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

基本信息

批准号：
10305606
负责人：
Achsah D. Keegan
金额：
$ 38.63万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-07 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10305606
关键词：
2&apos -adenylic acid 5&apos -AMP-activated protein kinase Ablation Adenosine Monophosphate Animal Model Anti-Inflammatory Agents 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 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 Signal Pathway Signal Transduction Site Smooth Muscle Myocytes Testing Tissue Banks Vascular Diseases Vasodilation base cell growth cell type chemokine demographics gene therapy hypoxia inducible factor 1 hypoxia-induced pulmonary hypertension insulin signaling macrophage mouse model neoplastic new therapeutic target novel marker primary pulmonary hypertension pulmonary arterial hypertension pulmonary arterial pressure pulmonary vascular remodeling receptor expression recruit right ventricular failure spatiotemporal targeted agent transcription factor vascular inflammation

项目摘要

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.

抽象的肺动脉高压（PH）的特点是肺血管重塑和血压升高越来越多的证据表明，肺动脉压力会导致进行性右心衰竭和死亡。表明遗传易感性、炎症和肺血管系统的代谢变化起着关键作用 PH 发病机制中的作用由于其巨大的影响，PH 的机制仍然是个谜。经测试，目前的 PH 治疗主要限于血管舒张。靶向 PH 发病机制中最邻近的信号传导中枢之一——胰岛素受体底物 2 (IRS2)，因为 IRS2 是胰岛素抵抗和细胞能量稳态的主要调节分子。胰岛素和胰岛素生长因子信号传导、IRS2 表达缺失会促进胰岛素抵抗和 II 型胰岛素抵抗事实上，IRS2 的缺失似乎对多种细胞类型和疾病状况有害。尽管 IRS2 在胰岛素信号传导中的作用已被研究，但对其对胰岛素信号转导的贡献知之甚少。心肺病理生理学，包括 PH 中所见的。我们的初步数据表明 IRS2 表达。肺动脉高压患者的造血细胞减少，IRS2 缺失使小鼠模型中的巨噬细胞活化恶化为亲 PH 表型和血管周围肌肉化根据我们的数据和其他已发表的结果，我们发现 IRS2 具有抗炎作用。 PH 发病机制中的抗过度增殖活性，以及骨髓源性 IRS2 的缺失细胞增强血管炎症并促进过度增殖的微环境。作为 PH 的新型生物标志物可能很有价值，恢复 IRS2 表达和功能可能代表多因素 PH 病理生理学的新治疗靶点具体目标 1 将研究相关性。淋巴细胞IRS2表达与肺动脉疾病患者临床特征的关系具体目标 2 将确定巨噬细胞衍生的 IRS2 在高血压中的抗炎作用。肺血管重塑和 PH 发展并检查 IRS2 是否影响巨噬细胞激活 pro-PH 表型具体目标 3 将检验 IRS2 和 5' 腺苷的假设。单磷酸激活蛋白激酶 (AMPK) 信号传导整合了与肺动脉平滑肌细胞增殖和通过腺病毒基因治疗恢复IRS2将该提案的目标是揭示 IRS2 未被认识到的保护作用—— 特别是其在 PH 发展过程中抑制炎症和过度增殖活性的能力。生成的数据将支持针对多种下游炎症的新药物的开发，该途径的肿瘤和代谢介质可用于治疗右心衰竭和 PH.

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

HIMF (Hypoxia-Induced Mitogenic Factor) Signaling Mediates the HMGB1 (High Mobility Group Box 1)-Dependent Endothelial and Smooth Muscle Cell Crosstalk in Pulmonary Hypertension.

HIMF（缺氧诱导有丝分裂因子）信号传导在肺动脉高压中介导 HMGB1（高迁移率族盒 1）依赖性内皮细胞和平滑肌细胞串扰。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Lin, Qing;Fan, Chunling;Gomez;Van Raemdonck, Katrien;Meuchel, Lucas W;Skinner, John T;Everett, Allen D;Fang, Xia;Macdonald, Andrew A;Yamaji;Johns, Roger A
通讯作者：
Johns, Roger A

Systemic evaluation and localization of resistin expression in normal human tissues by a newly developed monoclonal antibody.

通过新开发的单克隆抗体对正常人体组织中抵抗素表达进行系统评估和定位。