Insulin Resistance in Vascular Endothelial Cells and Foxo

血管内皮细胞的胰岛素抵抗和 Foxo

• 批准号: 8460254
• 负责人: DOMENICO ACCILI
• 金额: $ 54.01万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8460254
• 关键词: Ablation; Achievement; Address; Affect; Antiatherogenic; Area; Atherosclerosis; Attention; Automobile Driving; Biochemical; Biochemical Genetics; Biological; Biological Process; Biology; Biometry; Blood Pressure; Blood Vessels; Bone Marrow; Breeding; Cardiovascular system; Cause of Death; Cell Adhesion; Cell Adhesion Molecules; Cell Survival; Cell physiology; Cells; Cellular biology; Cessation of life; Clinic; Clinical Trials; Complementary DNA; Complications of Diabetes Mellitus; Data; Deacetylation; Development; Diabetes Mellitus; Dimensions; Disease; Dyslipidemias; Employee Strikes; Endothelial Cells; Experimental Models; Functional disorder; Funding; Generations; Genes; Genetic; Glucose; Goals; Heart Diseases; Hepatic; Human; Hyperglycemia; In Vitro; Inflammation; Instruction; Insulin; Insulin Resistance; Insulin Signaling Pathway; Knock-in Mouse; Knock-out; Knockout Mice; Knowledge; Kupffer Cells; Lesion; Light; Lipids; Lipoproteins; Liver; Mediating; Metabolic; Modeling; Mouse Protein; Mus; Mutagenesis; Mutant Strains Mice; Myocardial Infarction; Names; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Outcome; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphorylation; Physiological; Play; Predisposition; Prevention; Preventive; Principal Investigator; Process; Production; Protein Isoforms; Protein-Serine-Threonine Kinases; Proteins; Publications; Reagent; Regulation; Resources; Risk Factors; Role; Signal Transduction; Site; Smooth Muscle Myocytes; Testing; Time; Transgenic Mice; Transgenic Organisms; Vascular Diseases; Vascular Endothelial Cell; Very low density lipoprotein; Work; atherogenesis; atheroprotective; base; blood glucose regulation; cell type; diabetes control; diabetic; expectation; falls; feeding; gain of function; human NOS2A protein; improved; in vivo Model; innovation; insight; insulin sensitivity; insulin signaling; interest; loss of function; loss of function mutation; macrovascular disease; monocyte; mortality; mouse model; mutant; non-diabetic; novel; prevent; research study; transcription factor

The central theme of Project 3 is to investigate the biochemical, genetic, cell biological and integrated physiological basis of the predisposition to atherosclerotic cardiovascular disease in patients with type 2 diabetes. Within this larger context. Project 3 sets out to determine mechanisms of impaired insulin signaling in vascular endothelial cells-with a focus on the contribution of FoxO transcription factors to this process. We hypothesize that insulin signaling through isoforms of transcription factor FoxO plays an important role in endothelial cell function and that its alteration promotes endothelial dysfunction. To address this hypothesis, in AIM 1 we propose to characterize the susceptibility to atherosclerosis in mice with loss-of-function mutations of the three Foxo in endothelial cells. Preliminary data in triple Foxo knockout mice show a striking atheroprotective effect of FoxO ablation, associated with increased nitric oxide synthesis, reduced ROS generation, and reduced monocyte recruitment. We propose to characterize the mechanism of atherosclerosis protection and the vascular function phenotype in endothelial cell-specific triple Foxo knockouts. To understand how insulin resistance and hyperglycemia contribute to alter endothelial cell function, in AIM 2 we will generate two different FoxOI gain-of-function mutants in endothelial cells of transgenic mice. Insulin resistance results in FoxOI nuclear retention. We have shown in the past cycle that FoxOI nuclear retention is associated with increased ROS generation and monocyte recruitment. We will test the physiologic impact of these in vitro observations by developing models of FoxOI gain-of-function that mimic the effects of insulin resistance and hyperglycemia, respectively, on endothelial function. We envision that the following innovations will arise from this work: (i) Establishing FoxO proteins as the linchpin of cell biological processes that predispose to endothelial dysfunction in atherosclerosis, including inflammation, cell survival, NO generation, ROS production, and cell adhesion, (ii) Identifying effector genes and mechanisms of endothelial dysfunction in insulin resistance through the functional analysis of the triple Foxo knockout and Foxo gain-of-function models in vascular endothelial cells, (iii) Identification of a novel regulatory Foxo-Akt feed-forward loop, whereby Foxo function controls insulin sensitivity in endothelial cells, (iv) Development and analysis of mouse models to understand the effects of hyperglycemia on vascular function. Given the central role of endothelial dysfunction in diabetic atherosclerosis, the dearth of suitable reductionist experimental models, and the fact that atherosclerosis treatment must occur in the context of hyperglycemia, analyses of the targeted mouse mutants described in Aim 2 will provide unique mechanistic and treatment insight into the identification of biochemical and cell biological pathways that regulate the important interaction between hyperglycemia and endothelial dysfunction. RELEVANCE (See instructions): The proposed studies will reveal new dimensions to the interaction between disordered insulin action, vascular cell biology and atherosclerosis, and expand the repertoire of currently available targets for atherosclerosis therapy in type 2 diabetes. Building on lessons of the past funding cycle, we will explore new mechanisms of vascular disease with the potential to provide actionable targets for therapy. The driving theme is to define pathways that can be enlisted in the clinic against atherosclerosis and insulin resistance.

项目3的中心主题是研究生物化学、遗传、细胞生物学和综合 2型患者易患动脉粥样硬化性心血管疾病的生理学基础 糖尿病。在这个更大的背景下。项目 3 旨在确定胰岛素信号传导受损的机制 在血管内皮细胞中 - 重点关注 FoxO 转录因子对此过程的贡献。我们 假设通过转录因子 FoxO 亚型的胰岛素信号传导在 内皮细胞功能及其改变会促进内皮功能障碍。为了解决这个假设， 在 AIM 1 中，我们建议描述功能丧失小鼠对动脉粥样硬化的易感性 内皮细胞中三种 Foxo 的突变。三重 Foxo 基因敲除小鼠的初步数据显示， FoxO 消融的动脉粥样硬化保护作用与一氧化氮合成增加、ROS 减少相关 的产生，并减少单核细胞的募集。我们建议描述其机制 内皮细胞特异性三重 Foxo 的动脉粥样硬化保护作用和血管功能表型 淘汰赛。了解胰岛素抵抗和高血糖如何改变内皮细胞 功能，在 AIM 2 中，我们将在内皮细胞中生成两种不同的 FoxOI 功能获得突变体 转基因小鼠。胰岛素抵抗导致 FoxOI 核滞留。我们在过去的周期中已经表明 FoxOI 核保留与 ROS 生成和单核细胞募集增加有关。我们将 通过开发 FoxOI 功能获得模型来测试这些体外观察的生理影响 分别模拟胰岛素抵抗和高血糖对内皮功能的影响。我们 预计这项工作将产生以下创新：（i）建立 FoxO 蛋白作为 导致动脉粥样硬化内皮功能障碍的细胞生物过程的关键，包括 炎症、细胞存活、NO 生成、ROS 生成和细胞粘附，(ii) 识别效应基因 通过三联体的功能分析探讨胰岛素抵抗中内皮功能障碍的机制 血管内皮细胞中的 Foxo 敲除和 Foxo 功能获得模型，(iii) 一种新型的鉴定 调节 Foxo-Akt 前馈环，Foxo 功能控制内皮细胞中的胰岛素敏感性， (iv) 开发和分析小鼠模型以了解高血糖对血管的影响 功能。鉴于内皮功能障碍在糖尿病动脉粥样硬化中的核心作用，缺乏合适的治疗方法 还原论实验模型，以及动脉粥样硬化治疗必须在以下背景下进行的事实 高血糖症，对目标 2 中描述的目标小鼠突变体的分析将提供独特的机制 和治疗洞察力来识别调节调节的生化和细胞生物学途径 高血糖和内皮功能障碍之间的重要相互作用。 相关性（参见说明）： 拟议的研究将揭示胰岛素作用紊乱之间相互作用的新维度， 血管细胞生物学和动脉粥样硬化，并扩展目前可用的靶标库 2 型糖尿病的动脉粥样硬化治疗。根据过去融资周期的经验教训，我们将探索新的 血管疾病的机制有可能为治疗提供可行的目标。驾驶 主题是确定可用于临床治疗动脉粥样硬化和胰岛素抵抗的途径。