Diabetes: ERK5 and Vascular Inflammation

项目摘要 基本原理：糖尿病在我们的社会中很流行。2型糖尿病(T2 DM)是一种进行性病理 以胰岛素抵抗和高胰岛素血症为特征。心血管疾病的后遗症 这种疾病是我们退伍军人人口发病率和死亡率的主要原因。 动脉粥样硬化是糖尿病的主要后果，也是糖尿病的一个特殊特征。 动脉粥样硬化是一种炎症。研究表明，慢性胰岛素抵抗和高胰岛素血症 通过增强炎性细胞因子的作用，从而增加动脉粥样硬化的发生 分泌额外的炎性细胞因子和表达细胞黏附分子(CAM)。 肿瘤坏死因子-α(TNF)活性已被证明与胰岛素抵抗有关。 介导肿瘤坏死因子效应的途径也可能调节细胞内的胰岛素信号，因此相关 对动脉粥样硬化的影响。已知肿瘤坏死因子可增加血管细胞黏附分子-1(VCAM-1)的表达。 相比之下，胰岛素在动脉粥样硬化形成中的作用还存在争议。一些人争辩说，胰岛素刺激了 一氧化氮(NO)。另一些人则认为，高胰岛素血症会增加血管细胞的增殖， 炎症反应。我们在这里问的问题是，胰岛素是抑制还是增强了 肿瘤坏死因子对血管细胞黏附分子-1表达的影响及其机制是什么？ 在体外和体内的动物模型实验已经检测了一些信号通路， 介导CAM的表达，但在我们的理解中，识别途径和 它们在细胞和组织内的分子相互作用或在高胰岛素血症和高胰岛素血症存在时的“串扰” 炎性细胞因子。 意义：我们感兴趣的是确定调节胰岛素和肿瘤坏死因子的分子机制 刺激VCAM-1的表达，从而有助于确定新的药物靶点。这些发现可能 提供医疗保健策略，以减轻退伍军人的血管炎症和动脉粥样硬化。 我们假设-在代谢胰岛素抵抗的状态下，高胰岛素血症会夸大 肿瘤坏死因子相关炎症通过VCAM-1的表达增加。这些影响在一定程度上通过 多条信号通路，其中ERK5在VCAM-1的表达、核因子B的激活和 血管发炎。 研究目标：为了加深我们对血管炎症的了解，我们计划利用 目前的建议是通过以下方式促进我们对血管炎症分子机制的理解 研究胰岛素和肿瘤坏死因子刺激的血管细胞黏附分子-1表达中关键因子的作用。 具体目的：(1)确定信号通路串扰在高胰岛素血症和肿瘤坏死因子刺激中的作用 VCAM-1表达增加。(2)确定ERK5在高胰岛素血症和肿瘤坏死因子刺激中的作用 VCAM-1表达增加。(3)探讨高胰岛素血症对血管细胞黏附分子-1表达的影响。 糖尿病大鼠的颈总动脉。

Project Summary Rationale: Diabetes is epidemic in our society. Type-2 Diabetes Mellitus (T2DM) is a progressive pathology characterized by insulin resistance and hyperinsulinemia. Cardiovascular pathologies that are the sequelae of this disorder are the leading cause of morbidity and mortality in our Veteran population. Atherosclerosis is a major consequence of diabetes and one particular characteristic of atherosclerois is inflammation. Studies suggest that chronic insulin resistance and hyperinsulinemia contribute to atherogenesis by augmenting the effects of the inflammatory cytokines, thereby increasing the secretion of additonal inflammatory cytokines and expression of cellular adhesion molecules (CAMs). Tumor Necrosis Factor-alpha (TNF¿) activity has been shown to be linked to insulin resistance. Pathways that mediate the effects of TNF¿ may also regulate intracellular insulin signaling and thus correlated to atherogenesis. TNF¿ is known to increase the expression of vascular cell adhesion molecule-1 (VCAM-1). In contrast, insulin's role in atherogenesis is debated. Some contend that insulin stimulates the increase of nitric oxide (NO). Others argue that hyperinsulinemia increases the proliferaton of vascular cells and the inflammatory response. The question we asked here is, "does insulin dampen or augment the effects of TNF¿ on VCAM-1 expression and what mechanisms are attributed to these effects"? In vitro and in vivo animal model experiments have examined some of the signaling pathways that mediate CAM expression, but there is a significant gap in our understanding between identifying pathways and their molecular interactions or "cross talk" within cells and tissues in the presence of hyperinsulinemia and inflammatory cytokines. Significance: We are interested in determining the molecular mechanisms that regulate insulin and TNF¿ stimulation of VCAM-1 expression and thereby help define novel drug targets. These findings may provide healthcare strategies that will allay vascular inflammation and atherosclerosis in Veterans. We hypothesize - that in the state of metabolic insulin resistance hyperinsulinemia exaggerates the effects of TNF¿-associated inflammation via increased expression of VCAM-1. These effects are mediated in part by multiple signal pathways, in which ERK5 plays an important role in VCAM-1 expression, NF¿B activation and vascular inflammation. Goals of Research: To further our knowledge of vascular inflammation we plan to use the findings from the current proposal to advance our understanding of the molecular mechanisms of vascular inflammation by characterizing the roles of key players in insulin and TNF¿-stimulated VCAM-1 expression. Specific Aims: (1) Determine the role of kinase pathway crosstalk in hyperinsulinemia and TNF¿-stimulated increases in VCAM-1 expression. (2) Determine the role of ERK5 in hyperinsulinemia and TNF¿ stimulated increases in VCAM-1 expression. (3) Determine the role that hyprerinsulinemia plays in VCAM-1 expression in carotids of diabetic rats.