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:
  • 金额:
    $ 19.41万
  • 依托单位:
  • 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

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(HF)的定义发病率是运动不耐受,尽管存在运动不耐受,但运动不耐受会降低生活质量。 治疗目前,以心脏康复形式的规定运动可以提供益处,但是, 因此,有必要更好地了解负责运动的分子转换器。 效益有证据表明,HF患者对运动的心脏特异性适应是沉默的,因此外周血淋巴细胞减少。 假设血管水平的适应在调节运动中具有增加的重要性 效益为了支持这一假设,使用高通量蛋白质组学技术从健康成年人中获得的初步数据显示, 分析表明血管细胞外基质(ECM)蛋白的循环水平之间的关联 和运动适应。因此,研究策略利用Olink蛋白质组学分析前后, 运动训练以检验血管ECM的变化与运动适应相关的假设, 特别是在HF患者中与健康成人相比。在目标1中,申请人丹尼尔卡茨博士将 分析来自身体活动分子传感器联盟(MoTrPAC)的Olink蛋白质组数据, 阐明血管ECM蛋白以及其他蛋白质与运动训练之间的关系, 健康成人机器学习技术还将区分分子适应反应亚型。在 目的2,90例射血分数< 35%的非缺血性心肌病HF患者将被随机分配至 12周心脏康复vs 12周无康复。运动试验和血浆样本(用于 蛋白质组分析)将在干预期之前和之后获得。血管与 ECM蛋白质,以及其他蛋白质,和运动训练将被确定,并与健康相比, 来自MoTrPAC的成年人。在目标3中,确定血管ECM蛋白的血浆水平的遗传变体, 以及目标1和2中鉴定的其他蛋白质,将用于孟德尔随机化,以支持 与心血管健康结果的因果关系。Katz博士建立在先前的蛋白质组学培训的基础上, 自2013年以来发表的论文(13篇为第一作者或共同第一作者)。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博士是多组学专家,尤其是Olink 蛋白质组学,并在MoTrPAC蛋白质组学工作组合作。马修惠勒博士 (生物信息学),乔恩迈尔斯(运动测试和试验),和迈克尔斯奈德(运动生物学)提供 作为顾问的专业知识。总之,拟议的工作提高了对运动的理解 适应,并支持未来努力将分析扩展到外周组织样本(例如肌肉、脂肪) 为了更好地理解HF中作为治疗靶点的外周运动适应,计划R01的受试者。

项目成果

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Daniel Hunter Katz其他文献

Daniel Hunter Katz的其他文献

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