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

本提案描述了一种预防增殖性视网膜病变的创新营养/药理学策略。 在疾病的小鼠模型中，期望在以后的糖尿病视网膜病变(DR)患者的临床试验中。 DR有炎症和血管生成两种成分。我们将单独和互动地评估co-3的效果。 长链多不饱和脂肪酸(LCPUFAs)、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(COX)-2抑制剂，旨在靶向炎症和血管生成因子 与增殖性DR的发病机制有关，co-3LCPUFAs集中在视网膜，其状态是 不是所有西方饮食中都摄入的食物可以改变饮食，并依赖于饮食摄入，所以这些 血脂是预防DR干预的合理选择初步结果显示COX-2抑制剂可以预防 缺血诱导的视网膜新生血管和COX-2抑制与CO-3 LCPUFAs有协同作用。应该 塞来昔布被证明会导致心脏病，我们将改用阿司匹林(环氧合酶1，2抑制)。 一种新的技术将被用来敏感地测量 治疗对特定脂类、炎症和血管生成的mRNAs绝对拷贝数的微小变化 与疾病有关的途径。该小组将包括(但不限于)COX1，2和LOX，血管 内皮生长因子和受体1，2，细胞黏附分子(ICAM-1，CD18)，基质金属蛋白酶 2，9、细胞因子(TNFa.TGFp)、核激素受体(NFicB)和一氧化氮合酶。评估 我们将评估视网膜和血液中CO-3 LCPUFAs的水平， 花生四烯酸和二十碳二烯(血栓素类，前列腺素，白三烯)在摄入平衡， 添加或不添加co-3LCPUFAs的等热量饮食。对于这项翻译工作，机构间和机构内- 成立了由分子和细胞生物学领域的专家组成的学科研究小组 血管生成(L史密斯，(PI)，D Carper，蔡俊英，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)， 如果成功，这项工作可能会对预防增殖性DR产生巨大影响，因为干预是安全的， 价格低廉，且易于实施。初步结果显示，COX-2抑制剂，co-3LCPUFAs和 联合抑制视网膜病变。这些研究的创新之处在于：1.他们第一次考察了 含或不含环氧合酶-2抑制剂的LCPUFAs基因DR-2基因绝对拷贝数的新技术 疾病和干预期间的mRNA允许对干预措施进行比较，以评估补充治疗。 3.血脂分析可能产生DR和Risk的机制和新的替代标记物。

This proposal describes an innovative nutritional/pharmacological strategy to prevent proliferative retinopathy in a mouse model of disease with the expectation of a later clinicaltrial of patients with diabetic retinopathy(DR). DR has inflammatory and angiogenic components. We will evaluate alone and interactively the efficacy of the co-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. co-3LCPUFAs 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 inhibitionis synergistic with co-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 (butis 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.TGFp), nuclear hormone receptor (NFicB), and nitric oxide synthetase. To assess intervention and possible new surrogate markers of DR we will assess retinal and blood levels of co-3 LCPUFAs, arachidonic acid and eicosanoids (thromboxanes, prostaglandins, leukotrienes) in mice consuming balanced, isocaloric diets with, or without co-3LCPUFAs. 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, co-3LCPUFAs 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.