Dietary Control Angiogenesis in Retinopathy

描述(申请人提供)：哺乳动物不能自然地从更丰富的omega-6(n-6)脂肪酸中产生omega-3(n-3)脂肪酸，这是一种主要存在于鱼油中的基本营养物质。他们必须依靠饮食供应。基于脂质的分子作为血管生成和炎症的效应物；特别有效的是二十烷基类化合物，它来自20个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。饮食中摄入n-3LCPUFAs已被证明具有抗血管生成和抗炎的作用。鉴于LCPUFA的组织状态依赖于饮食摄入量，以及西方饮食中n-3 LCPUFA的摄入量相对较低，这些营养素是增殖性视网膜病变干预治疗的合理靶点。在我们的模型中，视网膜病变是由母亲的小鼠新生仔鼠从P7-P12开始给予75%的氧气，然后在室内空气中直到P17，FITC灌流后视网膜平贴以填充血管而诱导的。为了研究n-3LCPUFAs对视网膜病变的影响，孕鼠(从出生第1天开始)饲喂富含n-3LCPUFAs的饲料或添加n-6LCPUFAs的饲料。为探讨环氧合酶-2(COX-2)抑制对增殖性视网膜病变的影响，给哺乳小鼠母鼠喂食水中的塞来昔布，以达到对仔鼠的低剂量作用。在出生后17天，由富含n-3LCPUFA的母亲喂养的幼鼠的视网膜新生血管减少了-40%，非血管区域的非血管化区域减少了类似的显著减少，这表明n-3LCPUFA在抑制视网膜病变方面具有显著的效果。在两个独立的实验中，低剂量的COX-2抑制与P17的新生血管抑制-50%相关，这表明COX抑制具有显着的临床应用潜力。我们试图进一步研究增加n-3LCPUFAs的饮食摄入量和/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的抑制可能与n-3 LCPUFA的摄入具有协同作用。这项拟议的研究旨在确定和表征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)的发病。我们将应用系统生物学分子图谱的方法来建立对复杂疾病机制的新理解，以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改，它们是安全的，廉价的，并且很容易付诸实施

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