工的PUFA代谢物介导OIR和糖尿病视网膜病变的血管和神经元稳态。使用COX1,2, LOX5,12/15 KO小鼠和Cyp450内皮特异性基因？6还是？在OIR中，我们将(i)测试一种特定脂质酶的缺失是否会抑制或增强？3 vs. ？6 PUFA对NV的保护作用，通过脂质组学鉴定其生物活性代谢物，以及通过鉴定脂质受体来改变视网膜病变严重程度的机制（AIM I， II）；（ii）确定脂质衍生通路如何影响OIR和糖尿病视网膜病变的神经血管串扰、血管损失和再生（AIM III）。总结：这些研究将确定视网膜病变的相对重要性：3 vs. ？饮食中的多聚脂肪酸（是吃吗？）3PUFA（鱼）比不吃好吗？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(阿司匹林，COX抑制剂或Zileuton， LOX抑制剂或Cyp450相互作用药物如果阻止有益代谢物的产生，是否会否定吃鱼？是否有任何代谢物是增加或减少疾病风险的生物标志物？)多聚脂肪酸对视网膜神经元的影响(可以吗？3 PUFA代谢物预防糖尿病神经元丢失？)。尽管血脂异常与眼部血管疾病的进展密切相关，但血脂生化在这一领域的研究还不够充分。膳食脂质可能是安全、有效和廉价的治疗选择。

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.