A Biochemical Roadmap of Exercise Signaling

项目摘要/摘要 运动是预防和治疗心脏代谢性疾病的有效干预措施，但 锻炼对健康有益的机械基础仍未完全确定。近期工作 强调器官间回路在调节健康运动反应中的重要性。我们确认了β- 氨基异丁酸(BAIBA)作为一种新的促进棕色表达的小分子“肌动因子” 在体外，脂肪细胞特异性基因，并改善葡萄糖处置和减少小鼠的体重增加。在……里面 人类，血浆BAIBA浓度随着慢性运动的增加而增加，并表现出强烈的反转 与代谢危险因素有关。我们的团队也一直在组织内表征方面处于领先地位 对运动和饮食干预的反应。 这些经历，再加上研究问题的高度翻译相关性，促使我们采取 在人体和动物模型中研究运动对健康益处的一种系统方法。对这件事 最后，我们成立了一个多机构、多组学的中心，在这个中心的支持下进行合作研究 国家卫生研究院的MoTrPAC计划。我们的核心建立在杜克大学和哈佛大学团队之间持续的合作基础上 以及在代谢组学和蛋白质组学技术方面优势互补的博德研究所 在心脏代谢研究方面有数十年的经验。核心将提供深入的分析工具菜单，以 靶向和非靶向代谢组学、蛋白质图谱和关键蛋白质翻译后分析 修改。每个核心组件都有处理大样本集的记录，并且很好地- 准备分析一个国家产生的预计数以万计的组织和血液样本 研究动物和人类队列中的运动干预的研究人员联盟。 我们团队的另一个特点是能够将来自MoTrPAC的新发现与之前的 从大量人类队列中收集基因组、蛋白质组和代谢组数据。我们假设 运动中人体组织和血液的代谢组和蛋白质组学与遗传学的结合 而详细的人类表型分析将为器官间回路和器官内提供新的见解 调节运动有益效果的反应。所有的主要数据都由这个多- 学科建议将通过一个新的信息门户网站迅速提供给科学界，网址为 布罗德学院。重要的是，这一提议的核心的所有四位领导人(卡尔、克利什、格兹滕和纽加德) 在新陈代谢组学和蛋白质组学工具的使用方面有很强的记录 心脏代谢调节和疾病机制。这些经验将这个提议的核心定位为一个 这可能对分子图谱数据的产生、分析和解释产生最大的影响。

Project Summary/Abstract Exercise is an effective intervention for both the prevention and treatment of cardiometabolic diseases, but the mechanistic underpinnings of the health benefits of exercise remain incompletely defined. Recent work highlights the importance of inter-organ circuits in mediating healthful exercise responses. We identified β- aminoisobutyric acid (BAIBA) as a novel small molecule “myokine” that increases the expression of brown adipocyte-specific genes in vitro, and improves glucose disposal and decreases weight gain in mice. In humans, plasma BAIBA concentrations are increased with chronic exercise and demonstrate a strong inverse association with metabolic risk factors. Our team has also been a leader in characterizing within-tissue responses to exercise and dietary interventions. These experiences, coupled with the high translational relevance of the research problem, motivate us to take a systems wide approach to studying the health benefits of exercise in humans and animal models. To this end, we have formed a multi-institutional, multi-omics center to engage in collaborative studies under the aegis of the NIH MoTrPAC initiative. Our core builds upon ongoing collaborations between teams at Duke, Harvard and the Broad Institute with complementary strengths in metabolomics and proteomics technologies and decades of experience in cardiometabolic research. The core will provide a deep menu of analytical tools for targeted and non-targeted metabolomics, protein profiling, and the analysis of key protein post-translational modifications. Each of the core components has a track record for handling large sample sets, and is well- poised to analyze the expected tens of thousands of tissue and blood samples generated by a national consortium of investigators studying exercise interventions in animal and human cohorts. An additional distinction of our team is the ability to integrate new findings from MoTrPAC with previously collected genomic, proteomic and metabolomic data from large human cohorts. We hypothesize that integrating the metabolomic and proteomic profiles of human tissues and blood during exercise with genetics and detailed human phenotyping will provide novel insights into the inter-organ circuits and within-organ responses that mediate the salutary effects of exercise. All of the primary data generated by this multi- disciplinary proposal will be made rapidly available to the scientific community via a novel information portal at the Broad Institute. Importantly, all four leaders of this proposed core (Carr, Clish, Gerszten and Newgard) have strong track records in the use of metabolomics and proteomics tools for the identification of novel cardiometabolic regulatory and disease mechanisms. These experiences position this proposed core as one that can have maximal impact on the generation, analysis, and interpretation of molecular profiling data.