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.

抽象的 肺动脉高压（pH）的特征是肺血管重塑并升高 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 表明肺脉管系统的遗传敏感性，炎症和代谢转移 在pH发病机理中的作用。 pH基础的机制由于其巨大 复杂。因此，当前的pH疗法主要限于血管舒张。在此应用程序中，我们 靶向pH-胰岛素受体底物2（IRS2）， 胰岛素抵抗和细胞能量稳态中的关键分子。因为IRS2是 胰岛素和胰岛素生长因子信号传导，IRS2表达的丧失促进胰岛素抵抗和II型 糖尿病。实际上，在多种细胞类型和疾病状况中，IRS2的丧失似乎是有害的。 尽管IRS2在胰岛素信号传导中的作用已经研究了，但对其对其对的贡献知之甚少 心肺病理生理学，包括pH中看到的病理学。我们的初步数据表明IRS2表达 肺动脉高压患者的造血细胞中降低，IRS2缺失 加剧了巨噬细胞激活对PH表型的激活，而小鼠模型中的血管周肌肉化 ph。根据我们的数据和其他已发布的结果，我们假设IRS2具有抗炎作用 和pH发病机理中的抗Hyper增殖活性，以及​​骨髓衍生的IRS2丧失 细胞增强血管感染并促进过度增殖的微环境。因此，IRS2 作为pH的新型生物标志物可能很有价值，并且还原IRS2表达和功能可能代表 多因素pH病理生理学的新型热靶标。特定目标1将调查相关性 淋巴样细胞中IRS2表达与肺动脉患者的临床特征之间 高血压。特定的目标2将确定巨噬细胞衍生的IRS2在 肺血管重塑以及pH的发展和检查IRS2是否影响巨噬细胞 激活对PH表型。特定目标3将检验IRS2和5'腺苷的假设 单磷酸激活的蛋白激酶（AMPK）信号传导整合了在 肺动脉平滑肌细胞增殖和腺病毒基因治疗恢复IRS2将会 反向实验pH。该提案的目的是揭示IRS2的未被认可的受保护作用。 它在pH发育过程中抑制注射和过度增长活性的能力。那， 生成的数据将支持针对多个下游炎症的新药物的开发， 该途径的肿瘤和代谢介体可用于治疗正确的心力衰竭和 ph。