Dietary control of angiogenesis in retinopathy model; basis for clinical trials

视网膜病变模型中血管生成的饮食控制；

• 批准号: 7879248
• 负责人: Lois Smith
• 金额: $ 60.07万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7879248
• 关键词: Affect; Aftercare; Angiogenic Factor; Arachidonic Acids; Aspirin; Blood; Blood Vessels; Carbon; Cell Adhesion Molecules; Clinical Research; Clinical Trials; Complex; Coxibs; Diabetic Retinopathy; Diet; Dietary Intervention; Dietary intake; Dinoprostone; Disease; Disease Pathway; Docosahexaenoic Acids; Dose; Eicosanoids; Eicosapentaenoic Acid; Engineering; Epoprostenol; Equilibrium; Eye; Fatty Acids; Fatty acid glycerol esters; Food; Foundations; Gelatinase A; Gene Dosage; Genes; Heart Diseases; Hypoxia; ITGB2 gene; Inflammation; Inflammatory; Intake; Intercellular adhesion molecule 1; Intervention; Ischemia; Leukotriene B4; Leukotrienes; Lipid Biochemistry; Lipids; Lipoxygenase; Lipoxygenase 2; Maps; Matrix Metalloproteinases; Measures; Messenger RNA; Modeling; Molecular; Molecular Biology; Molecular Profiling; Molecular and Cellular Biology; Mus; National Institute on Alcohol Abuse and Alcoholism; Nitric Oxide Synthase; Nuclear Hormone Receptors; Nutrient; Nutritional; Pathogenesis; Pathway interactions; Patients; Physiological; Polyunsaturated Fatty Acids; Prevention; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Regulation; Relative (related person); Research; Retina; Retinal; Retinal Diseases; Retinal Neovascularization; Risk; Severities; Surrogate Markers; Systems Biology; Techniques; Thromboxanes; Tissues; Translational Research; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Work; angiogenesis; base; bevacizumab; celecoxib; comparative; cyclooxygenase 1; cyclooxygenase 2; cytokine; design; diabetic; dietary control; disorder control; expectation; innovation; laser capture microdissection; mouse model; neovascularization; novel; novel strategies; nutrition; prevent; proliferative diabetic retinopathy; randomized trial; retina blood vessel structure

DESCRIPTION (provided by applicant): This proposal describes an innovative nutritional/pharmacological strategy to prevent proliferative retinopathy in a mouse model of disease with the expectation of a later clinical trial of patients with diabetic retinopathy (DR). DR has inflammatory and angiogenic components. We will evaluate alone and interactively the efficacy of the ?-3 long-chain polyunsaturated fatty acids (LCPUFAs) docosahexaenoic acid and eicosapentaenoic acid and Celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, designed to target inflammatory and angiogenic factors implicated in the pathogenesis of proliferative DR. ?-3 LCPUFAs are concentrated in the retina and the status is modifiable by and dependent on dietary intake from foods that are not consumed in all Western diets, so these lipids are reasonable choices for interventions to prevent DR. Preliminary results show COX-2 inhibitors prevent ischemia-induced retinal neovascularization and that COX-2 inhibition is synergistic with ?-3 LCPUFAs. Should Celecoxib prove to cause cardiac disease we will switch to aspirin (COX 1,2 inhibition). To determine mechanism of inhibition and to determine complementary interventions, a new technique will be used to sensitively measure small changes with treatment in absolute copy number of mRNAs of specific lipid, inflammatory and angiogenic pathways involved in disease. The panel will include (but is not limited to) COX1,2, and LOX, vascular endothelial growth factor and receptors 1,2, cell adhesion molecules (ICAM-1, CD18), matrix metalloproteinases 2,9, cytokines (TNFa, TGF?), nuclear hormone receptor (NF?B), and nitric oxide synthetase. To assess intervention and possible new surrogate markers of DR we will assess retinal and blood levels of ?-3 LCPUFAs, arachidonic acid and eicosanoids (thromboxanes, prostaglandins, leukotrienes) in mice consuming balanced, isocaloric diets with, or without ?-3 LCPUFAs. For this translational work an inter-institutional and intra-disciplinary research group has been established with experts in the fields of molecular and cellular biology and angiogenesis (L Smith, (PI), D Carper, J-Y Tsai, NEI), clinical research (E Chew, J-P SanGiovanni, NEI), nutrition and lipid biochemistry (N Salem, NIAAA, C Serhan, Harvard). If successful, this work could have a great impact on preventing proliferative DR, as the interventions are safe, inexpensive, and can be easily implemented. Preliminary results show that COX-2 inhibitors, ?-3 LCPUFAs and combination inhibit retinopathy. These studies are innovative in that: 1. they are the first to examine the effect of LCPUFAs with or without COX-2 inhibitors on DR. 2. a new technique of finding absolute copy numbers of mRNA during disease and intervention allows comparison of interventions to evaluate complementary treatments. 3. lipid analysis may yield mechanism as well as new surrogate markers of DR and risk.

描述（由申请人提供）：该提案描述了一种创新的营养/药理学策略，用于预防疾病小鼠模型中的增殖性视网膜病变，并期望在糖尿病视网膜病变（DR）患者的后续临床试验中进行。DR具有炎症和血管生成成分。我们将单独和交互地评估？- 3种长链多不饱和脂肪酸（LCPUFA）、二十二碳六烯酸和二十碳五烯酸以及塞来昔布（一种选择性环氧合酶（考克斯）-2抑制剂，旨在靶向与增殖性DR发病机制有关的炎症和血管生成因子。3 LCPUFA集中在视网膜中，其状态可通过并依赖于所有西方饮食中不消耗的食物的饮食摄入量来改变，因此这些脂质是预防DR的干预措施的合理选择。初步结果显示，考克斯-2抑制剂可预防缺血诱导的视网膜新生血管形成，并且考克斯-2抑制剂与？3 LCPUFA。如果塞来昔布被证明会导致心脏疾病，我们将改用阿司匹林（考克斯1，2抑制剂）。为了确定抑制机制并确定补充干预措施，将使用一种新技术来灵敏地测量疾病中涉及的特定脂质、炎症和血管生成途径的mRNA绝对拷贝数的治疗微小变化。该组将包括（但不限于）COX 1、2和LOX、血管内皮生长因子和受体1、2、细胞粘附分子（ICAM-1、CD 18）、基质金属蛋白酶2、9、细胞因子（TNF α、TGF？）、核激素受体（NF？B）和一氧化氮合成酶。为了评估干预措施和可能的新的DR替代标志物，我们将评估视网膜和血液中的？3 LCPUFA、花生四烯酸和类二十烷酸（血栓烷、白细胞生成素、白三烯）在摄入平衡、等热量饮食（含或不含？-）的小鼠中的作用3 LCPUFA。为了这项翻译工作，已经建立了一个机构间和学科内的研究小组，成员包括分子和细胞生物学和血管生成（L Smith，（PI），D Carper，J-Y Tsai，NEI），临床研究（E Chew，J-P SanGiovanni，NEI），营养和脂质生物化学（N Salem，NIAAA，C Serhan，哈佛）领域的专家。如果成功，这项工作可能对预防增殖性DR产生重大影响，因为干预措施安全，廉价，易于实施。初步结果表明，考克斯-2抑制剂，？- 3 LCPUFA和组合抑制视网膜病变。本研究的创新之处在于：1.他们是第一个研究LCPUFA与或不与考克斯-2抑制剂对DR的作用的人。在疾病和干预期间发现mRNA绝对拷贝数的新技术允许比较干预以评估补充治疗。3.脂质分析可能产生机制以及新的DR和风险的替代标志物。