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

DMGV 和 AGXT2 通路在慢性运动引起的心脏代谢适应中的作用。

基本信息

批准号：
10456635
负责人：
Jeremy Robbins
金额：
$ 16.89万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-10 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10456635
关键词：
Aerobic Exercise Affect African American Alanine Alanine-glyoxylate aminotransferase Aminoisobutyric Acids Attenuated Award Biochemical Biochemical Pathway Biological Biological Markers Blood Pressure Cardiac Output Cardiology Cardiometabolic Disease Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Chronic Clinical Clinical Trials Cohort Studies Data Data Set Development Diabetes Mellitus Enzymes Exercise Exercise Physiology Faculty Family Study Fatty acid glycerol esters Foundations Future Genetic Genetic Determinism Genome Genomics Glycine Goals Guidelines Health Health Benefit Heart Rate Heart failure Individual Individual Differences Investigation Israel Jackson Heart Study Left Lipids Liver Measures Medical center Mendelian randomization Mentors Mentorship Meta-Analysis Metabolic Metabolic Diseases Metabolic syndrome Metabolism Methods Molecular Molecular Profiling Myocardial dysfunction N,N-dimethylarginine Outcome Oxygen Participant Pathway interactions Patients Phenotype Physiological Pilot Projects Plasma Population Prevention Production Protocols documentation Publishing Research Resources Science Standardization Stimulus Supervision Techniques Training Training Programs Translating Translational Research VO2max Ventricular Work bariatric surgery base cardiac magnetic resonance imaging cardiometabolism cardiovascular disorder prevention cardiovascular health career development caucasian American clinically relevant cohort design endurance exercise exercise training heart imaging high risk human data improved insight insulin sensitivity laboratory experience member metabolic phenotype metabolomics n-pentanoic acid novel novel therapeutics population based prevent response sedentary skills small molecule symposium trait uptake

项目摘要

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.

项目概要/摘要该提案详细介绍了一项为期五年的转化研究培训计划，用于指导职业发展该候选人是最近任命的心脏病学专家。贝斯以色列女执事医疗中心的教职人员，概述的提案建立在候选人的基础上心血管预防和运动生理学背景提供三个新的专业领域 - 申请人的开发将通过代谢组学、遗传学和运动临床试验的结合进行。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。额外的指导团队拥有分子分析、运动科学和心脏代谢疾病领域的专家。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型血浆代谢物，二甲基胍戊酸 (DMGV)，它是一种非常早期的血浆代谢物。心脏代谢疾病的标志物和与运动相关的生化途径（AGXT2）的参与者在最近发表的人类数据中，我们发现 DMGV 水平。经过 20 周的有氧运动训练 (ET) 后，该指标有所下降，但基线水平较高的个体 DMGV 证明完成 ET 后血脂性状和胰岛素敏感性的改善减弱。申请人现在寻求通过关联 DMGV 水平和额外的 AGXT2 途径来扩展这些研究运动诱发心血管（例如最大摄氧量）的中间体（例如 BAIBA、ADMA、甘氨酸） [VO2max] 和血压）适应（目标 1）此外，申请人将应用无偏见的代谢组学。识别与运动反应性相关的新生化途径的技术（目标 2）。申请人将通过询问大量的、具有现有遗传学和代谢组学数据的基于人群的队列，并将研究结果与长期研究相结合健康结果，以确定参与运动和心脏代谢健康的新生化途径（目标 3) 同时，申请人将把相同的代谢组学技术与受试者的心脏 MRI 数据相结合。患有代谢综合征，以表征亚临床心脏功能障碍，并设计练习作为 R01 级奖励和向独立过渡的一部分，对该人群进行临床试验（目标 4）。定期锻炼可以改善心脏代谢健康，但个体间的差异却很显着差异是存在的，而且定期运动有益效果的分子基础仍然很差定义该提案将为申请人提供分子谱分析所需的培训和专业知识，运动生理学和临床试验，以研究健康受试者的长期运动适应。最终，这项工作将为未来研究临床和分子反应奠定基础。患有明显心脏代谢疾病（例如代谢综合征）且心脏病高风险的患者定期锻炼申请人向研究独立过渡的失败。