Molecular Mechanisms of the Multi-Organ Response and Adaptation to Exercise

项目摘要 虽然体育锻炼的健康益处是普遍公认的，但其潜在的分子 机制仍然不完全确定，并可能最终被利用的治疗效益。的 运动引发的多器官广泛反应使我们对经典的 还原论者的观点。此外，器官不会孤立地作出反应， 参与器官间通讯的细胞是组织适应运动的重要组成部分。 新的蛋白质组学和代谢组学技术现在允许高通量，无偏见和整体的 哺乳动物组织内的蛋白质和代谢物的表征。重要的是，这些因素的整合 大规模技术在确定生理反应的重要机制方面显示出了希望。 该提案旨在整合蛋白质组学和代谢组学数据，研究多个器官对 锻炼的拟议的研究将在史蒂夫卡尔（蛋白质组学专家， 布罗德研究所），与领先的代谢组学和临床小组合作，通过参与 NIH物理活动分子传感器联盟（MoTrPAC）。 将采用卡尔实验室成熟的方法进行深层次的蛋白质组分析。 来自运动大鼠的组织的表征，特别是已知参与由以下引起的病症的器官： 缺乏身体活动，在运动的背景下仍然缺乏特征：心脏，肝脏和大脑。的 生成的蛋白质组学数据将与MoTrPAC提供的代谢组学数据相结合， 蛋白质依赖的代谢适应机制。最后，信号传导因子和途径 在运动的背景下，参与器官串扰的蛋白质将通过测量运动中的蛋白质分泌因子来定义。 血液对运动有反应。这项研究有望提供一个前所未有的，详细的分子观点， 通过一个有机体的途径，并预计将确定新形式的蛋白质依赖性代谢 调控由于这项工作揭示了关于组织对运动的反应的关键机制知识， 与缺乏身体活动相关的疾病直接相关，如心血管疾病。

Project Summary While the health-benefits of physical exercise are universally recognized, the underlying molecular mechanisms remain incompletely defined, and might ultimately be exploited for therapeutic benefit. The extensive response triggered by exercise across multiple organs complicates our understanding via classic reductionists approaches. Furthermore, organs do not respond in isolation, and secreted proteins factors involved in inter-organ communication are an important component of tissue adaptation to exercise. Novel proteomic and metabolomic technologies now allow high-throughput, unbiased, and holistic characterization of proteins and metabolites within mammalian tissues. Importantly, the integration of these large-scale technologies have shown promise in identifying important mechanisms of physiological responses. This proposal aims to integrate proteomics and metabolomics data to study the response of multiple organs to exercise. The proposed research will be performed under the mentorship of Steve Carr (proteomics expert, Broad Institute), in collaboration with leading metabolomics and clinical groups through participation within the NIH Molecular Transducers of Physical Activity Consortium (MoTrPAC). Well-established methods from the Carr lab will be implemented to perform deep-scale proteome characterization of tissues from exercised rats, specifically organs known to be involved in disorders caused by physical inactivity and that remain poorly characterized in the context of exercise: heart, liver, and brain. The proteomics data generated will then be integrated with metabolomic data available through MoTrPAC to define protein-dependent mechanisms of metabolic adaptation to exercise. Finally, signaling factors and pathways involved in organ cross-talk in the context of exercise will be defined by measuring protein secreted factors in blood that respond to exercise. This study is expected to provide an unprecedented, detailed view of molecular pathways across an organism and is expected to identify novel forms of protein-dependent metabolic regulation. As this work reveals key mechanistic knowledge about the response of tissues to exercise, it is directly relevant to diseases associated to physical inactivity, such as cardiovascular disease.