A Biochemical Roadmap of Exercise Signaling

项目概要/摘要 运动是预防和治疗心脏代谢疾病的有效干预措施，但 运动对健康有益的机械基础仍然没有完全确定。最近的工作 强调了器官间回路在调节健康运动反应中的重要性。我们发现β- 氨基异丁酸（BAIBA）作为一种新的小分子"肌因子"，增加棕色表达， 体外脂肪细胞特异性基因，并改善葡萄糖处理和减少小鼠体重增加。在 在人类中，血浆BAIBA浓度随着慢性运动而增加，并表现出强烈的反作用。 与代谢危险因素相关。我们的团队也一直是表征组织内 对运动和饮食干预的反应。 这些经验，加上研究问题的高度翻译相关性，激励我们采取 一个系统的方法来研究人类和动物模型运动的健康益处。本 最后，我们成立了一个多机构，多组学中心，在该计划的支持下进行合作研究。 NIH MoTrPAC计划的一部分。我们的核心是建立在杜克大学、哈佛大学团队之间的持续合作之上 和布罗德研究所在代谢组学和蛋白质组学技术方面的优势互补， 数十年的心脏代谢研究经验。核心将提供一个深入的分析工具菜单， 靶向和非靶向代谢组学、蛋白质谱分析和关键蛋白质翻译后分析 修改.每个核心组件都有处理大型样品集的记录，并且非常好- 准备分析由一个全国性的组织产生的成千上万的组织和血液样本， 研究动物和人类队列运动干预的研究者联盟。 我们团队的另一个区别是能够将MoTrPAC的新发现与以前的研究结果相结合。 从大型人群中收集基因组学、蛋白质组学和代谢组学数据。我们假设 整合运动期间人体组织和血液的代谢组学和蛋白质组学特征与遗传学 详细的人类表型分析将为器官间回路和器官内回路提供新的见解。 调节运动有益效果的反应。所有的原始数据都是由这个多- 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， 布罗德研究所重要的是，这一拟议核心的所有四位领导人（卡尔、克利什、格斯滕和纽加德） 在使用代谢组学和蛋白质组学工具鉴定新的 心脏代谢调节和疾病机制。这些经验将拟议的核心定位为一个 这可能对分子谱数据的生成、分析和解释产生最大影响。

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.