Peripheral Limitations in Pulmonary Hypertension and Effects of Muscle Training

肺动脉高压的外周局限性和肌肉训练的影响

基本信息

批准号：
10661187
负责人：
Yogesh Nellore Vilambi Reddy
金额：
$ 16.77万
依托单位：
MAYO CLINIC ROCHESTER
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：
2023-04-10 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661187
关键词：
Accelerometer Address Adopted Aerobic Exercise Affect Aftercare Age Award Biology Biopsy Biostatistical Methods Blood Vessels Blood flow Blood gas Body mass index Cardiac Output Cardiovascular Abnormalities Cardiovascular system Clinic Clinical Clinical Trials Complement Consumption Data Educational Intervention Exercise Exercise Physiology Exercise Tolerance Exertion Extensor Femur Functional disorder Funding Goals Grant Heart Heart Rate Heart failure Impairment Individual Intervention K-Series Research Career Programs Knee Knowledge Left Leg Life Lung Magnetic Resonance Imaging Measurement Measures Medicine Mentors Mentorship Methods Mitochondria Monitor Muscle Muscle Mitochondria Outcome Oxidative Stress Oxygen Participant Patient Care Patient Outcomes Assessments Patients Performance Peripheral Persons Physiology Positioning Attribute Production Pulmonary Hypertension Quality of life Questionnaires Randomized Reporting Research Personnel Residual state Respiration Role Scientist Skeletal Muscle Supination Surveys Symptoms Techniques Therapeutic Thermodilution Time Training United States National Institutes of Health Vasodilator Agents Walking Woman Work clinically significant comparison control exercise capacity exercise intolerance exercise program exercise training exhaustion experience fitbit hemodynamics improved indexing mathematical model multidisciplinary muscle form novel primary endpoint professor pulmonary arterial hypertension pulmonary vascular disorder quadriceps muscle randomized trial randomized, clinical trials recruit right ventricular failure sedentary sex skills standard of care targeted treatment time use translational clinical trial week trial

项目摘要

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.

项目概要/摘要 Yogesh Reddy 博士，MBBS，理学硕士，是心血管医学系的助理教授梅奥诊所 (Mayo Clinic) 雷迪博士正在寻求指导职业发展奖，以开展所需的培训研究骨骼肌异常对肺病患者运动表现的影响 Reddy 医生接受过肺血管血流动力学方面的广泛培训。在之前的 T32 补助金培训期间，他获得了 PAH 学位，为研究 PAH 提供了必要的技能和经验导致 PAH 运动不耐受的中枢心血管异常，而治疗则针对这些异常。中心局限性已显着改善了 PAH 的临床结果，但仍然存在很大的治疗差距，因为几乎 90% 的患者报告即使在接受肺血管活性治疗后仍有明显的残留症状。初步研究表明，骨骼肌的外周异常可能导致 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 运动期间肌肉氧气 (O2) 的利用填补这一知识空白并培养新技能。为了描述 PAH 外周缺陷的特征，Reddy 博士建议：1) 确定与对照组相比，PAH 患者运动表现中骨骼肌和线粒体 O2 运输异常对照，2) 进行一项基于孤立股四头肌（膝关节伸展）训练的随机临床试验评估其对 PAH 患者外周 O2 运输和全身运动表现的影响。 Reddy 正在寻求 Barry Borlaug 博士的主要指导，Barry Borlaug 博士是一位经验丰富、由 NIH 资助的研究员，肺动脉高压运动生理学方面的专业知识，拥有成功的记录 Borlaug 博士指导的导师团队包括多学科专家。他将提供线粒体生物学领域必要的高级培训（Sreekumaran Nair 博士），腿部血流量化和运动训练干预（托马斯·奥尔森博士），迭代数学建模和生物统计方法（Rickey Carter 博士）、患者报告结果（Shannon Dunlay 博士）和临床试验通过拟议的培训，Reddy 博士将获得以下必要的技能：1) 全面评估运动过程中线粒体和外周 O2 转移生理学，以及 2) 进行基于运动的干预的随机试验在该奖项期间获得的骨骼方面的高级培训。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 运动不耐受的病理生理学和治疗，了解并“从各个角度”调查问题。获得的数据和专业知识将构成问题的基础。竞争性 R01 应用集中于针对 PAH 患者外周缺陷的新型治疗方法。