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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：
8606763
负责人：
DOMENICO ACCILI
金额：
$ 52.93万
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/8606763
关键词：
Ablation Achievement Address Affect Antiatherogenic Atherosclerosis Attention Automobile Driving Biochemical Biochemical Genetics Biological Biological Process Blood Pressure Blood Vessels Bone Marrow Breeding Cell Adhesion Cell Adhesion Molecules Cell Survival Cell physiology Cells Cellular biology Clinic Complementary DNA Data Deacetylation Development Dimensions Disease Dyslipidemias Employee Strikes Endothelial Cells Experimental Models Functional disorder Funding Generations Genes Genetic Glucose Hepatic Human Hyperglycemia In Vitro Inflammation Instruction Insulin Insulin Resistance Insulin Signaling Pathway Knock-in Mouse Knock-out Knockout Mice Kupffer Cells Light Lipids Liver Mediating Metabolic Modeling Mus Mutagenesis Mutant Strains Mice Names Nitric Oxide Non-Insulin-Dependent Diabetes Mellitus Nuclear Outcome Pathogenesis Pathway interactions Patients Phenotype Phosphorylation Physiological Play Predisposition Process Production Protein Isoforms Protein-Serine-Threonine Kinases Proteins Regulation Risk Factors Role Site Smooth Muscle Myocytes Testing Transgenic Mice Transgenic Organisms Vascular Diseases Vascular Endothelial Cell Very low density lipoprotein Work atherogenesis atheroprotective base blood glucose regulation cell type diabetic endothelial dysfunction expectation feeding gain of function in vivo Model innovation insight insulin sensitivity insulin signaling interest loss of function loss of function mutation monocyte mouse model mutant 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.