Dietary control of angiogenesis in retinopathy models

视网膜病变模型中血管生成的饮食控制

• 批准号: 8511650
• 负责人: Lois Smith
• 金额: $ 55.26万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511650
• 关键词: Ablation; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonate 12-Lipoxygenase; Arachidonate 15-Lipoxygenase; Area; Aspirin; Biological Markers; Blindness; Blood Vessels; Cell Density; Cell Survival; Clinical Trials; Cyclooxygenase Inhibitors; Cytochromes; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Diet; Dietary Fats; Dropout; Dyslipidemias; Eating; Economics; Electroretinography; Enzymes; Epoxide hydrolase; Family; Figs - dietary; Fishes; Healthcare Systems; Homeostasis; Human; Hypertension; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Intake; Intervention; Link; Lipid Biochemistry; Lipid Chemistry; Lipids; Lipoxygenase; Lipoxygenase Inhibitors; Meat; Mediating; Mediator of activation protein; Modeling; Mus; Neurons; Oral; Oxygen; PTGS1 gene; Pathogenesis; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Polyunsaturated Fatty Acids; Process; Production; Prostaglandin-Endoperoxide Synthase; Protein Isoforms; Relative (related person); Research; Research Personnel; Retina; Retinal; Retinal Diseases; Retinal Ganglion Cells; Retinal Neovascularization; Role; Severities; Societies; Stress; Testing; Tissues; Transgenic Mice; Vascular Diseases; Vasodilation; Work; Zileuton; age related; angiogenesis; base; burden of illness; cost; cyclooxygenase 1; cyclooxygenase 2; diabetic; dietary control; disorder risk; feeding; in vivo; inhibitor/antagonist; lipid metabolism; macula; neovascularization; neuron loss; neuroprotection; prevent; protective effect; receptor; receptor function; research study; retina blood vessel structure; retinal neuron

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.

描述（由申请人提供）：治疗视网膜新血管化（NV）的成本很高，不治疗视网膜病的经济和人为成本更高。我们必须制定有效的廉价干预措施。尽管视网膜血管疾病的特征是血脂血症，但视网膜病中脂质代谢的研究有限。我们发现高3 vs. 6多不饱和脂肪酸（PUFA）饮食对视网膜诱导的视网膜病变（OIR）产生了深远的有益作用；我们建议定义涉及的特定代谢产物和酶。视网膜病的特征是炎症，并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作用。有效的促炎和促血管生成介质通过环氧酶（COX）和脂氧合酶（LOX）从6-PUFAS代谢。相同的酶将3-PUFA代谢为抗炎，抗血管生成，神经保护介质。了解这些主要脂质代谢途径的每一种的特定贡献，并确定传达？3和6-PUFA对视网膜病的作用的代谢产物的特定贡献至关重要。然后，可以使用鉴定酶的抑制剂或活化剂来特异性诱导或增强使用？3-PUFA饮食观察到的有益作用。第三个主要的PUFA代谢途径，细胞色素P450S（CYP450）与血管舒张和炎症有关。 CYP450？6或3PUFA代谢物对视网膜病变中NV或神经保护作用的影响鲜为人知。调节CYP450S的药物正在临床试验中进行高血压。我们假设从Cox，Lox和Cyp450酶促处理的特定的？3和6 PUFA代谢产物介导OIR和糖尿病性视网膜病中的血管和神经元稳态。使用COX1,2，LOX5,12/15 KO小鼠和CYP450在OIR中的3或3 pufa饮食上的内皮内皮特异性跨植物，如果损失了特定的脂质酶会抑制或增强特定的脂质酶的损失？视网膜病，鉴定脂质受体（AIM I，II）； （ii）确定脂质衍生的途径如何影响OIR和糖尿病性视网膜病的神经血管串扰，血管损失和再生（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如果CYP450互动药物阻止了有益的代谢产物的产生，是否有任何代谢物是疾病风险增加或降低的生物标志物？尽管血脂异常与眼血管疾病的进展密切相关，但在该领域探索了脂质生物化学。饮食脂质可能是安全，有效且廉价的治疗选择。