Bioenergetic impairment in Group 3 pulmonary hypertension

由基础慢性肺部疾病（第3组，CLD-PH）引起的肺动脉高压（PH）是常见的 与显著症状和死亡风险相关的疾病。CLD-PH发病机制的传统概念 关注缺氧性肺血管收缩的机制，但血管扩张疗法未能提供 对CLD-PH患者有益。目前的证据表明，促增殖和抗凋亡的变化， 肺血管细胞通过进行性肺血管重构导致CLD-PH。改变 线粒体能量代谢在这种肺血管重建中起关键作用， 未开发的治疗目标。该提案概述了研究和培训，使PI能够在其基础上建立 临床PH护理和流行病学经验。PI的长期目标是成为独立的 以患者为导向的临床和转化研究的合作领导者，专注于开发和评估 CLD-PH的新治疗方法。为了实现这一目标，PI将需要进一步培训：1）实践 和理论方面的细胞代谢表型和应用于人类样本;和2）进行 前瞻性临床试验，以评估PH患者的机械靶向干预措施。 临床前证据表明，主要代谢酶的表达和功能的减少， 过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体γ）在线粒体和 肺血管细胞的代谢紊乱。不断发展的证据表明， 线粒体代谢超出肺血管组织，在右心室中观察到 心肌细胞，骨骼肌和循环血小板，表明更多的全球代谢紊乱， 博士此外，临床上可用的抗糖尿病噻唑烷二酮（TZD）药物可激活PPARγ， 预防或逆转实验性PH。该项目的首要假设是， CLD-PH中的生物能量紊乱反映在循环血小板中，并且可以用TZD改善 疗法目的1将检查血小板糖酵解和线粒体生物能量功能的横截面 研究招募了患有CLD-PH的受试者、不患有PH的CLD受试者和健康对照。拟议的研究将 提供了新鲜分离的CLD-PH血小板中生物能量功能的第一个定义，并进行了离体检测。 吡格列酮（TZD）治疗。目标2将涉及一项2期随机交叉试验，以评估 吡格列酮对CLD-PH患者的代谢影响。吡格列酮与安慰剂相比对 将评估线粒体能量产生（主要机制结局）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， 支持一个经验丰富的多维导师团队，以解决该领域的关键临床需求 肺血管生物学完成拟定的培训和研究将使PI能够参与竞争 成功获得独立资金，并对PH的临床管理产生持久影响。

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.