Diabetes: ERK5 and Vascular Inflammation

项目摘要 理由：糖尿病是我们社会的流行病。2型糖尿病（T2 DM）是一种进行性病理 其特征在于胰岛素抵抗和高胰岛素血症。心血管疾病是 这种疾病是退伍军人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而有助于动脉粥样硬化的形成，从而增加 分泌额外的炎性细胞因子和表达细胞粘附分子（CAM）。 肿瘤坏死因子-α（TNF-α）活性已被证明与胰岛素抵抗有关。 介导TNF？作用的途径也可能调节细胞内胰岛素信号传导，因此与TNF？相关。 动脉粥样硬化已知TNF可增加血管细胞粘附分子-1（VCAM-1）的表达。 与此相反，胰岛素在动脉粥样硬化形成中的作用是有争议的。有些人认为胰岛素刺激了 一氧化氮（NO）。另一些人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 TNF对VCAM-1表达的影响以及这些影响的机制是什么？ 体外和体内动物模型实验已经检查了一些信号通路， 介导CAM表达，但在我们对识别途径和 它们在高胰岛素血症存在下在细胞和组织内的分子相互作用或“串扰”， 炎性细胞因子 意义：我们有兴趣确定调节胰岛素和TNF的分子机制。 刺激VCAM-1表达，从而帮助确定新的药物靶点。这些发现可能 提供医疗保健策略，将减轻血管炎症和动脉粥样硬化的退伍军人。 我们假设-在代谢性胰岛素抵抗状态下，高胰岛素血症夸大了 通过VCAM-1表达增加的TNF相关炎症。这些影响部分由以下因素介导： 多种信号通路，其中ERK 5在VCAM-1表达、NF B激活和 血管炎症 研究目标：为了进一步了解血管炎症，我们计划使用来自 目前的建议，以促进我们的血管炎症的分子机制的理解， 表征胰岛素和TNF刺激的VCAM-1表达中关键参与者的作用。 具体目的：（1）确定激酶通路串扰在高胰岛素血症和TNF-α刺激的高胰岛素血症中的作用。 增加VCAM-1的表达。(2)确定ERK 5在高胰岛素血症和TNF刺激中的作用 增加VCAM-1的表达。(3)确定高胰岛素血症在VCAM-1表达中的作用， 糖尿病大鼠的颈动脉。

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.