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: 10089467
• 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
• 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/10089467
• 关键词: 2' -adenylic acid; 5' -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; 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 肺动脉高压（PH）的特征是肺血管重构和肺动脉高压的升高。 肺动脉压力，导致进行性右侧心力衰竭和死亡。越来越多的证据 表明遗传易感性、炎症和肺血管的代谢变化起着关键作用， 在PH发病机制中的作用。PH的潜在机制仍然是个谜，因为它的巨大 复杂性因此，目前对PH的治疗主要限于血管扩张。在本申请中，我们 靶向PH-胰岛素受体底物2（IRS 2）发病机制中更近端的信号中枢之一， 胰岛素抵抗和细胞能量稳态中的关键分子。因为IRS 2是 胰岛素和胰岛素生长因子信号传导，IRS 2表达的丧失促进胰岛素抵抗和II型糖尿病。 糖尿病事实上，IRS 2的丢失在多种细胞类型和疾病状况中似乎是有害的。 尽管已经研究了IRS 2在胰岛素信号传导中的作用，但关于其对胰岛素抵抗的作用知之甚少。 我们的初步数据表明，IRS 2表达与肺动脉高压的发生、发展和预后密切相关。 肺动脉高压患者造血细胞中IRS 2的表达降低， 在小鼠模型中加剧巨噬细胞活化为pro-PH表型和血管周围肌化 根据我们的数据和其他已发表的结果，我们假设IRS 2具有抗炎作用， 和抗过度增殖活性的PH的发病机制，并认为IRS 2的损失，在骨髓来源的 细胞增强血管炎症并促进过度增殖的微环境。因此，IRS 2 可能作为PH的一种新的生物标志物是有价值的，恢复IRS 2的表达和功能可能代表了PH的一种新的生物标志物。 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 肺动脉高压患者淋巴细胞IRS 2表达与临床特征的关系 高血压特定目标2将确定巨噬细胞衍生的IRS 2在以下方面的抗炎作用 肺血管重塑和PH发展，并检查IRS 2是否影响巨噬细胞 活化为pro-PH表型。具体目标3将检验IRS 2和5'腺苷 单磷酸活化蛋白激酶（AMPK）信号转导整合了几个关键途径， 肺动脉平滑肌细胞增殖和腺病毒基因治疗恢复IRS 2将 反向实验PH。该提案的目标是解开IRS 2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。因此，在本发明中， 所产生的数据将支持靶向多种下游炎症的新药剂的开发， 肿瘤和代谢介质，可用于治疗右心衰竭， 博士