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;
基本信息
- 批准号:7460890
- 负责人:
- 金额:$ 57.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AffectAftercareAngiogenic FactorArachidonic AcidsAspirinBloodBlood VesselsCarbonCell Adhesion MoleculesClinical ResearchClinical TrialsComplexCoxibsDiabetic RetinopathyDietDietary InterventionDietary intakeDinoprostoneDiseaseDisease MarkerDisease PathwayDocosahexaenoic AcidsDoseEicosanoidsEicosapentaenoic AcidEngineeringEpoprostenolEquilibriumEyeFatty AcidsFatty acid glycerol estersFoodFoundationsGelatinase AGene DosageGenesHeart DiseasesHypoxiaITGB2 geneInflammationInflammatoryIntakeIntercellular adhesion molecule 1InterventionIschemiaLeukotriene B4LeukotrienesLipid BiochemistryLipidsLipoxygenaseLipoxygenase 2MapsMatrix MetalloproteinasesMeasuresMessenger RNAModelingMolecularMolecular BiologyMolecular ProfilingMolecular and Cellular BiologyMusNational Institute on Alcohol Abuse and AlcoholismNitric Oxide SynthaseNuclear Hormone ReceptorsNumbersNutrientNutritionalPathogenesisPathway interactionsPatientsPhysiologicalPolyunsaturated Fatty AcidsPreventionProstaglandin-Endoperoxide SynthaseProstaglandinsRandomized Controlled Clinical TrialsRegulationRelative (related person)ResearchRetinaRetinalRetinal DiseasesRetinal NeovascularizationRiskSeveritiesSurrogate MarkersSystems BiologyTechniquesThromboxanesTissuesTranslational ResearchUnited States Environmental Protection AgencyVascular Endothelial Growth Factor Receptor-1Vascular Endothelial Growth FactorsWorkangiogenesisbasebevacizumabcelecoxibcomparativecyclooxygenase 1cyclooxygenase 2cytokinedesigndiabeticdietary controldisorder controlexpectationinnovationlaser capture microdissectionlong chain fatty acidmouse modelneovascularizationnovelnovel strategiesnutritionpreventproliferative diabetic retinopathyretina blood vessel structure
项目摘要
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,并期望随后在糖尿病视网膜病变(DR)患者中进行临床试验。DR有炎症和血管生成成分。我们将单独评估和互动评估?-3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(一种选择性环氧化酶(COX)-2抑制剂),旨在靶向与增殖性dr发病机制相关的炎症和血管生成因子。LCPUFAs集中在视网膜中,其状态可以通过饮食摄入而改变,并依赖于饮食摄入,但并非所有西方饮食都摄入这些食物,因此这些脂质是预防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形成,COX-2抑制与?3 LCPUFAs。如果塞来昔布被证明会引起心脏病,我们将改用阿司匹林(COX 1,2抑制)。为了确定抑制机制和确定补充干预措施,将使用一种新技术来敏感地测量与疾病相关的特定脂质、炎症和血管生成途径的mrna绝对拷贝数的微小变化。专家组将包括(但不限于)COX1,2和LOX,血管内皮生长因子和受体1,2,细胞粘附分子(ICAM-1, CD18),基质金属蛋白酶2,9,细胞因子(TNFa, TGF?),核激素受体(NF?)B)和一氧化氮合成酶。为了评估DR的干预和可能的新替代标志物,我们将评估视网膜和血液中?-3 LCPUFAs,花生四烯酸和类二十烷(血栓素,前列腺素,白三烯)在均衡的等热量饮食中,或不含?3 LCPUFAs。为了这项转化工作,一个跨机构和跨学科的研究小组已经成立,由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, Harvard)领域的专家组成。如果取得成功,这项工作将对预防增殖性耐药产生重大影响,因为这些干预措施是安全、廉价且易于实施的。初步结果表明,COX-2抑制剂,?-3 LCPUFAs及联合用药可抑制视网膜病变。这些研究的创新之处在于:他们首次研究了LCPUFAs加或不加COX-2抑制剂对DR. 2的影响。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措施以评估互补治疗。3. 脂质分析可以提供DR和风险的机制以及新的替代标记物。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Lois Smith其他文献
Lois Smith的其他文献
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{{ truncateString('Lois Smith', 18)}}的其他基金
Glucose/lipid metabolism and vessel development in phase I ROP
I 期 ROP 中的葡萄糖/脂质代谢和血管发育
- 批准号:
10540713 - 财政年份:2020
- 资助金额:
$ 57.09万 - 项目类别:
Glucose/lipid metabolism and vessel development in phase I ROP
I 期 ROP 中的葡萄糖/脂质代谢和血管发育
- 批准号:
10311520 - 财政年份:2020
- 资助金额:
$ 57.09万 - 项目类别:
Neuronal guidance molecules control revascularization in retinopathy
神经元引导分子控制视网膜病变的血运重建
- 批准号:
8317800 - 财政年份:2012
- 资助金额:
$ 57.09万 - 项目类别:
Neuronal guidance molecules control revascularization in retinopathy
神经元引导分子控制视网膜病变的血运重建
- 批准号:
8656349 - 财政年份:2012
- 资助金额:
$ 57.09万 - 项目类别:
Neuronal guidance molecules control revascularization in retinopathy
神经元引导分子控制视网膜病变的血运重建
- 批准号:
8461559 - 财政年份:2012
- 资助金额:
$ 57.09万 - 项目类别:
Dietary control of angiogenesis in retinopathy models
视网膜病变模型中血管生成的饮食控制
- 批准号:
8328687 - 财政年份:2006
- 资助金额:
$ 57.09万 - 项目类别:
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:
7013914 - 财政年份:2006
- 资助金额:
$ 57.09万 - 项目类别:
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 - 财政年份:2006
- 资助金额:
$ 57.09万 - 项目类别:
Dietary control of angiogenesis in retinopathy models
视网膜病变模型中血管生成的饮食控制
- 批准号:
8511650 - 财政年份:2006
- 资助金额:
$ 57.09万 - 项目类别:
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:
7645703 - 财政年份:2006
- 资助金额:
$ 57.09万 - 项目类别:
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