Skeletal Muscle Molecular Drug Targets for Exercise-induced Cardiometabolic Health

运动引起的心脏代谢健康的骨骼肌分子药物靶点

基本信息

批准号：
10212161
负责人：
WILLIAM E KRAUS
金额：
$ 76.4万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-20 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10212161
关键词：
Address Adopted Advisory Committees Aerobic American Area Automobile Driving Bioinformatics Biological Biology Blood Body Composition Characteristics Chromatin Chronic Clinical Complex DNA DNA Methylation Data Data Set Databases Development Drug Targeting Epigenetic Process Evaluation Exercise Exposure to Gene Expression Generations Genes Genome Goals Guidelines Health Health Benefit Hour Human In Vitro Individual Insulin Kinetics Knowledge Life Style Lipids Lipoproteins Literature Maintenance Maps Mediating Mediation Mediator of activation protein Medicine Metabolic Metabolic syndrome Metabolism Methods Methylation Modality Modeling Modification Molecular Molecular Target Muscle Organ Outcome Pathway interactions Pharmacology Physical Fitness Physical activity Physiological Physiology Process Proteome Proteomics Regimen Regulatory Pathway Reporting Resistance Resources Sampling Science Scientist Signal Pathway Signal Transduction Skeletal Muscle System Talents Testing Time Training Training Programs Work biobank blood glucose regulation cardiometabolic risk cardiometabolism cardiorespiratory fitness causal model cohort epigenetic profiling epigenome exercise intensity exercise program exercise training functional genomics health goals health knowledge innovation insight insulin signaling interest metabolome metabolomics methylome microphysiology system molecular drug target novel therapeutics organ on a chip programs protein expression response skeletal transcriptome transcriptomics

项目摘要

Skeletal Muscle Molecular Drug Targets for Exercise-induced Cardiometabolic Health The health benefits of exercise training are substantial, summarized in the Physical Activity Guidelines Advisory Committee Report, and incorporated into the Physical Activity Guidelines for Americans in both 2008 and 2018. Understanding the mechanisms whereby exercise mediates its effects will have two major benefits. It will promote an understanding how to tailor exercise programs to an individual’s specific clinical needs— personalized lifestyle medicine. Also, it will provide critical information for the development of new therapeutics for the myriad of health conditions exercise treats so well. It is likely that exercise—like many environmental bodily exposures—induces epigenetic modifications directing gene expression, protein expression and metabolic responses in target organs whereby exercise mediates its effects. Adaptations in skeletal muscle to exercise training mediate many of the health benefits of exercise. However, how these beneficial effects are mediated are little understood. It is the purpose of this project to understand these processes in three human STRRIDE cohorts containing a broad range of seven different exercise exposures—and inactive control—with extensive clinical, physiologic data paired with a biorepository of blood and skeletal muscle samples. The hypothesis driving this work is that epigenetic modifications in skeletal muscle—serves a mediator and integrator over time— DNA chromatin methylation—drives a major biological program mediating improvement in cardiometabolic health in humans undergoing exercise training. Our work will be conducted in three specific aims. 1) Determine the time course of the effects of exercise training and subsequent detraining on the human skeletal muscle epigenome, transcriptome, proteome and metabolome. This will be approached through classical associative modeling. Although we know that some DNA methylation targets and downstream molecular signaling are responsive to a single bout of exercise, we do not know how long these modifications persist; how they might integrate responses of single exercise bouts, and how they are related to other downstream molecular targets at the epigenome, transcriptome, proteome and metabolome levels. 2) Determine the specific and differential effects of exercise amount (dose), intensity and mode on the human skeletal muscle methylome and downstream molecular signaling pathways on important physiologic and clinical outcomes. In order to understand the pathways mediating exercise effects on human health, it is important to relate the specific effects of exercise characteristics on molecular determinants of exercise responsiveness with a focus on dose-response relationships. This aim will be approached through a team-science approach involving causal modeling and regulatory circuits and known regulatory networks—stable dynamic networks—consistent with the known literature generation. 3) Determine and test putative drug targets mimicking exercise effects in an in vitro system. We will test regulatory nodes by manipulating candidate regulatory pathways in our muscle organ-on-chip microphysiological system. At the end of this work we will understand better how exercise has its salutary effects on human health and how this knowledge may be used to develop both individualized exercise programs targeting an individual’s health goals, and an understanding of the cellular molecular physiology at a level leading to new therapeutic drug targets.

运动诱导的心脏代谢健康的骨骼肌分子药物靶标体育锻炼指南总结了运动训练的健康益处是很大的咨询委员会报告，并在2008年的美国人的体育活动指南中纳入和2018年。了解运动介导其效果的机制将有两个主要好处。它将促进理解如何根据个人的特定临床需求量身定制运动计划 - 个性化的生活方式医学。此外，它将为开发新的治疗剂提供关键信息对于无数的健康状况，行使珍宝的行使非常好。运动很可能 - 就像许多环境身体暴露 - 引导基因表达，蛋白质表达和目标器官中的代谢反应介导了其作用。骨骼肌适应运动训练调解了运动的许多健康益处。但是，这些有益的影响是如何介导的人几乎没有理解。该项目的目的是在三个人中了解这些过程 strride队列包含七种不同的运动暴露和不活动控制的广泛范围广泛的临床生理数据与血液和骨骼肌样本的生物座配对。这推动这项工作的假设是骨骼肌的表观遗传修饰 - 主导介体和随着时间的推移积分剂 - DNA染色质甲基化 - 驱动了主要的生物学计划介导的改进在人类接受运动训练的心脏代谢健康中。我们的工作将以三个特定的目标。 1）确定锻炼训练的影响的时间过程以及随后对人骨骼肌表观基因组，转录组，蛋白质组和代谢组。这将接近通过经典的关联建模。尽管我们知道一些DNA甲基化靶标和下游分子信号对单次运动有反应，我们不知道这些多长时间修改持续存在；他们如何整合一次单次锻炼的响应，以及它们与之相关的其他下游分子靶标在表观基因组，转录组，蛋白质组和代谢组水平上。 2）确定运动量的特定和差异效应（剂量），强度和模式对人类骨骼肌肉甲基甲基和下游分子信号通路生理和临床结果。为了了解介导运动影响的途径人类健康，重要的是将运动特征对分子确定剂的特定影响联系起来很重要锻炼反应能力，专注于剂量反应。这个目标将通过涉及因果建模和监管电路和已知监管网络的团队科学方法 - 稳定动态网络 - 与已知的文献生成一致。 3）确定并测试推定的药物目标模仿体外系统中的运动效果。我们将通过操纵候选人测试调节节点我们的肌肉机器人片微生物生理系统中的调节途径。在这项工作结束时，我们将更好地了解运动如何对人类健康产生有益的影响以及如何使用这些知识制定针对个人健康目标的个性化锻炼计划，也是理解细胞分子生理学的水平，导致新的治疗药物靶标。