Peripheral Limitations in Pulmonary Hypertension and Effects of Muscle Training

项目摘要/摘要 Yogesh Reddy博士，MBBS，理学硕士，心血管内科助理教授 梅奥诊所。雷迪博士正在寻求一项有指导的职业发展奖，以发展所需的培训 肺心病患者骨骼肌异常对运动能力影响的研究 动脉高压(PAH)。雷迪医生在肺血管血流动力学方面接受了广泛的培训 在他之前的T32资助下的培训期间，提供了必要的技能和经验来学习 导致帕金森病患者运动不耐受的中枢心血管异常。虽然针对这些人的治疗 中心性限制显著改善了PAH的临床结果，仍有很大的治疗差距，因为 90%的患者报告有明显的残留症状，即使在接受肺血管活性治疗后也是如此。 初步研究表明，骨骼肌中的外周异常可能与 PAH患者的运动不耐受，但尚未有研究使用金标准方法来测量骨骼 PAH运动过程中肌肉氧的利用。要填补这一知识空白，并在 对于PAH外周缺陷的特征，雷迪博士建议：1)确定 PAH患者运动能力中骨骼肌和线粒体氧转运异常的比较 对照，以及2)进行基于孤立股四头肌(伸膝)的训练的随机临床试验 评价其对PAH患者外周血氧转运和全身运动能力的影响。在这项提案中，Dr。 雷迪正在寻求巴里·博洛格博士的主要指导，巴里·博洛格博士是一名经验丰富的、由NIH资助的研究员， 在肺动脉高压的运动生理学方面的专业知识，谁有成功的跟踪记录 指导初级调查员。博洛格博士指导的导师团队包括多学科专家 世卫组织将在线粒体生物学领域提供必要的高级培训(Sreekumaran Nair博士)，LEG 血流量化和运动训练干预(Thomas Olson博士)，迭代数学建模 和生物统计学方法(Rickey Carter博士)、患者报告的结果(Shannon Dunlay博士)和临床试验 在PAH(Robert Frantz博士)。作为拟议的培训的结果，雷迪博士将获得必要的技能，以：1) 综合评价运动过程中线粒体和外周组织氧传递生理学，2)传导 以运动为基础的干预的随机试验。在该奖项中获得的骨骼高级训练 肌肉生物学和运动生理学将极大地补充他已经获得的表征技能 PAH的中枢血流动力学异常，使他成为一名独立资助的成功人士 临床科学家专注于PAH运动耐量不足的病理生理和治疗，了解 并“从各个角度”调查问题。得出的数据和获得的专业知识将构成 竞争性的R01应用集中在针对PAH患者外周缺陷的新治疗上。

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.