Identifying Proteomic Markers of Exercise Training in Heart Failure

项目摘要 心力衰竭(HF)的定义发病率是运动不耐受，它降低了生活质量，尽管存在 治疗。目前，以心脏康复的形式进行的处方运动可以提供益处，但 未得到充分利用，因此有必要更好地了解负责运动的分子转导 利益。有证据表明，心力衰竭患者对运动的心脏特异性适应减弱，因此是外周的。 假设血管系统水平上的适应在调节运动中的重要性增加。 利益。为了支持这一假设，来自健康成年人的初步数据使用高通量蛋白质组 图谱显示循环中血管细胞外基质(ECM)蛋白水平之间存在关联 和运动适应。因此，该研究策略利用了Olink蛋白质组学前后的分析 运动训练，以检验血管内皮细胞的变化与运动适应有关的假设， 特别是在与健康成人相比的心力衰竭患者中。在目标1中，申请者丹尼尔·卡茨博士将 分析来自体力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的关系 健康的成年人。机器学习技术也将区分分子适应反应亚型。在……里面 目的：90名非缺血性心肌病心衰患者，射血分数<35%将被随机分为 12周的心脏康复与12周的不康复。运动测试和血浆样本(用于 蛋白质组图谱)将在干预期前后获得。血管与血气的关系 ECM蛋白质以及其他蛋白质和运动训练将被测定并与健康进行比较 来自MoTrPAC的成年人。在目标3中，决定血浆血管ECM蛋白水平的基因变体， 和在AIMS 1和2中确定的其他蛋白质，将被用于孟德尔随机化以支持 与心血管健康结果的因果联系。卡茨博士建立在之前的蛋白质组学训练的基础上，已经产生了25 自2013年以来出版了13本(第一作者或联合第一作者)。职业发展计划将在以下方面提供新的培训 运动生理学和测试、临床试验、生物信息学、机器学习和遗传原因分析， 通过沉浸和课程学习。导师尤安·阿什利博士是运动生理学和训练方面的专家， 遗传学和精准医学。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，两人都在MoTrPAC蛋白质组工作组合作。马修·惠勒博士 (生物信息学)、Jon Myers(运动测试和试验)和Michael Snyder(运动生物学)提供 作为顾问提供免费的专业知识。总之，拟议的工作加强了对锻炼的理解 适应，并支持今后将侧写扩展到外围组织样本(例如肌肉、脂肪)的努力 为了更好地了解心衰患者的外周运动适应作为治疗目标，计划进行R01试验。

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.