Diabetes: ERK5 and Vascular Inflammation

糖尿病：ERK5 和血管炎症

• 批准号: 8630125
• 负责人: MARC Lee GOALSTONE
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630125
• 关键词: Advanced Glycosylation End Products; Age; Animal Model; Atherosclerosis; Binding; Blood; Blood Glucose; Blood Vessels; Brain; Cardiovascular Diseases; Cardiovascular Pathology; Cell Adhesion; Cell Adhesion Molecules; Cell surface; Cells; Characteristics; Chronic; Diabetes Mellitus; Diet Habits; Disease; Disinhibition; Drug Targeting; Dyslipidemias; Epidemic; Event; Genes; Genetic; Glucose; Goals; Growth Factor; Healthcare; Heart; Hyperinsulinism; Immune System Diseases; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Knowledge; Lead; Left; Life Style; Link; MAP Kinase Gene; MAPK14 gene; MAPK3 gene; MAPK7 gene; Mediating; Metabolic; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Mitogens; Modeling; Molecular; Morbidity - disease rate; Myocardial Infarction; Neuropathy; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Obesity; PI3K/AKT; Pathology; Pathway interactions; Phosphotransferases; Play; Population; Rattus; Research; Retinal Diseases; Role; Serum; Signal Pathway; Signal Transduction; Societies; Stroke; TNF gene; Therapeutic; Tissues; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Vascular remodeling; Veterans; Work; atherogenesis; constriction; cytokine; diabetic rat; endothelial dysfunction; extracellular; genetic inhibitor; in vivo; insulin signaling; interest; mortality; neointima formation; novel; public health relevance; research study; sedentary; stress-activated protein kinase 1; sugar; vascular inflammation; vascular smooth muscle cell migration

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.

项目摘要 理由：糖尿病在我们社会中流行。 2型糖尿病（T2DM）是一种进行性病理 以胰岛素抵抗和高胰岛素血症为特征。心血管病理是后遗症 这种疾病是我们退伍军人人口中发病和死亡率的主要原因。 动脉粥样硬化是糖尿病的主要结果，也是一个特殊的特征 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 通过增加炎症细胞因子的作用来促进动脉粥样硬化，从而增加 添加剂炎症细胞因子的分泌和细胞粘附分子（CAM）的表达。 肿瘤坏死因子-Alpha（TNF¿）活性已显示与胰岛素抵抗有关。 介导TNF效应的途径也可能调节细胞内胰岛素信号传导，从而相关 进行动脉粥样硬化。众所周知，TNF会增加血管细胞粘附分子-1（VCAM-1）的表达。 相比之下，胰岛素在动脉粥样硬化中的作用是辩论的。有些人认为胰岛素刺激了增加 一氧化氮（NO）。其他人则认为高胰岛素血症增加了血管细胞的增殖和 炎症反应。我们在这里问的问题是：“胰岛素抑制或增加了 TNF缺在VCAM-1表达以及哪些机制归因于这些效果”？ 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，但在识别途径和 在高胰岛素血症和 炎症细胞因子。 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，从而有助于定义新的药物靶标。这些发现可能 提供医疗保健策略，这些策略将在退伍军人中所有血管感染和动脉粥样硬化。 我们假设 - 在代谢胰岛素抵抗状态下，高胰岛素血症夸大了 通过增加VCAM -1的表达，TNF®相关炎症。这些影响部分由 多个信号途径，其中ERK5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的了解 目前的提议旨在提高我们对血管注射分子机制的理解 表征主要参与者在胰岛素和TNF¿刺激的VCAM -1表达中的作用。 具体目的：（1）确定激酶途径串扰在高胰岛素血症和TNF刺激中的作用 VCAM-1表达的增加。 （2）确定ERK5在高胰岛素血症和TNF刺激中的作用 VCAM-1表达的增加。 （3）确定氢氧毒素血症在VCAM-1表达中的作用 糖尿病大鼠的颈动脉。