Insulin Receptor Substrate Signaling in Pulmonary Hypertension

摘要 肺动脉高压(PH)的特征是肺血管重构和升高。 导致进行性右心衰竭和死亡的肺动脉压力。越来越多的证据 表明遗传易感性、炎症和肺血管代谢改变起着关键作用。 在PH发病机制中的作用。PH背后的机制仍然是个谜，因为它具有巨大的 复杂性。因此，目前对PH的治疗主要局限于血管扩张。在此应用程序中，我们 靶向PH-胰岛素受体底物2(IRS2)发病机制中较近的信号中枢之一， 胰岛素抵抗和细胞能量动态平衡的关键分子。因为IRS2是主要的调节器 胰岛素和胰岛素生长因子信号转导，IRS2表达缺失促进胰岛素抵抗和II型 糖尿病。事实上，IRS2的缺失在多种细胞类型和疾病条件下似乎是有害的。 虽然已经研究了IRS2在胰岛素信号转导中的作用，但对其在胰岛素信号转导中的作用知之甚少 心肺病理生理学，包括在PH中见到的。我们的初步数据显示IRS2的表达 在肺动脉高压患者的造血细胞中是减少的和IRS2缺失 在小鼠模型中促进巨噬细胞活化为促PH表型和血管周围肌化 PH值。根据我们的数据和其他发表的结果，我们假设IRS2具有抗炎作用 和抗增殖活性在PH的发病机制中的作用，以及骨髓来源的IRS2的丢失 细胞可增强血管炎症，促进过度增殖的微环境。因此，IRS2 可能是一种新的PH生物标志物，恢复IRS2的表达和功能可能代表一种 多因素PH病理生理学的新治疗靶点。特定目标1将调查两者之间的相关性 淋巴样细胞IRS2的表达与肺动脉高压患者临床特征的关系 高血压。特异性靶点2将确定巨噬细胞来源的IRS2的抗炎作用 肺血管重塑和肺高压的发展及检测IRS2是否影响巨噬细胞 激活为促PH表型。特殊目标3将检验IRS2和5‘腺苷的假设 单磷酸激活的蛋白激酶(AMPK)信号通路整合了几个关键的信号通路 肺血管平滑肌细胞增殖及腺病毒基因治疗恢复IRS2的研究 逆转实验PH值。这项提议的目标是解开IRS2未被认识到的保护作用- 具体地说，它能够抑制炎症和在PH发展过程中的过度增殖活动。因此， 产生的数据将支持以多个下游炎症为靶点的新制剂的开发， 这一途径的肿瘤和代谢介质可用于治疗右心衰竭和 pH值

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.