Bioenergetic impairment in Group 3 pulmonary hypertension

慢性肺病所致的肺动脉高压(第三组，CLD-PH)是常见的 与显著症状和死亡风险相关的疾病。慢性阻塞性肺疾病发病机制的传统观念 关注缺氧性肺血管收缩的机制，但血管扩张治疗未能提供 对CLD-PH患者的好处。目前的证据表明，促增殖和抗凋亡的变化在 肺血管细胞通过进行性肺血管重塑导致CLD-PH。更改后的 线粒体能量代谢在肺血管重塑中起关键作用，是一种潜在的 未开发的治疗目标。这份提案概述了研究和培训，使PI能够在HIS的基础上 具有PH值临床护理和流行病学经验。PI的长期目标是成为一名独立的 面向患者的临床和转化性研究领域的合作领导者，专注于开发和评估 CLD-PH的新治疗方法。为了实现这一目标，和平倡议将需要在以下方面进行进一步的培训：1)实用 和理论方面的细胞代谢表型及其在人类样本中的应用；以及2)进行 评估PH患者机械性靶向干预的前瞻性临床试验。富饶 临床前证据表明，主要代谢产物表达和功能的减少 过氧化物酶体增殖物激活受体γ(PPARγ)调节因子在线粒体和线粒体中发挥重要作用。 肺血管细胞代谢紊乱。不断发展的证据表明，不正常的 线粒体代谢超越肺血管组织，见于右心室。 心肌细胞、骨骼肌和循环中的血小板，提示更多的全球代谢紊乱 pH值此外，用临床上可用的抗糖尿病、噻唑烷二酮(TZD)药物激活PPARγ可以 预防或逆转实验性PH。这个项目的首要假设是线粒体 CLD-PH的生物能量紊乱反映在循环中的血小板中，TZD可以改善这一现象 心理治疗。目的1将在横断面上检查血小板糖酵解和线粒体生物能量功能 研究招募患有慢性阻塞性肺疾病的患者、无慢性阻塞性肺疾病的患者和健康对照组。拟议的研究将 首次定义新鲜分离的CLD-PH血小板的生物能量功能并进行体外试验 用吡格列酮(一种TZD)治疗。AIM 2将包括2期随机交叉试验，以评估 吡格列酮对慢性阻塞性肺疾病患者代谢的影响吡格列酮与安慰剂对血管紧张素转换酶活性的影响 将评估线粒体能量产生(主要机制结果)以及安全性和疾病 疗效(次要结果)。该提案利用了出色的培训计划和环境， 支持一支经验丰富的多层面指导团队，以满足以下领域的关键临床需求 肺血管生物学。完成拟议的培训和研究将使PI能够参加竞争 成功获得独立资金，并对PH的临床管理产生持久的影响。

Pulmonary hypertension (PH) resulting from underlying chronic lung disease (Group 3, CLD-PH) is a common disorder associated with significant symptoms and risk of death. Traditional concepts of CLD-PH pathogenesis focus on mechanisms of hypoxic pulmonary vasoconstriction yet vasodilating therapies have failed to provide benefit for CLD-PH patients. Current evidence indicates that pro-proliferative and anti-apoptotic changes in pulmonary vascular cells lead to CLD-PH through progressive pulmonary vascular remodeling. Altered mitochondrial energy metabolism plays a key role in this pulmonary vascular remodeling and is a potential but unexploited treatment target. This proposal outlines research and training that will enable the PI to build on his experience in clinical PH care and epidemiology. The PI’s long-term goal is to become an independent collaborative leader in patient-oriented clinical and translational research focused on developing and evaluating novel treatment approaches for CLD-PH. To achieve this goal, the PI will require further training in: 1) practical and theoretical aspects of cellular metabolic phenotyping and application to human samples; and 2) conduct of prospective clinical trials to assess mechanistically-targeted interventions in patients with PH. Abundant preclinical evidence demonstrates that reductions in the expression and function of the major metabolic regulator, peroxisome proliferator-activated receptor gamma (PPARγ), play a critical role in mitochondrial and metabolic derangements in pulmonary vascular cells. Evolving evidence demonstrates that abnormal mitochondrial metabolism extends beyond pulmonary vascular tissues and is observed in right ventricle cardiomyocytes, skeletal muscle, and circulating platelets, suggesting more global metabolic perturbations in PH. Further, activation of PPARγ with clinically available, antidiabetic, thiazolidinedione (TZD) medications can prevent or reverse experimental PH. The overarching hypothesis for this project is that mitochondrial bioenergetic derangements in CLD-PH are reflected in circulating platelets and can be improved with TZD therapy. Aim 1 will examine platelet glycolytic and mitochondrial bioenergetic function in a cross-sectional study recruiting subjects with CLD-PH, CLD without PH, and healthy controls. The proposed studies will provide the first definition of bioenergetic function in freshly isolated CLD-PH platelets and test for ex vivo treatment with pioglitazone (a TZD). Aim 2 will involve a phase 2 randomized cross-over trial to assess the metabolic impact of pioglitazone in CLD-PH patients. The influence of pioglitazone versus placebo on mitochondrial energy production will be assessed (primary mechanistic outcome) as well as safety and disease efficacy (secondary outcomes). The proposal leverages an outstanding training plan and environment with the support of an experienced multi-dimensional mentorship team to address a critical clinical need in the field of pulmonary vascular biology. Completion of the proposed training and studies will position the PI to compete successfully for independent funding and exert durable impact on the clinical management of PH.