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.

项目摘要心力衰竭的定义发病率（HF）是运动intlerance，它降低了现有的生活质量目的地疗法。目前，以心脏康复形式的规定运动可以提供好处，但未充分利用，因此有必要更好地了解负责运动的分子传感器益处。有证据表明，心脏特异性适应运动在HF患者中被静音，因此外周假设在脉管系统水平上的适应性在中介运动中提高了重要性好处。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外基质（ECM）蛋白的循环水平之间存在关联和运动适应。这就是研究策略在之前和之后利用Olink蛋白质组学分析锻炼训练以检验以下假设：血管ECM的变化与运动适应有关特别是在HF患者中与健康成年人相比。在AIM 1中，申请人Daniel Katz博士将分析从体育活动联盟（MOTRPAC）的分子传感器到的Olink蛋白质组学数据到阐明血管ECM蛋白以及其他蛋白质之间的关系，并在健康的成年人。机器学习技术还将区分分子适应反应亚型。在 AIM 2，90例非缺血性心肌病患者，射血分数<35％将被随机分为 12周的心脏康复与无康复的12周。运动测试和血浆样品（用于蛋白质组学分析将在干预期之前和之后获得。血管之间的关系 ECM蛋白质以及其他蛋白质以及运动训练将被确定并与健康进行比较来自Motrpac的成年人。在AIM 3中，确定血管ECM蛋白的血浆水平的遗传变异， AIM 1和2中确定的其他蛋白质将被杠杆用于Mendelian随机化以支持A 与心血管健康结果的因果关系。 Katz博士以先前的蛋白质组学培训为基础，并产生了25 自2013年以来的出版物（第13名或联合第一作者）。职业发展计划将提供新的培训运动生理学和测试，临床试验，生物信息学，机器学习和遗传因果分析，通过沉浸和课程工作。导师Euan Ashley博士是运动生理学和培训专家，遗传学和精密医学。 Robert Gerszten博士是多派的专家，尤其是Olink 蛋白质组学，并且都在Motrpac蛋白质组学工作组上合作。博士。马修·惠勒（Matthew Wheeler）（生物信息学），乔恩·迈尔斯（Jon Myers）（运动测试和试验）和迈克尔·斯奈德（Michael Snyder）（运动生物学）提供作为顾问的免费专业知识。拟议的工作一起增强了对锻炼的理解适应，并支持未来将分析扩展到外围组织样品的努力（例如肌肉，脂肪）为了更好地理解HF作为治疗目标的外围运动适应，这是计划中的R01的主题。