Insulin Receptor Substrate Signaling in Pulmonary Hypertension

肺动脉高压中的胰岛素受体底物信号转导

• 批准号: 9918611
• 负责人: Kazuyo Kegan
• 金额: $ 28.25万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-07 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918611
• 关键词: 2' -adenylic acid; 5' -AMP-activated protein kinase; Ablation; Adenosine Monophosphate; Animal Model; Anti-inflammatory; Biological; Biological Markers; Biosensor; Blood Vessels; Bone Marrow; Cardiopulmonary; Cell Proliferation; Cell physiology; Cells; Cessation of life; Characteristics; Chronic; Clinical; Complex; Data; Databases; Development; Disease; Disease Progression; Down-Regulation; Energy Metabolism; Etiology; Exhibits; Fluorescence Resonance Energy Transfer; Functional disorder; Gene Expression Profiling; Genes; Genetic; Genetic Predisposition to Disease; Goals; Growth Factor; Heart failure; Hematopoietic; Homeostasis; Human; Hypoxia; IRS2 gene; Immune; In Vitro; Inflammation; Inflammatory; Insulin; Insulin Receptor; Insulin Resistance; Interleukin 4 Receptor; Knock-out; Literature; Lung; Lymphoid Cell; Macrophage Activation; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolic syndrome; Metabolism; Modeling; Mus; Muscle; New Agents; Non-Insulin-Dependent Diabetes Mellitus; Organelles; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Phosphorylation; Play; Protein Kinase; Publishing; Pulmonary Hypertension; Pulmonary artery structure; Pulmonary vessels; Rattus; Role; Sampling; Scleroderma; Side; Signal Pathway; Signal Transduction; Site; Smooth Muscle Myocytes; Testing; Tissue Banks; Vascular Diseases; Vascular remodeling; Vasodilation; base; cell growth; cell type; chemokine; demographics; gene therapy; hypoxia inducible factor 1; insulin signaling; macrophage; mouse model; neoplastic; new therapeutic target; novel marker; pressure; primary pulmonary hypertension; pulmonary arterial hypertension; receptor expression; recruit; spatiotemporal; targeted agent; transcription factor; vascular inflammation

ABSTRACT Pulmonary hypertension (PH) is characterized by pulmonary vasculature remodeling and elevated pulmonary artery pressure that leads to progressive right-sided heart failure and death. Growing evidence indicates that genetic susceptibility, inflammation, and metabolic shifts in the pulmonary vasculature play key roles in PH pathogenesis. The mechanisms that underlie PH remain enigmatic because of its tremendous complexity. Consequently, current therapy for PH is limited primarily to vasodilation. In this application, we target one of the more proximal signaling hubs in the pathogenesis of PH—insulin receptor substrate 2 (IRS2), a critical molecule in insulin resistance and cellular energy homeostasis. Because IRS2 is the main regulator of insulin and insulin growth factor signaling, loss of IRS2 expression promotes insulin resistance and type II diabetes. Indeed, the loss of IRS2 appears to be deleterious in multiple cell types and disease conditions. Although the role of IRS2 in insulin signaling has been studied, very little is known about its contribution to cardiopulmonary pathophysiology, including that seen in PH. Our preliminary data show that IRS2 expression is decreased in hematopoietic cells of patients with pulmonary arterial hypertension and that IRS2 deletion exacerbates macrophage activation to pro-PH phenotype, and perivascular muscularization in a mouse model of PH. Based on our data and other published results, we hypothesize that IRS2 possesses anti-inflammatory and anti-hyper-proliferative activity in the pathogenesis of PH, and that loss of IRS2 in bone marrow-derived cells enhances vascular inflammation and promotes a hyper-proliferative microenvironment. Hence, IRS2 might be valuable as a novel biomarker for PH, and restoring IRS2 expression and function might represent a novel therapeutic target for multifactorial PH pathophysiology. Specific Aim 1 will investigate the correlation between IRS2 expression in lymphoid cells and the clinical characteristics of patients with pulmonary arterial hypertension. Specific Aim 2 will determine the anti-inflammatory role of macrophage-derived IRS2 in pulmonary vascular remodeling and PH development and examine whether IRS2 influences macrophage activation to a pro-PH phenotype. Specific Aim 3 will test the hypothesis that IRS2 and 5' adenosine monophosphate-activated protein kinase (AMPK) signaling integrate several key pathways implicated in pulmonary artery smooth muscle cell proliferation and that restoring IRS2 by adenoviral gene therapy will reverse experimental PH. The goal of this proposal is to unravel the unrecognized protective role of IRS2— specifically its ability to suppress inflammation and hyper-proliferative activity during PH development. Thus, the data generated will support the development of new agents that target multiple downstream inflammatory, neoplastic, and metabolic mediators of this pathway that can be used for treatment of right heart failure and PH.

摘要