Bioenergetic impairment in Group 3 pulmonary hypertension

第 3 组肺动脉高压的生物能损伤

基本信息

批准号：
10740337
负责人：
Aaron Wayne Trammell
金额：
$ 17.82万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10740337
关键词：
Acute Address Adult Affect Age Animal Model Antidiabetic Drugs Apoptotic Bioenergetics Biology Blood Platelets Blood Vessels Cardiac Myocytes Caring Chronic Chronic lung disease Clinical Clinical Management Clinical Research Clinical Trials Control Groups Cross-Over Trials Cross-Sectional Studies Dimensions Disease Energy Metabolism Environment Epidemiology Exposure to Funding Gender Glucose Goals Human Hypertension Hypoxia Impairment Intervention Knowledge Lead Lesion Ligands Lipids Lung Lung diseases Measures Mentors Mentorship Metabolic Metabolism Mitochondria Modeling Nature Outcome Outpatients Oxygen PPAR gamma Participant Pathogenesis Pathogenicity Patients Persons Pharmaceutical Preparations Phase Phenotype Pioglitazone Placebos Play Positioning Attribute Pre-Clinical Model Predisposition Production Pulmonary Circulation Pulmonary Fibrosis Pulmonary Hypertension Randomized Research Research Project Grants Respiration Respiratory Signs and Symptoms Right ventricular structure Role Safety Sampling Severities Skeletal Muscle Specimen Symptoms Testing Therapeutic Thiazolidinediones Time Tissues Training Training Programs Translating Translational Research Vasodilation Vasodilator Agents Veterans career clinical phenotype clinical trial implementation cohort disorder control disorder risk effective therapy experience extracellular high risk human old age (65+)improved in vivo individual patient innovation lung hypoxia metabolic phenotype mitochondrial metabolism mortality risk novel novel strategies overtreatment patient oriented platelet phenotype pre-clinical pressure prevent primary outcome prospective pulmonary arterial hypertension pulmonary vascular cells pulmonary vascular remodeling pulmonary vasoconstriction recruit response secondary outcome therapeutic target training opportunity translational study

项目摘要

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.

由潜在慢性肺部疾病（第 3 类，CLD-PH）引起的肺动脉高压 (PH) 是一种常见的疾病与显着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，但血管舒张疗法未能提供目前的证据表明，促增殖和抗凋亡变化。肺血管细胞通过进行性肺血管重塑改变导致 CLD-PH。线粒体能量代谢在肺血管重塑中发挥着关键作用，是一种潜在的但该提案概述了研究和培训，使 PI 能够在其基础上继续发展。 PI 的长期目标是成为一名独立的临床PH 护理和流行病学经验。以患者为导向的临床和转化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，PI 将需要在以下方面进行进一步培训：1) 实用。细胞代谢表型分析的理论方面及其在人类样本中的应用；2) 的实施；评估对 PH 患者进行机械靶向干预的前瞻性临床试验。临床前证据表明，主要代谢因子的表达和功能减少调节剂过氧化物酶体增殖物激活受体 γ (PPARγ) 在线粒体和不断变化的证据表明肺血管细胞的代谢紊乱。线粒体代谢延伸到肺血管组织之外，并在右心室中观察到心肌细胞、骨骼肌和循环血小板，表明更多的整体代谢扰动此外，临床可用的抗糖尿病药物噻唑烷二酮 (TZD) 可以激活 PPARγ。预防或逆转实验性PH。该项目的总体假设是线粒体。 CLD-PH 中的生物能紊乱反映在循环血小板中，并且可以通过 TZD 得到改善治疗目标 1 将检查血小板糖酵解和线粒体生物能功能的横截面。研究招募患有 CLD-PH 的受试者、不患有 PH 的 CLD 受试者以及健康对照。首次定义了新鲜分离的 CLD-PH 血小板的生物能功能并进行离体测试吡格列酮（TZD）治疗将涉及 2 期随机交叉试验来评估疗效。吡格列酮对 CLD-PH 患者代谢的影响吡格列酮与安慰剂的影响。将评估线粒体能量产生（主要机制结果）以及安全性和疾病该提案利用了出色的培训计划和环境以及经验丰富的多维指导团队的支持，以满足该领域的关键临床需求完成拟议的培训和研究将使 PI 具备竞争能力。成功获得独立资助并对 PH 的临床管理产生持久影响。