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

基本信息

  • 批准号:
    9122766
  • 负责人:
  • 金额:
    $ 6.41万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

 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)是一种肺血管系统的进行性疾病,可导致右心室(RV)衰竭。尽管靶向肺血管的药物可用,但PH诊断后的估计中位生存期仍然低得不可接受。RV功能是PH患者发病率和死亡率的最重要决定因素。然而,PH患者RV功能障碍的亚细胞机制尚不完全清楚。RV上的长时间压力超负荷导致组织重塑和最终收缩失败。RV在实验和人体PH中表现出糖酵解增加,表明代谢异常。实验PH中RV产生的活性氧(ROS)似乎增加,表明氧化剂信号紊乱和细胞损伤机制。由于线粒体在能量代谢、细胞存活和增殖(凋亡信号传导)以及氧化剂信号传导中的中心作用,线粒体对心肌细胞功能至关重要。然而,RV心肌细胞线粒体的缺陷还没有在人类或实验PH中进行全面测量。此外,RV的线粒体病理学和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的肺动脉带状模型中的初步数据显示,在失代偿性RV衰竭发作之前,早期线粒体变化(呼吸减少,生物发生信号增加和ROS增加)。我们推测心肌细胞线粒体形态和功能受损导致压力超负荷性肺动脉高压时RV衰竭。我们将通过在RV衰竭失代偿的时间过程中对线粒体功能进行全面评估来验证这一假设。我们将结合联合收割机的器官和组织水平的RV结构和功能的评估与线粒体呼吸,能量的能力(ATP生产),电子传递链酶的活性,和氧化剂的生产测量。这项调查将提供 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。这个NRSA将为候选人,一个肺和重症监护医学研究员,有机会开发一个研究剧目桥梁线粒体生物学与肺血管疾病。Sruti Shiva博士(基础研究和线粒体生物学专家),Mark Gladwin(肺科医生和PH专家)和Marc Simon(心脏病专家和生物力学专家)的指导团队经验,以及匹兹堡大学血管医学研究所(VMI)和心脏病学和肺医学部门的资源将确保候选人的成功培训。

项目成果

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Quyen Nguyen其他文献

Quyen Nguyen的其他文献

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{{ truncateString('Quyen Nguyen', 18)}}的其他基金

Development of Human-Selective Nerve Illumination Peptide for Surgery
开发用于手术的人类选择性神经照明肽
  • 批准号:
    9788444
  • 财政年份:
    2018
  • 资助金额:
    $ 6.41万
  • 项目类别:
Testing Fluorescently Labeled Probes for Nerve Imaging during Surgery
在手术期间测试用于神经成像的荧光标记探针
  • 批准号:
    8525398
  • 财政年份:
    2012
  • 资助金额:
    $ 6.41万
  • 项目类别:
Testing Fluorescently Labeled Probes for Nerve Imaging during Surgery
测试手术期间神经成像的荧光标记探针
  • 批准号:
    8902140
  • 财政年份:
    2012
  • 资助金额:
    $ 6.41万
  • 项目类别:
Testing Fluorescently Labeled Probes for Nerve Imaging during Surgery
在手术期间测试用于神经成像的荧光标记探针
  • 批准号:
    8399499
  • 财政年份:
    2012
  • 资助金额:
    $ 6.41万
  • 项目类别:
Testing Fluorescently Labeled Probes for Nerve Imaging during Surgery
测试手术期间神经成像的荧光标记探针
  • 批准号:
    8710216
  • 财政年份:
    2012
  • 资助金额:
    $ 6.41万
  • 项目类别:
Injectable reporters to image tumors and guide resection
可注射报告基因对肿瘤进行成像并指导切除
  • 批准号:
    8898737
  • 财政年份:
    2011
  • 资助金额:
    $ 6.41万
  • 项目类别:
Testing Surgery Guided by Molecular Fluorescence Imaging
分子荧光成像引导的测试手术
  • 批准号:
    7912902
  • 财政年份:
    2007
  • 资助金额:
    $ 6.41万
  • 项目类别:
Testing Surgery Guided by Molecular Fluorescence Imaging
分子荧光成像引导的测试手术
  • 批准号:
    7667201
  • 财政年份:
    2007
  • 资助金额:
    $ 6.41万
  • 项目类别:
Testing Surgery Guided by Molecular Fluorescence Imaging
分子荧光成像引导的测试手术
  • 批准号:
    7360551
  • 财政年份:
    2007
  • 资助金额:
    $ 6.41万
  • 项目类别:
Testing Surgery Guided by Molecular Fluorescence Imaging
分子荧光成像引导的测试手术
  • 批准号:
    7495644
  • 财政年份:
    2007
  • 资助金额:
    $ 6.41万
  • 项目类别:

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