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Metabolic Regulation of Pulmonary Vascular Remodeling

肺血管重塑的代谢调节

基本信息

批准号：
9197683
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 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9197683
关键词：
Acute Address Affect Altitude Alveolar Antioxidants Area Attenuated Blood Vessels Catabolic Process Cells Chronic Chronic lung disease Clinical Cyclic AMP-Dependent Protein Kinases Cytosol Development Disease Electron Transport Electron Transport Complex III Equilibrium Generations Genetic Glucose Glucose-6-Phosphate Glycolysis Growth 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 Pharmacology 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 public health relevance 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）：慢性肺病或高海拔暴露引起的肺泡缺氧患者会发生肺动脉高压。这些疾病影响大量患者，并且缺氧诱导的肺血管重构是肺动脉高压（PH）的最常见原因。我们认为重塑是由线粒体O2传感器引发的，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。我们以前的工作涉及线粒体作为活性氧（ROS）信号的来源，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一问题至关重要。慢性缺氧激活肺血管细胞氧化还原信号并诱导缺氧诱导因子（HIF-1和HIF-2）。这促进代谢重编程朝向糖酵解并且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还激活AMP依赖性蛋白激酶（AMPK），AMPK是一种细胞能量传感器，其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，从而反对PH的发展。为了实现这些目标，我们已经组装了一套强大的工具来量化和修改氧化还原信号和代谢途径，这将应用于PH的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。