Peripheral Limitations in Pulmonary Hypertension and Effects of Muscle Training

项目总结/摘要 博士Yogesh Reddy，MBBS，MSc，是纽约大学心血管医学系的助理教授， 马约诊所。Reddy博士正在寻求一个指导职业发展奖，以发展所需的培训， 研究骨骼肌异常对肺动脉高压患者运动能力的影响， 动脉高血压（PAH）。Reddy医生接受过肺血管血流动力学方面的广泛培训 在他以前的培训期间在PAH下的T32补助金，提供必要的技能和经验，研究 导致PAH患者运动不耐受的中枢心血管异常。虽然针对这些疾病的治疗方法 中心局限性显著改善了PAH的临床结局，但仍存在很大的治疗差距， 90%的患者报告即使在肺血管活性药物治疗后仍有显著的残留症状。 初步研究表明，骨骼肌的外周异常可能有助于 PAH患者的运动不耐受，但尚未有研究使用金标准方法测量骨骼 PAH患者运动期间的肌肉氧（O2）利用率。为了填补这一知识空白， 为了描述PAH外周功能缺陷的特征，Reddy博士建议：1）确定 PAH患者运动能力的骨骼肌和线粒体O2转运异常与 对照，和2）进行一项随机临床试验的孤立股四头肌（膝盖伸展）为基础的训练， 评估其对PAH患者外周O2转运和全身运动能力的影响。在这份报告中，博士。 Reddy正在寻求巴里博拉格博士的主要指导，他是一位经验丰富的NIH资助的研究人员， 在肺动脉高压运动生理学方面的专业知识，他有成功的 指导初级调查员由Borlaug博士监督的导师团队包括多学科专家 谁将提供线粒体生物学（Sreekumaran Nair博士），腿领域的必要的高级培训 血流定量和运动训练干预（托马斯奥尔森博士），迭代数学建模 和生物统计学方法（Rickey Carter博士），患者报告结局（Shannon Dunlay博士）和临床试验 PAH（Robert Frantz博士）。作为拟议培训的结果，Reddy博士将获得必要的技能：1） 综合评价运动过程中线粒体和外周O2传递生理学，2）进行 运动干预的随机试验。在此期间获得的高级培训在骨骼 肌肉生物学和运动生理学将大大补充他已经获得的技能， PAH的中心血流动力学异常，使他成为一名独立资助的 临床科学家专注于PAH运动不耐受的病理生理学和治疗，了解 并“从各个角度”调查问题。所获得的数据和专业知识将构成 竞争性R 01应用集中于针对PAH患者外周功能缺损的新型治疗。

PROJECT SUMMARY/ABSTRACT Dr. Yogesh Reddy, MBBS, MSc, is an Assistant Professor in the Department of Cardiovascular Medicine at Mayo Clinic. Dr. Reddy is seeking a Mentored Career Development Award to develop the training required to study the contribution of skeletal muscle abnormalities to exercise performance in patients with Pulmonary Arterial Hypertension (PAH). Dr. Reddy has received extensive training in pulmonary vascular hemodynamics in PAH during his previous training under the T32 grant, providing necessary skills and experience to study the central cardiovascular abnormalities that drive exercise intolerance in PAH. While therapies targeted to these central limitations have markedly improved clinical outcomes in PAH, a wide therapeutic gap remains, as nearly 90% of patients report significant residual symptoms even after treatment with pulmonary vasoactive therapy. Preliminary studies have suggested that peripheral abnormalities in skeletal muscle may contribute to the exercise intolerance of patients with PAH, but no study has yet used gold standard methods to measure skeletal muscle oxygen (O2) utilization during exertion in PAH. To fill this knowledge gap and build new skills in the characterization of peripheral deficits in PAH, Dr. Reddy proposes to: 1) determine the independent role of skeletal muscle and mitochondrial O2 transport abnormalities in exercise performance in PAH compared to controls, and 2) perform a randomized clinical trial of isolated quadriceps (knee-extension) based training to assess its effect on peripheral O2 transport and whole-body exercise performance in PAH. In this proposal, Dr. Reddy is seeking the primary mentorship of Dr. Barry Borlaug, an experienced, NIH-funded investigator with expertise in exercise physiology in pulmonary hypertension, who has a proven track record of successfully mentoring junior investigators. The mentorship team supervised by Dr. Borlaug includes multidisciplinary experts who will provide necessary advanced training in the fields of mitochondrial biology (Dr. Sreekumaran Nair), leg blood flow quantification and exercise training interventions (Dr. Thomas Olson), iterative mathematical modeling and biostatistical methods (Dr. Rickey Carter), patient reported outcomes (Dr. Shannon Dunlay) and clinical trials in PAH (Dr. Robert Frantz). As a result of the training proposed, Dr. Reddy will obtain the skills necessary to: 1) comprehensively evaluate mitochondrial and peripheral O2 transfer physiology during exertion, and 2) conduct randomized trials of an exercise-based intervention. The advanced training obtained during this award in skeletal muscle biology and exercise physiology will greatly complement the skills he has already obtained characterizing central hemodynamic abnormalities in PAH, uniquely positioning him to succeed as an independently-funded clinician scientist focused on the pathophysiology and treatment of exercise intolerance in PAH, understanding and investigating the problem “from all angles”. The data derived and expertise gained will form the basis for a competitive R01 application centered on novel treatments targeting peripheral deficits for patients with PAH.