Metabolic Regulation of Pulmonary Vascular Remodeling

肺血管重塑的代谢调节

基本信息

批准号：
8990882
负责人：
PAUL T SCHUMACKER
金额：
$ 49.1万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8990882
关键词：
Acute Address Affect Altitude Alveolar Antioxidants Area Attenuated Blood Vessels Catabolic Process Cells Chronic Chronic lung disease Clinical Cytosol Development Disease Electron Transport Electron Transport Complex III Equilibrium Generations Genetic Glucose Glucose-6-Phosphate Glycolysis Growth Health Hexokinase 2 Human Hypoxia Hypoxia Inducible Factor Intervention Lung Lung diseases Malignant Neoplasms Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Mus NADP Outcome Oxidants Oxidation-Reduction Oxidative Phosphorylation Pathway interactions Patients Pentosephosphate Pathway Phenotype Positron-Emission Tomography Proliferating Protein Kinase Pulmonary Hypertension Pulmonary artery structure Reactive Oxygen Species Regulation Research Respiration Ribose Role Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Source System Testing Vascular Smooth Muscle Vascular remodeling Work bHLH-PAS factor HLF glucose metabolism hypoxia inducible factor 1 inorganic phosphate insight metabolic phenotype mitochondrial metabolism mouse model novel nucleotide metabolism prevent residence response sensor therapeutic target tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Pulmonary hypertension develops in patients with alveolar hypoxia arising from chronic lung diseases or high altitude exposure. These diseases affect large numbers of patients, and hypoxia-induced pulmonary vascular remodeling is the most common cause of pulmonary hypertension (PH). We propose that remodeling is triggered by mitochondrial O2 sensors that initiate redox signaling in vascular smooth muscle, thereby promoting cell contraction, growth and proliferation. Our previous work implicates mitochondria as a source of reactive oxygen species (ROS) signals that activate functional responses to acute hypoxia in pulmonary artery smooth muscle cells (PASMC). We now propose to test whether these signals also drive vascular remodeling and metabolic reprogramming in PASMC, leading to PH during chronic hypoxia. The role of ROS in PH has been highly controversial, so these studies are critically important for clarifying this issue. Chronic hypoxia activates redox signaling and induces Hypoxia-Inducible Factors (HIF-1 and HIF-2) in pulmonary vascular cells. This promotes metabolic reprogramming toward glycolysis and away from mitochondrial oxidative phosphorylation. We will test whether this reprogramming promotes vascular remodeling and PH. Hypoxia and ROS also activate AMP- dependent Protein Kinase (AMPK), a cellular energy sensor that activates catabolic pathways and inhibits anabolic metabolism, potentially opposing the remodeling response. We will determine whether AMPK activation can limit the growth, proliferation and metabolic reprogramming of PASMC, thereby opposing the development of PH. To achieve these aims we have assembled a powerful set of tools to quantify and modify redox signaling and metabolic pathways, which will be applied in genetic mouse models of PH and in pulmonary vascular cells from patients with pulmonary hypertension. These studies will provide novel insight into the mechanisms regulating the remodeling and PH arising in response to chronic hypoxia, and will identify potential therapeutic targets for the treatment of hypoxia-associated PH in humans.

描述（由申请人提供）：肺动脉高压发生在因慢性肺部疾病或高原暴露引起的肺泡缺氧的患者中。这些疾病影响大量患者，缺氧引起的肺血管重塑是肺动脉高压（PH）的最常见原因。我们认为，重塑是由线粒体 O2 传感器触发的，线粒体 O2 传感器启动血管平滑肌中的氧化还原信号，从而促进细胞收缩、生长和增殖。我们之前的工作表明线粒体是活性氧（ROS）信号的来源，可激活肺动脉平滑肌细胞（PASMC）对急性缺氧的功能反应。我们现在建议测试这些信号是否也驱动 PASMC 中的血管重塑和代谢重编程，从而导致慢性缺氧期间的 PH。 ROS 在 PH 中的作用一直备受争议，因此这些研究对于澄清这个问题至关重要。慢性缺氧会激活氧化还原信号并诱导肺血管细胞中缺氧诱导因子（HIF-1 和 HIF-2）。这促进了代谢重编程，向糖酵解方向发展，远离线粒体氧化磷酸化。我们将测试这种重编程是否促进血管重塑和 PH。缺氧和 ROS 还会激活 AMP 依赖性蛋白激酶 (AMPK)，这是一种细胞能量传感器，可激活分解代谢途径并抑制合成代谢，可能对抗重塑反应。我们将确定 AMPK 激活是否可以限制 PASMC 的生长、增殖和代谢重编程，从而阻止 PH 的发展。为了实现这些目标，我们组装了一套强大的工具来量化和修改氧化还原信号传导和代谢途径，这些工具将应用于 PH 遗传小鼠模型和肺动脉高压患者的肺血管细胞。这些研究将为调节慢性缺氧引起的重塑和PH产生的机制提供新的见解，并将确定治疗人类缺氧相关PH的潜在治疗靶点。