Insulin Resistance in Vascular Endothelial Cells and Foxo

血管内皮细胞的胰岛素抵抗和 Foxo

基本信息

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
项目类别：
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

项目摘要

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化，遗传，细胞生物学和综合 2型患者动脉粥样硬化心血管疾病的生理基础糖尿病。在这个较大的上下文中。项目3规定确定胰岛素信号受损机制在血管内皮细胞中，重点是FoxO转录因子对该过程的贡献。我们假设通过转录因子Foxo的同工型Foxo信号传导在内皮细胞功能及其改变会促进内皮功能障碍。为了解决这一假设，在AIM 1中，我们建议表征具有功能丧失的小鼠动脉粥样硬化的敏感性内皮细胞中三个FOXO的突变。三重Foxo淘汰小鼠中的初步数据显示出惊人的 FOXO消融的动脉保护作用，与一氧化氮合成增加有关，降低了ROS 产生并减少了单核细胞募集。我们建议表征内皮细胞特异性三重FOXO中的动脉粥样硬化保护和血管功能表型淘汰赛。了解胰岛素抵抗和高血糖如何有助于改变内皮细胞功能，在AIM 2中，我们将在内皮细胞中产生两个不同的FOXOI功能收益突变体转基因小鼠。胰岛素抵抗会导致FOXOI核保留。我们在过去的周期中表明 FOXOI核保留与ROS产生和单核细胞募集的增加有关。我们将通过开发FOXOI功能获得的模型来测试这些体外观察的生理影响分别模仿胰岛素抵抗和高血糖对内皮功能的影响。我们设想这项工作将产生以下创新：（i）将FOXO蛋白质建立为细胞生物学过程的关键，易于动脉粥样硬化的内皮功能障碍，包括炎症，细胞存活，无产生，ROS产生和细胞粘附，（ii）识别效应基因通过三重功能分析，胰岛素抵抗中内皮功能障碍的机制和机制 FOXO敲除和FOXO在血管内皮细胞中的功能获得模型，（iii）鉴定一种新型调节性FOXO-AKT馈送回路，FOXO功能控制内皮细胞中的胰岛素敏感性，（iv）小鼠模型的开发和分析，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，还原主义实验模型，以及在高血糖，对AIM 2中描述的靶向小鼠突变体的分析将提供独特的机械以及对调节生化和细胞生物学途径鉴定的治疗洞察高血糖和内皮功能障碍之间的重要相互作用。相关性（请参阅说明）：拟议的研究将揭示无序胰岛素作用之间相互作用的新维度，血管细胞生物学和动脉粥样硬化，并扩大目前可用目标的曲目 2型糖尿病的动脉粥样硬化治疗。在过去的资金周期的课程上，我们将探索新的血管疾病的机制，有可能提供可行的治疗靶标。驾驶主题是定义可以在诊所中抗击动脉粥样硬化和胰岛素抵抗的途径。