GLUCOSE, INSULIN IN DIABETIC VASCULAR DISEASE

该计划项目将调查高血糖和胰岛素抵抗在糖尿病引起的过度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，即升高血糖和/或胰岛素抵抗通过增加血管壁中的氧化应激和炎症信号而导致心血管疾病加速。在最初的资助期提出的一个假说将被扩展，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。该计划的一个优势将是使用小动物和大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作用，以防止糖尿病患者加速的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将验证这样的假设，即激活LO通路可以通过诱导调控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。该项目的一个独特方面将是使用新的核酶和动物模型来测试体内氧化应激和12-LO在这些过程中的作用。项目2将测试葡萄糖和糖尿病状态诱导主动脉内皮细胞LO表达的假设，以及花生四烯酸或亚油酸衍生的氧化脂质激活关键信号机制和氧化磷脂导致单核细胞与血管壁结合的假设。该项目将在核心中利用新的核酶、小鼠和猪模型。项目3将从机械上评估ID3等螺旋-环-螺旋转录因子在胰岛素抵抗和糖尿病状态下VSMC对损伤的加速生长反应中的作用。研究将利用趋化因子，趋化因子受体决定单核细胞对动脉粥样硬化病变的募集，以及b)糖尿病动脉粥样硬化率的增加可以部分解释为这些分子更强健或更早的表达。该项目的一个新方面将是在隔离灌流颈动脉模型中的使用，以及新型抗炎药利索茶碱在适当的小鼠模型中的治疗和机制作用。这些项目和核心的使用之间的协同作用将大大加快这项研究的步伐，以了解糖尿病大血管疾病加速的机制。该项目的结果将为降低糖尿病心血管疾病的发生率提供新的治疗进展。

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.