GLUCOSE, INSULIN IN DIABETIC VASCULAR DISEASE

葡萄糖、胰岛素在糖尿病血管疾病中的作用

基本信息

批准号：
8098768
负责人：
JERRY L. NADLER
金额：
$ 9.87万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8098768
关键词：
Address Animal Model Anti-Inflammatory Agents Arachidonate 12-Lipoxygenase Arterial Fatty Streak Atherosclerosis Binding Blood Vessels Cardiovascular Diseases Carotid Arteries Catalytic RNA Diabetes Mellitus Diabetic Angiopathies Endothelial Cells Evaluation Family suidae Funding Genes Glucose Growth Helix-Turn-Helix Motifs Hyperglycemia Inflammatory Injury Insulin Insulin Resistance Lead Linoleic Acids Lipids Lipoxygenase Lisofylline Mediating Modeling Molecular Genetics Mus Oxidative Stress Pathway interactions Phospholipids Play Process Research Role Signal Transduction Testing Therapeutic Transcriptional Regulation chemokine chemokine receptor diabetic in vivo innovation macrovascular disease monocyte mouse model novel novel therapeutics prevent programs response to injury transcription factor vascular smooth muscle cell migration

项目摘要

This program project will investigate the role of hyperglycemia and insulin resistance in the excess cardiovascular disease due to diabetes. The program will utilize innovative and multi-disciplinary approaches to address the overall unifying theme that elevate glucose and/of insulin resistance leads to accelerated cardiovascular disease by increasing oxidative stress and inflammatory signals in the vessel wall. A hypothesis developed in the initial funding period will be expanded to evaluate the role of lipoxygenase (LO) activation in mediating the oxidative and inflammatory changes associated with atherosclerosis and vascular injury. A strength of the program will be the use of both small and large animal models to more clearly evaluate the genetic and molecular mechanisms leading to cardiovascular disease in diabetes. These models will also allow the evaluation of potentially therapeutic to prevent the accelerated atherosclerosis and injury response in people with diabetes. The program involves 4 projects and 3 cores. Project 1 will examine the hypothesis that activation of LO pathway can play a role in atherosclerosis and vascular injury by inducing the transcriptional regulation of key genes which regulate vascular smooth muscle cell migration and matrix remodeling. A unique aspect of this project will be the use of novel ribozymes and animal models to test the in vivo role of oxidative stress and 12-LO in these processes. Project 2 will test the hypothesis that glucose and the diabetic state induce LO expression in aortic endothelial cells and that arachidonic or linoleic acid derived oxidative lipids activate key signalling mechanisms and oxidative phospholipids which lead to the binding of monocytes to the vessel wall. This project will utilize novel ribozymes, mouse, and swine models in the cores. Project 3 will mechanistically evaluate the role of helix-loop-helix transcription factors such as Id3 in accelerated VSMC growth response to injury in insulin resistant and diabetic states. Studies will utilizes chemokines, and chemokine receptors determine monocyte recruitment to atherosclerotic lesions and b) the increased rate of atherosclerosis in diabetes can in part be explained by a more robust or earlier expression of these molecules. A novel aspect of this project will be the use of in isolated perfused carotid artery model and the therapeutic and mechanistic actions of a novel anti- inflammatory agent Lisofylline in appropriate mouse models. The synergy between the projects and use of the cores will greatly accelerate the pace of this research to understand the mechanisms of accelerated macrovascular disease in diabetes. The results form this program should provide new therapeutic advances to reduce the rate of cardiovascular disease in diabetes.

该计划项目将研究高血糖和胰岛素抵抗在糖尿病引起的过多心血管疾病中的作用。该计划将利用创新和多学科的方法来解决总体统一的主题，即通过增加血管壁中的氧化应激和炎症信号来提高葡萄糖和/胰岛素抵抗导致加速心血管疾病。最初资助期间提出的假设将得到扩展，以评估脂氧合酶（LO）激活在介导与动脉粥样硬化和血管损伤相关的氧化和炎症变化中的作用。该计划的优势在于使用小型和大型动物模型来更清楚地评估导致糖尿病心血管疾病的遗传和分子机制。这些模型还将允许评估潜在的治疗方法，以防止糖尿病患者加速动脉粥样硬化和损伤反应。该计划涉及4个项目和3个核心。项目1将检验这样的假设：LO通路的激活可以通过诱导调节血管平滑肌细胞迁移和基质重塑的关键基因的转录调节在动脉粥样硬化和血管损伤中发挥作用。该项目的一个独特之处是使用新型核酶和动物模型来测试氧化应激和 12-LO 在这些过程中的体内作用。项目 2 将测试以下假设：葡萄糖和糖尿病状态诱导主动脉内皮细胞中 LO 表达，以及花生四烯酸或亚油酸衍生的氧化脂质激活关键信号传导机制和氧化磷脂，从而导致单核细胞与血管壁结合。该项目将在核心中利用新型核酶、小鼠和猪模型。项目 3 将从机制上评估螺旋-环-螺旋转录因子（例如 Id3）在加速 VSMC 生长对胰岛素抵抗和糖尿病状态损伤的反应中的作用。研究将利用趋化因子，趋化因子受体决定单核细胞向动脉粥样硬化病变的募集，b）糖尿病中动脉粥样硬化发生率的增加可以部分解释为这些分子的更强烈或更早的表达。该项目的一个新颖方面是在分离的灌注颈动脉模型中的使用以及新型抗炎剂利索茶碱在适当的小鼠模型中的治疗和机制作用。这些项目之间的协同作用和核心的使用将大大加快这项研究的步伐，以了解糖尿病中加速大血管疾病的机制。该计划的结果应该提供新的治疗进展，以降低糖尿病患者心血管疾病的发病率。