Dietary Control Angiogenesis in Retinopathy

饮食控制视网膜病变中的血管生成

• 批准号: 7275072
• 负责人: Kip M Connor
• 金额: $ 4.68万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-13 至 2009-02-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275072
• 关键词: Aftercare; Air; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonic Acids; Area; Aspirin; Carbon; Complex; Data; Diabetic Retinopathy; Diet; Dietary Intervention; Dietary intake; Discipline of Nursing; Disease; Disease Marker; Disease Pathway; Dose; Effectiveness; Eicosanoids; Engineering; Essential Fatty Acids; Fatty Acids; Fatty acid glycerol esters; Fish Oils; Fluorescein-5-isothiocyanate; Genes; Heart Diseases; Hypoxia; Inflammation; Intake; Intervention; Lipids; Lipoxygenase; Mammals; Maps; Measures; Messenger RNA; Modeling; Modification; Molecular; Molecular Profiling; Mothers; Mus; Numbers; Nutrient; Nutritional; Omega-3 Fatty Acids; Oxygen; Pathway interactions; Patient currently pregnant; Perfusion; Physiological; Polyunsaturated Fatty Acids; Prevention intervention; Prostaglandin-Endoperoxide Synthase; Randomized Controlled Clinical Trials; Relative (related person); Retina; Retinal; Retinal Diseases; Retinal Neovascularization; Retinopathy of Prematurity; Role; Severities; Signal Pathway; Systems Biology; Techniques; Therapeutic Intervention; Tissues; Water; angiogenesis; base; celecoxib; comparative; cyclooxygenase 1; cyclooxygenase 2; day; design; dietary control; disorder control; feeding; interest; laser capture microdissection; mRNA Expression; neonate; neovascularization; novel; novel strategies; prenatal; prevent; pup; research study; retina blood vessel structure

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

描述（由申请人提供）：哺乳动物不能从更丰富的omega-6（n-6）脂肪酸中天然产生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给。基于脂质的分子充当血管生成和炎症的效应物;特别有效的是类二十烷酸，其通过环氧合酶（考克斯）和脂氧合酶（LOX）途径衍生自20个碳长链多不饱和脂肪酸（LCPUFA）。膳食摄入n-3 LCPUFA已被证明具有抗血管生成和抗炎作用。考虑到LCPUFA组织状态取决于饮食摄入量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，视网膜病变是通过使具有母亲的小鼠新生儿的窝从P7-P12暴露于75%氧气，然后暴露于室内空气直到P17（此时在FITC灌注以填充血管后将视网膜平放）来诱导的。为了研究n-3 LCPUFA对视网膜病的影响，给妊娠小鼠喂食（从产前第1天开始）富含n-3 LCPUFA的饮食或n-6 LCPUFA升高的饮食。通过向水中哺乳的小鼠母亲喂食塞来昔布以在幼崽中达到低剂量，分析了考克斯-2抑制对增殖性视网膜病变的影响。在P17时，用富含n-3 LCPUFA饮食的母体喂养的幼仔与用缺乏n-3的饮食喂养的幼仔相比，视网膜新生血管形成减少约40%，非血管化面积也有类似的显著减少，表明n-3 LCPUFA对视网膜病变的抑制具有显著作用。在两个单独的实验中，低剂量的考克斯-2抑制与P17时约50%的新血管形成抑制相关，表明考克斯抑制具有临床上有用的显著潜力。我们寻求进一步研究n-3 LCPUFA和/或考克斯-2抑制剂的饮食摄入量增加在调节增殖性视网膜病变中的作用。我们目前的数据表明，考克斯-2抑制可能与n-3 LCPUFA摄入量协同作用。拟议的研究旨在确定和表征新的营养和药理干预措施，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作图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改良，它们是安全的，廉价的，易于付诸实践