Mitochondrial Dysfunction Underlies Right Ventricular Failure in Pulmonary Hypertension

线粒体功能障碍是肺动脉高压右心室衰竭的基础

• 批准号: 9122766
• 负责人: Quyen Nguyen
• 金额: $ 6.41万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9122766
• 关键词: Achievement; Adenosine Triphosphate; Animal Model; Antioxidants; Apoptosis; Attenuated; Basic Science; Bioenergetics; Biogenesis; Biology; Biomechanics; Blood Vessels; Calcium; Cardiac; Cardiac Myocytes; Cardiology; Cell Proliferation; Cell Survival; Cessation of life; Critical Care; Data; Defect; Development; Diagnosis; Drug Targeting; Electron Transport; Energy Metabolism; Ensure; Event; Exhibits; Failure; Functional disorder; Generations; Glycolysis; Goals; Grant; Heart; Homeostasis; Human; Hypertrophy; Institute of Medicine (U.S.); Investigation; Lung; Maintenance; Measurement; Measures; Medicine; Mentorship; Metabolic; Metabolism; Mitochondria; Modeling; Morbidity - disease rate; Morphology; Myocardial; Myocardial Contraction; Myocardial tissue; Myocardium; National Research Service Awards; Organ; Oxidants; Oxidative Phosphorylation; Pathogenesis; Pathology; Patients; Physiological; Play; Positioning Attribute; Prevention; Process; Production; Progressive Disease; Property Rights; Pulmonary Hypertension; Pulmonary artery structure; Pulmonology; Rattus; Reactive Oxygen Species; Research; Research Infrastructure; Resources; Respiration; Right Ventricular Dysfunction; Right Ventricular Function; Right Ventricular Hypertrophy; Right ventricular structure; Role; Signal Transduction; Stress; Structure; Testing; Therapeutic; Time; Tissues; Training; Universities; Vascular Diseases; Ventricular; Ventricular Remodeling; base; cell injury; enzyme activity; experience; fatty acid oxidation; hemodynamics; innovation; mitochondrial dysfunction; mortality; oxidative damage; pressure; prevent; public health relevance; pulmonary arterial hypertension; response; targeted treatment; treatment strategy

 DESCRIPTION (provided by applicant): Pulmonary hypertension (PH) is a progressive disease of the pulmonary vasculature which leads to right ventricular (RV) failure. Despite the availability of drugs targeting the pulmonary vasculature, estimated median survival after diagnosis of PH remains unacceptably low. RV function is the most important determinant of morbidity and mortality in patients with PH. However, the subcellular mechanisms underlying RV dysfunction in PH are not completely clear. Prolonged pressure overload on the RV leads to tissue remodeling and eventual contractile failure. The RV exhibits increased glycolysis in experimental and human PH, suggesting abnormal metabolism. Reactive oxygen species (ROS) generation by the RV in experimental PH appears to be increased, suggesting deranged oxidant signaling and a mechanism for cell damage. Mitochondria are vital to cardiac myocyte function owing to their central role in energy metabolism, cell survival and proliferation (apoptosis signaling), and oxidant signaling. However, defects in RV cardiac myocyte mitochondria have not been comprehensively measured in human or experimental PH. Furthermore, the chronological relationship between mitochondrial pathology and structural or hemodynamic dysfunction of the RV is not known. Our preliminary data in a pulmonary artery banding model of PH shows early mitochondrial changes (decreased respiration, increased biogenesis signaling, and increased ROS) prior to the onset of decompensated RV failure. We hypothesize that impaired cardiac myocyte mitochondrial morphology and function causes RV failure in pressure overload pulmonary hypertension. We will test this hypothesis by performing a comprehensive assessment of mitochondrial function over the time course of RV failure decompensation. We will combine the assessment of organ- and tissue-level RV structure and function with measurements of mitochondrial respiration, energetic capacity (ATP production), electron transport chain enzyme activity, and oxidant production. This investigation will offer the first steps to the development of mitochondrial targeted therapeutic strategies for the treatment of RV failure in PH. Moreover, understanding the time course of mitochondrial dysfunction and RV biomechanical changes could guide time-based strategies for delivering existing therapeutics. This NRSA will provide the candidate, a pulmonary and critical care medicine fellow, with an opportunity to develop a research repertoire bridging mitochondrial biology with pulmonary vascular disease. The experience of mentorship team Drs. Sruti Shiva (expert in basic research and mitochondrial biology), Mark Gladwin (pulmonologist and expert in PH), and Marc Simon (cardiologist and expert in biomechanics), and resources at the Vascular Medicine Institute (VMI) at the University of Pittsburgh and the Divisions of Cardiology and Pulmonary Medicine will ensure the candidate's successful training.

 描述（由申请人提供）：肺动脉高压（PH）是肺血管系统的一种进行性疾病，会导致右心室（RV）衰竭，尽管有针对肺血管系统的药物，但诊断 PH 后的估计中位生存率仍然低得令人无法接受。右心室功能是 PH 患者发病和死亡的最重要决定因素。然而，右心室功能障碍的亚细胞机制尚不完全清楚。 RV 在实验和人类 PH 值中表现出糖酵解增加，表明在实验 PH 值中 RV 产生的活性氧 (ROS) 似乎增加，表明氧化信号紊乱和细胞机制。线粒体对心肌细胞功能至关重要，因为它们在能量代谢、细胞存活和增殖（细胞凋亡信号传导）以及氧化信号传导中发挥着核心作用。然而，RV 心肌细胞线粒体的缺陷尚未得到解决。此外，线粒体病理学与 RV 结构或血流动力学功能障碍之间的时间关系尚不清楚，我们在 PH 肺动脉带模型中的初步数据显示早期线粒体变化（呼吸减少、生物发生信号传导增加）。在失代偿性 RV 衰竭发生之前，我们发现心肌细胞线粒体形态和功能受损会导致压力超负荷肺动脉高压时的 RV 衰竭。我们将通过对线粒体进行全面评估来检验这一假设。我们将对器官和组织水平的 RV 结构和功能的评估与线粒体呼吸、能量容量（ATP 产生）、电子传递链酶活性和氧化剂产生的测量结合起来。调查将提供 此外，了解线粒体功能障碍和 RV 生物力学变化的时间过程可以指导基于时间的策略来提供现有的治疗方法。肺和重症监护医学研究员，有机会开发将线粒体生物学与肺血管疾病联系起来的研究库。导师团队 Sruti Shiva 博士（基础研究和线粒体生物学专家）的经验。 Gladwin（肺病学家和肺动脉高压专家）和 Marc Simon（心脏病学家和生物力学专家）以及匹兹堡大学血管医学研究所 (VMI) 以及心脏病学和肺病学部门的资源将确保候选人的成功培训。