Interventions Against the Molecular Etiology of BMPR2-induced PAH

项目摘要： ACE 2在肺动脉高压（PAH）的治疗中显示出巨大的前景。它 纠正了许多由最常见的遗传性疾病原因引起的分子缺陷， BMPR 2突变。它在多种PAH动物模型中逆转了疾病，包括遗传性， 缺氧和炎症模型。我们已经在人类特发性PAH患者中进行了急性测试， 显示出各种血流动力学和分子改善，包括40%的改善， 心输出量与肺血管阻力的相关降低。可惜因为 由于综合和交付方面的困难，很难将其转化为共同使用。 因此，了解其效果的关键介质是有效翻译这一信息的主要障碍。 非常有希望的干预。拟议的研究将确定关键分子 ACE 2在PAH背景下调节细胞骨架的下游作用机制 (aim 1），代谢（目标2），并改善右心室功能的心脏（目标3）。的 这些目标的统一假设是ACE 2的治疗作用主要是通过MAS 1- 介导的由抑制的BMPR 2引起的细胞骨架缺陷的校正。这些缺陷包括 细胞-细胞连接、线粒体动力学和eNOS的调节。该项目利用遗传 小鼠模型，包括一种新的远红报告小鼠，它允许对心脏进行非侵入性成像 压力，患者来源的内皮前体细胞，我们新的人工小动脉系统， 在细胞培养系统中再现脉动压力、刚度、流动和剪切，从而将人， 小鼠和新的细胞培养系统来回答这些问题。

Project Summary: ACE2 shows tremendous promise in the treatment of pulmonary arterial hypertension (PAH). It corrects many of the molecular defects caused by the most common heritable cause of disease, BMPR2 mutation. It has reversed disease in a variety of animal models of PAH, including heritable, hypoxic, and inflammatory models. We have tested it acutely in human idiopathic PAH patients, and shown a variety of hemodynamic and molecular improvements, including a 40% improvement in cardiac output with associated reduction in pulmonary vascular resistance. Unfortunately, because of difficulties with both synthesis and delivery, it will be difficult to translate to common use. Understanding key mediators of its effect is thus the primary barrier to effective translation of this extraordinarily promising intervention. The proposed studies will identify the key molecular mechanisms of downstream effect of ACE2 in the context of PAH, in regulation of the cytoskeleton (aim 1), metabolism (aim 2), and improvements in right ventricle function in the heart (aim 3). The unifying hypothesis to these aims is that ACE2’s therapeutic effect is primarily through MAS1- mediated correction of cytoskeletal defects caused by suppressed BMPR2. These defects include cell-cell junctions, mitochondrial dynamics, and regulation of eNOS. The project makes use of genetic mouse models, including a new far-red reporter mouse which allows non-invasive imaging of heart stress, patient-derived endothelial precursor cells, our new artificial arteriole system which accurately reproduces pulse pressure, stiffness, flow, and shear in a cell culture system, thus combining human, mouse, and new cell culture systems to answer these questions.