DMGV and the AGXT2 pathway in chronic exercise-induced cardiometabolic adaptations.

项目总结/摘要 该提案详细介绍了一个为期五年的转化研究培训计划，用于指导职业发展， 分子分析、运动生理学和试验进行。候选人是最近任命的心脏科 贝丝以色列女执事医疗中心的一名教员，概述的提案建立在候选人的 心血管预防和运动生理学的背景，提供三个新的专业领域- 代谢组学、遗传学和运动临床试验。申请人的发展将通过以下几种方式的结合来实现 实验室培训、教学课程和科学会议。候选人的导师是公认的领导者 在分子分析、运动科学和心脏代谢疾病方面。额外的辅导团队有一个 在代谢组学、遗传学和运动科学方面拥有杰出的指导记录和丰富的专业知识。 我们最近发现了一种新的血浆代谢物，二甲基胍基戊酸（DMGV），这是一个非常早期的 心脏代谢疾病的标志物和与运动相关的生化途径（AGXT 2）的参与者 反应性和心血管疾病。在最近发表的人类数据中，我们发现DMGV水平 在有氧运动训练（ET）20周后， DMGV显示完成ET后脂质性状和胰岛素敏感性的改善减弱。的 申请人现在试图通过将DMGV水平与另外的AGXT 2途径相关联来扩展这些研究 中间体（如BAIBA，ADMA，甘氨酸）运动诱导的心血管（如最大摄氧量 [VO 2 max]和血压）适应（目标1）。此外，申请人将应用无偏代谢组学 技术，以确定新的生化途径有关的运动反应（目标2）。最后 申请人将通过询问大的， 基于人群的队列与现有的遗传学和代谢组学数据，并将研究结果与长期 健康结果，以确定新的生化途径参与运动和心脏代谢健康（目的 3）。与此同时，申请人将在受试者中整合相同的代谢组学技术与心脏MRI数据 代谢综合征，以表征亚临床心功能不全，并设计一个运动 在该人群中进行临床试验（目标4），作为R 01级奖励的一部分，并过渡到独立。 定期锻炼可改善心脏代谢健康，但个体间差异显著 差异是存在的，而且，定期锻炼的有益效果的分子基础仍然很差 定义了本建议书将为申请人提供所需的分子特征分析培训和专业知识， 运动生理学和临床试验，以研究健康受试者的慢性运动适应。 最终，这项工作将为未来研究对以下疾病的临床和分子反应奠定基础： 患有明显心脏代谢疾病（如代谢综合征）且心脏病风险较高的患者应定期运动 失败是申请人向研究独立过渡的一部分。

PROJECT SUMMARY/ABSTRACT This proposal details a five-year translational research training program for mentored career development in molecular profiling, exercise physiology and trial conduct. The candidate is a recently appointed Cardiology faculty member at Beth Israel Deaconess Medical Center and the outlined proposal builds on the candidate’s background in cardiovascular prevention and exercise physiology to provide three new domains of expertise – metabolomics, genetics, and exercise clinical trials. The applicant’s development will occur through a blend of laboratory training, didactic courses, and scientific conferences. The candidate’s mentor is a recognized leader in molecular profiling, exercise science, and cardiometabolic disease. The additional mentorship team has a distinguished mentoring record and vast expertise in metabolomics, genetics and exercise science. We recently identified a novel plasma metabolite, Dimethylguanidino valeric acid (DMGV) that is a very early marker of cardiometabolic disease and participant in a biochemical pathway (AGXT2) relevant to exercise responsiveness and cardiovascular disease. In recently published human data, we found that DMGV levels decreased after 20 weeks of aerobic exercise training (ET), however individuals with higher baseline levels of DMGV demonstrated attenuated improvements in lipid traits and insulin sensitivity after completing ET. The applicant now seeks to extend these studies by relating DMGV levels, and additional AGXT2 pathway intermediates (e.g. BAIBA, ADMA, glycine) to exercise-induced cardiovascular (e.g. maximal oxygen uptake [VO2max] and blood pressure) adaptations (Aim 1). Further, the applicant will apply unbiased metabolomics techniques to identify novel biochemical pathways related to exercise responsiveness (Aim 2). Finally, the applicant will identify genetic determinants of relevant metabolites identified in Aim 2 by interrogating large, population-based cohorts with existing genetics and metabolomics data, and integrate findings with long-term health outcomes to identify novel biochemical pathways involved in exercise and cardiometabolic health (Aim 3). In parallel, the applicant will integrate the same metabolomics techniques with cardiac MRI data in subjects with metabolic syndrome in order to characterize subclinical cardiac dysfunction, and design an exercise clinical trial in this population (Aim 4) as part of an R01-level award and transition to independence. Regular exercise leads to improvements in cardiometabolic health, however significant inter-individual differences exist and, further, the molecular underpinnings of regular exercise’s salutary effects remain poorly defined. This proposal will provide the applicant with the required training and expertise in molecular profiling, exercise physiology, and clinical trials in order to study chronic exercise adaptation in healthy subjects. Ultimately, this work will lay the foundation for future investigation into the clinical and molecular responses to regular exercise in patients with overt cardiometabolic disease (e.g. metabolic syndrome) at high risk for heart failure as part of applicant’s transition to research independence.