Meta-Analysis of Metabolic Determinants of Exercise Response in Common Funds Data

摘要 运动对健康有许多好处，但确定这些影响的分子介质仍然存在 生物医学研究的一个活跃焦点。随着组学科学的到来，包括正在进行的研究 体力活动分子传感器联合会(MoTrPAC)和多项较小规模的努力 试图绘制出对急性和慢性运动的“完整”分子反应图。许多研究目前正在进行 专注于在此类研究中整合基因组学、蛋白质组学和代谢组学数据，但另一项研究 重要的策略是对不同的数据集进行荟萃分析，以评估分子中的一致性和差异性 观察到不同锻炼方式、性别、年龄、物种和其他因素之间的反应。演习的一部分- 到目前为止，进行的相关元研究大多集中在基因组和转录组上，而很少有 包括代谢组学数据。造成这一缺陷的原因包括分析方法的差异， 复合命名和数据报告的不一致，以及非目标中未知特征的流行 代谢组学数据。未知代谢物鉴定和交叉研究整合具有挑战性，需要 协调应用计算和实验策略。然而，潜在的好处是 新代谢物的实质性鉴定和一致反应模式的检测导致了 与基础生物学和人类健康相关的生物学见解，包括锻炼。 利用NIH共同基金数据档案中的数据，我们建议开发一种多研究、多组织和 代谢组已识别和未知的运动反应特征的多条件数据库。我们会 整合研究中的数据，并在可用的情况下整合数据，以确定其中的未知因素并确定优先顺序 数据库。我们将通过两个具体目标来实现这些目标：1)我们将全面开展 MotrPAC数据中运动相关小分子特征的调查和比对 代谢组学工作台。我们将使用我们首创的代谢组学数据清理计算工具， 实验室间数据对齐，以及基于网络和关联的分析，以确定未知功能的优先顺序 后续行动。2)我们将系统地跟踪、注释和识别高优先级练习-响应未知 使用我们和其他人设计的软件和实验技术在代谢组学数据中的特征 MS/MS数据收集，用于识别和注释常规图书馆搜索无法处理的特征。我们的研究 代表着MoTrPAC的地图构建目标和详细的 通过有针对性的干预措施使人类健康受益的具体途径和潜力。我们将分享 我们的数据库和相关数据通过出版物和上传到公共数据与研究界 档案馆。我们预计我们的努力将有助于更好地了解运动的影响 并将为未来的研究提供靶点，以帮助描绘 小分子有助于它对健康的有益作用。

Abstract Exercise is associated numerous health benefits, but defining the molecular mediators of these effects remains an active focus of biomedical research. With the advent of the ‘omics sciences, studies including the ongoing Molecular Transducers of Physical Activity Consortium (MoTrPAC) and multiple smaller-scale efforts have sought to map the “complete” molecular response to acute and chronic exercise. Much research is currently focused on integration of genomics, proteomics and metabolomics data within such studies, but another important strategy is meta-analysis of distinct data sets to evaluate consistencies and differences in molecular responses observed between different modes of exercise, sex, age, species, and other factors. Of the exercise- related meta-studies performed to date, most have focused on the genome and transcriptome whereas few have included metabolomics data. Reasons for this shortcoming include differences in analytical methods, inconsistency in compound naming and data reporting, and prevalence of unknown features in untargeted metabolomics data. Unknown metabolite identification and cross-study integration is challenging and requires application of computational and experimental strategies in a coordinated manner. Yet, the potential benefits are substantial – identification of novel metabolites and detection of consistent patterns of response have led to biological insights relevant to fundamental biology and human health, including exercise. Using data from NIH Common Fund data archives, we propose to develop a multi-study, multi-organism and multi-condition database of identified and unknown exercise responsive features of the metabolome. We will integrate data across studies and, when available, across ‘omes, to prioritize and identify unknowns within this database. We will achieve these goals by carrying out two specific aims: 1) We will perform a comprehensive survey and alignment of exercise-related small molecule features in MotrPAC data and from studies in the Metabolomics Workbench. We will use computational tools we have pioneered for metabolomics data cleaning, inter-laboratory data alignment, and network- and correlation-based analysis to prioritize unknown features for follow-up. 2) We will systematically track, annotate and identify high-priority exercise-responsive unknown features in metabolomics data using software and experimental techniques we and others have devised for MS/MS data collection to identify and annotate features not tractable by routine library search. Our study represents a crucial step between the map-building aims of MoTrPAC and detailed mechanistic studies of specific pathways and that hold potential for human health benefits through targeted interventions. We will share our database and associated data with the research community through publications and uploads to public data archives. We anticipate our efforts will contribute to improved understanding of the effects of exercise at the biochemical pathway level and will offer targets for future studies to help delineate the mechanisms by which small molecules contribute to its salutary effects on health.