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

项目摘要/摘要 这份提案详细说明了一项为期五年的翻译研究培训计划，该计划旨在 分子图谱、运动生理学和试验行为。候选人是一名新近任命的心脏科医生 贝丝以色列女执事医疗中心的教职员工和概述的提案建立在候选人的 心血管预防和运动生理学背景，提供三个新的专业领域- 代谢组学、遗传学和运动临床试验。申请者的发展将通过以下方式进行 实验室培训、教学课程和科学会议。候选人的导师是一位公认的领袖 在分子图谱、运动科学和心脏代谢性疾病方面。额外的指导团队有一个 在代谢组学、遗传学和运动科学方面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)，它是一种非常早期的 心脏代谢性疾病的标志物和与运动相关的生化途径(AGXT2)的参与者 反应性和心血管疾病。在最近公布的人类数据中，我们发现DMGV水平 在有氧运动训练(ET)20周后下降，但基线水平较高的个体 DMGV显示完成ET后血脂特征和胰岛素敏感性的改善减弱。这个 申请者现在寻求通过关联DMGV水平和额外的AGXT2途径来扩展这些研究 运动诱导心血管(如最大摄氧量)的中间体(如BAIBA、ADMA、甘氨酸) [最大摄氧量]和血压)适应(目标1)。此外，申请者将应用无偏见代谢组学。 识别与运动反应相关的新生化途径的技术(目标2)。最后， 申请人将通过询问大的， 以人群为基础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 确定运动和心脏代谢健康涉及的新生化途径的健康结果(目的 3)。同时，申请者将把相同的代谢组学技术与受试者的心脏MRI数据相结合 代谢综合征，以确定亚临床心功能障碍的特征，并设计一项练习 在这一人群中进行临床试验(目标4)，作为R01级奖项的一部分，并过渡到独立。 有规律的锻炼有助于心脏代谢健康的改善，但对个体而言意义重大 存在差异，而且，定期锻炼有益效果的分子基础仍然很差 已定义。这项建议将为申请人提供所需的培训和分子图谱方面的专业知识， 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临床和分子反应奠定基础。 心脏高风险的明显心脏代谢性疾病(如代谢综合征)患者的定期运动 不及格是申请者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.