Dietary control of angiogenesis in retinopathy models

描述(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更高。我们必须制定有效、廉价的干预措施。虽然视网膜血管疾病以血脂异常为特征，但对视网膜病变中脂代谢的研究有限。我们发现高？3多不饱和脂肪酸(PUFA)与高？6多不饱和脂肪酸(PUFA)饮食对氧诱导视网膜病变(OIR)的视网膜NV有深远的有益影响；我们建议定义涉及的特定代谢物和酶。视网膜病变以炎症为特征，同时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。6-多不饱和脂肪酸通过环氧合酶(COX)和脂氧合酶(LOX)代谢产生有效的促炎和促血管生成介质。同样的酶将3-多不饱和脂肪酸代谢成抗炎、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，并确定在视网膜病变中传递β3和6多不饱和脂肪酸各自作用的代谢物是至关重要的。确定的酶的抑制剂或激活剂然后可以用来特定地诱导或增强在3-多不饱和脂肪酸充分饮食中观察到的有益效果。PUFA的第三个主要代谢途径是细胞色素P450(Cyp450)，它与血管扩张和炎症有关。在视网膜病变中，CYP450？6或？3PUFA代谢产物对NV或神经保护作用的影响知之甚少。调节Cyp450的药物正在进行高血压的临床试验。我们假设，COX、LOX和CYP450中的特异性？3和？6多不饱和脂肪酸代谢产物，在OIR和糖尿病视网膜病变中调节血管和神经元的动态平衡。我们将使用COX1，2，LOX5，12/15 KO小鼠和CYP450内皮细胞特异性突变剂对OIR中的？6或？3PUFA饮食进行研究，我们将(I)测试特定脂酶的丢失是否抑制或增强？3PUFA对NV的保护作用，用脂组学方法鉴定活性代谢物，并通过鉴定脂类受体(AIM I，II)来确定它们改变视网膜病变严重程度的机制；以及(Ii)确定脂类衍生途径如何影响OIR和糖尿病视网膜病变(AIM III)中的神经血管串扰、血管丢失和再生。摘要：这些研究将确定视网膜病变：i)饮食中3PUFA和6PUFA的相对重要性(吃3PUFA(鱼)比不吃6PUFA(肉)好吗？)Ii)产生主要生物活性多不饱和脂肪酸代谢物的酶途径(S)的积极和消极贡献(阿司匹林、环氧合酶抑制剂或齐留通、LOX抑制剂或细胞色素P450相互作用药物)如果阻止有益代谢物的产生，是否会否定食用鱼类？是否有任何代谢物是疾病风险增加或降低的生物标记物？)3/6多不饱和脂肪酸对OIR和糖尿病大鼠视网膜神经元的影响(3多不饱和脂肪酸代谢产物能否防止糖尿病大鼠的神经元丢失？)尽管血脂异常与眼部血管疾病的进展密切相关，但脂类生化在这方面的研究还不够深入。饮食脂质可能是安全、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.