Identifying Proteomic Markers of Exercise Training in Heart Failure

识别心力衰竭运动训练的蛋白质组标记

基本信息

批准号：
10663612
负责人：
Daniel Hunter Katz
金额：
$ 19.41万
依托单位：
STANFORD 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：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663612
关键词：
Address Adipose tissue Adult Angiopoietin-2 Area Attention Bioinformatics Biological Biological Process Biology Biopsy Blood Vessels Cardiac Cardiac rehabilitation Cardiomyopathies Cardiopulmonary Cardiovascular system Classification Clinical Clinical Trials Collaborations Data Development Development Plans Disease Drug Targeting EFRAC Endoglin Enrollment Exercise Exercise Physiology Exercise Test Extracellular Matrix Extracellular Matrix Proteins Future Genetic Genetic Medicine Genetic Techniques Heart failure Human Immersion Intervention Investigation Life Link MME gene Machine Learning Measures Mediating Mediator Mendelian randomization Mentors Methods Molecular Molecular Profiling Morbidity - disease rate Muscle Myocardial dysfunction Nature Outcome Participant Pathway interactions Patients Performance Peripheral Pharmacotherapy Physical activity Physiological Plasma Play Population Population Study Protein Tyrosine Kinase Proteins Proteomics Protocols documentation Publications Quality of life Randomized Rehabilitation therapy Research Sampling Shortness of Breath Standardization Stimulus Subgroup Symptoms Techniques Testing Tissue Sample Tissues Training Transducers Treatment Failure Vascular Endothelium Work adverse outcome biobank cardiovascular health career development cohort exercise intolerance exercise prescription exercise training experience genetic variant improved instrument interest link protein machine learning algorithm multiple omics novel population based precision medicine prevent proteomic signature reduce symptoms response symptomatic improvement targeted treatment therapeutic target trait working group

项目摘要

Project Summary The defining morbidity of heart failure (HF) is exercise intolerance, which reduces quality of life despite existing therapies. Currently, prescribed exercise in the form of cardiac rehabilitation can provide benefit, but is underutilized, thus there is a need to better understand the molecular transducers responsible for exercise’s benefit. Evidence suggests that cardiac-specific adaptation to exercise is muted in HF patients, thus peripheral adaptation at the level of the vasculature is hypothesized to be of increased importance in mediating exercise benefit. In support of this hypothesis, preliminary data from healthy adults using high-throughput proteomic profiling demonstrates an association between circulating levels of vascular extracellular matrix (ECM) proteins and exercise adaptation. Thus, the Research Strategy leverages Olink proteomic profiling before and after exercise training to test the hypothesis that changes in vascular ECM are associated with exercise adaptation, particularly among HF patients as compared to healthy adults. In Aim 1, the applicant Dr. Daniel Katz, will analyze Olink proteomic data from the Molecular Transducers of Physical Activity Consortium (MoTrPAC) to elucidate the relationship between vascular ECM proteins, as well as other proteins, and exercise training in healthy adults. Machine learning techniques will also differentiate molecular adaptation response subtypes. In Aim 2, 90 HF patients with non-ischemic cardiomyopathy and an ejection fraction < 35% will be randomized to 12 weeks of cardiac rehabilitation vs 12 weeks of no rehabilitation. Exercise testing and plasma samples (for proteomic profiling) will be obtained before and after the intervention period. The relationship between vascular ECM proteins, as well as other proteins, and exercise training will be determined and compared to healthy adults from MoTrPAC. In Aim 3, genetic variants which determine plasma levels for vascular ECM proteins, and other proteins identified in Aims 1 and 2, will be leveraged for Mendelian Randomization to support a causal link to cardiovascular health outcomes. Dr. Katz builds on prior proteomic training, and has produced 25 publications (13 as first or co-first author) since 2013. The career development plan will provide new training in exercise physiology and testing, clinical trials, bioinformatics, machine learning, and genetic causal analysis, through immersion and course work. Mentor Dr. Euan Ashley is an expert in exercise physiology and training, genetics, and precision medicine. Co-mentor Dr. Robert Gerszten is an expert in multi-omics, especially Olink proteomics, and both collaborate on the MoTrPAC proteomic working group. Drs. Matthew Wheeler (bioinformatics), Jon Myers (exercise testing and trials), and Michael Snyder (exercise biology) offer complimentary expertise as advisors. Together, the proposed work enhances understanding of exercise adaptation, and supports future efforts to expand profiling into peripheral tissue samples (e.g. muscle, adipose) to better understand peripheral exercise adaptation in HF as a therapeutic target, the subject of a planned R01.

项目概要心力衰竭（HF）的定义发病率是运动不耐受，尽管存在运动不耐受，但它会降低生活质量目前，以心脏康复形式进行的规定运动可以提供益处，但也有一定的局限性。未得到充分利用，因此需要更好地了解负责运动的分子传感器有证据表明，心力衰竭患者的心脏对运动的特异性适应性减弱，因此是外周益处。脉管系统水平的适应在调节运动中变得越来越重要为了支持这一假设，使用高通量蛋白质组学的健康成年人的初步数据。分析表明血管细胞外基质 (ECM) 蛋白的循环水平之间存在关联因此，研究策略在前后利用了 Olink 蛋白质组分析。运动训练来检验血管 ECM 变化与运动适应相关的假设，尤其是在心力衰竭患者中，与健康成年人相比，在目标 1 中，申请人 Daniel Katz 博士将这样做。分析来自体能活动联盟分子传感器 (MoTrPAC) 的 Olink 蛋白质组数据阐明血管 ECM 蛋白以及其他蛋白与运动训练之间的关系健康的成年人也将区分分子适应反应亚型。目标 2，90 名患有非缺血性心肌病且射血分数 < 35% 的 HF 患者将被随机分配到 12 周心脏康复与 12 周无康复运动测试和血浆样本（针对。蛋白质组分析）将在干预期之前和之后获得。 ECM 蛋白质以及其他蛋白质和运动训练将被确定并与健康的进行比较在目标 3 中，决定血管 ECM 蛋白血浆水平的基因变异，以及目标 1 和 2 中确定的其他蛋白质，将利用孟德尔随机化来支持 Katz 博士以之前的蛋白质组学培训为基础，得出了 25 个结果的因果关系。自 2013 年以来已发表论文（13 篇作为第一或共同第一作者）。职业发展计划将提供以下方面的新培训：运动生理学和测试、临床试验、生物信息学、机器学习和因果遗传分析，通过沉浸式学习和课程学习，导师 Euan Ashley 博士是运动生理学和训练方面的专家，共同导师 Robert Gerszten 博士是多组学方面的专家，尤其是 Olink。蛋白质组学，并且两人在 MoTrPAC 蛋白质组学工作组中进行合作。（生物信息学）、Jon Myers（运动测试和试验）和 Michael Snyder（运动生物学）提供作为顾问的互补专业知识共同增强了对运动的理解。适应，并支持未来将分析扩展到外周组织样本（例如肌肉、脂肪）的努力更好地了解心力衰竭的外周运动适应作为治疗目标，这是计划的 R01 的主题。