Dietary Control Angiogenesis in Retinopathy

描述（由申请人提供）：哺乳动物不能从更丰富的omega-6 （n-6）脂肪酸中自然产生omega-3 （n-3）脂肪酸，这是一种主要存在于鱼油中的必需营养素。它们必须依靠食物供应。脂质分子是血管生成和炎症的效应器；特别有效的是由20碳长链多不饱和脂肪酸（LCPUFAs）通过环氧合酶（COX）和脂氧合酶（LOX）途径衍生的二十烷类化合物。饮食摄入n-3 LCPUFAs已被证明具有抗血管生成和抗炎作用。鉴于LCPUFA组织状态依赖于饮食摄入和西方饮食中相对较低的n-3 LCPUFA摄入量，这些营养素是增殖性视网膜病变干预治疗的合理目标。在我们的模型中，视网膜病变是通过将幼鼠和母鼠分别置于P7-P12的75%氧气环境中，然后再置于室内空气中，直到P17，当FITC灌注血管后视网膜平装。为了研究n-3 LCPUFAs对视网膜病变的影响，从出生前第1天开始，给怀孕小鼠喂食富含n-3 LCPUFAs的饮食或富含n-6 LCPUFAs的饮食。通过在水中给哺乳小鼠母鼠喂食塞来昔布，以达到幼鼠低剂量，分析COX-2抑制对增殖性视网膜病变的影响。与缺乏n-3 LCPUFA的幼鼠相比，富含n-3 LCPUFA的幼鼠在P17时视网膜新生血管减少了-40%，非血管化区域也有类似的显著减少，这表明n-3 LCPUFA对抑制视网膜病变有显著作用。在两个单独的实验中，低剂量COX-2抑制与P17处新生血管的-50%抑制相关，这表明COX抑制在临床上有很大的潜在价值。我们寻求进一步研究饮食中n-3 LCPUFAs摄入量增加和/或COX-2抑制在调节增殖性视网膜病变中的作用。我们目前的数据表明COX-2抑制可能与n-3 LCPUFA摄入协同作用。该研究旨在确定和描述新的营养和药物干预措施，以帮助预防增殖性视网膜病变（糖尿病视网膜病变和早产儿视网膜病变）的发生。我们将应用系统生物学分子定位方法来建立对复杂疾病机制的新认识，确定抑制增殖性视网膜病变的新策略，并了解脂质信号通路在血管生成中的作用。这项研究的潜在影响是巨大的，因为它们是众所周知的营养修饰，它们是安全的，廉价的，并且很容易付诸实践

DESCRIPTION (provided by applicant): Mammals cannot naturally produce omega-3 (n-3) fatty acids, an essential nutrient found mainly in fish oil, from the more abundant omega-6 (n-6) fatty acids. They must rely on a dietary supply. Lipid-based molecules act as effectors of angiogenesis and inflammation; of particular effectiveness are the eicosanoids, derived from the 20 carbon long chain polyunsaturated fatty acids (LCPUFAs), through the cyclooxygenase (COX) and lipoxygenase (LOX) pathways. Dietary intake of n-3 LCPUFAs has been demonstrated to have anti-angiogenic and anti-inflammatory consequences. Given that LCPUFA tissue status is dependent on dietary intake and the relatively low n-3 LCPUFA intake in western diets, these nutrients are reasonable targets for proliferative retinopathy intervention therapy. In our model retinopathy is induced by subjecting, litters of mouse neonates with mothers to 75% oxygen from P7-P12 and then room air until P17 when retinas are flat mounted after FITC perfusion to fill vessels. To study the effects of n-3 LCPUFAs on retinopathy pregnant mice are fed (from prenatal day 1) a diet enriched with n-3 LCPUFAs or a diet elevated in n-6 LCPUFAs. The effects of COX-2 inhibition on proliferative retinopathy was analyzed by feeding Celecoxib to nursing mouse mothers in the water to achieve a low dose in the pups. There was a -40% reduction in retinal neovascularization and a similar significant decrease in the non-vascularized area at P17 with pups fed from mothers with an enriched n-3 LCPUFA diet verses a n-3 deficient diet, indicating a significant effect of n-3 LCPUFAs on inhibition of retinopathy. In two separate experiments low dose COX-2 inhibition was associated with -50% inhibition of neovascularization at P17 indicating that there is significant potential for COX inhibition to be clinically useful. We seek to further study the role of elevated dietary intake of n-3 LCPUFAs and/or COX-2 inhibition in regulating proliferative retinopathy. Our current data suggests that COX-2 inhibition may be synergistic with n-3 LCPUFA intake. The proposed study is aimed at the identification and characterization of new nutritional and pharmacologic interventions to help prevent the onset of proliferative retinopathy (both diabetic retinopathy and retinopathy of prematurity). We will apply a systems biology molecular mapping approach to establish a new understanding of complex disease mechanisms, to identify novel strategies for the suppression of proliferative retinopathy, and to understand the contribution of lipid signaling pathways in angiogenesis. The potential impact of this study is great since they are nutritional modifications that are well known, they are safe, inexpensive and readily put into practice