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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：
10602536
负责人：
WILLIAM E KRAUS
金额：
$ 70.21万
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/10602536
关键词：
Address Adopted Advisory Committees Aerobic American Area Automobile Driving Bioinformatics Biological Biology Blood Body Composition Characteristics Chromatin Chronic Clinical Clinical Data Complex DNA DNA Methylation Data Data Discovery 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 Medicine Metabolic Metabolic syndrome Metabolism Methods Methylation Modality Modeling Modification Molecular Molecular Target Muscle Organ Outcome Pathway interactions 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 demethylation epigenetic profiling epigenome exercise program exercise training functional genomics health goals improved innovation insight insulin signaling interest metabolome metabolomics methylome microphysiology system molecular drug target novel therapeutics organ on a chip pharmacologic 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.

运动引起的心脏代谢健康的骨骼肌分子药物靶点《体育活动指南》中总结了运动训练对健康的巨大益处咨询委员会报告，并于 2008 年纳入美国人身体活动指南和 2018 年。了解运动调节其影响的机制将有两个主要好处。它将促进人们了解如何根据个人的特定临床需求定制锻炼计划—— 个性化生活方式医学。此外，它将为新疗法的开发提供关键信息对于多种健康状况来说，运动都有很好的治疗效果。锻炼很可能像许多环境一样身体暴露——诱导表观遗传修饰，指导基因表达、蛋白质表达和目标器官的代谢反应，由此运动介导其效果。骨骼肌的适应运动训练可以调节运动的许多健康益处。然而，这些有益效果如何中介很少被理解。该项目的目的是了解三个人类的这些过程 STRRIDE 队列包含广泛的七种不同的运动暴露和非活动控制，其中广泛的临床、生理数据与血液和骨骼肌样本的生物储存库相结合。这推动这项工作的假设是骨骼肌的表观遗传修饰——充当中介者和随着时间的推移，DNA 染色质甲基化的整合器驱动了介导改善的主要生物程序接受运动训练的人类心脏代谢健康。我们的工作将在三个具体方面进行目标。 1) 确定运动训练和随后的停止训练对身体的影响的时间过程人类骨骼肌表观基因组、转录组、蛋白质组和代谢组。这将被接近通过经典的联想建模。尽管我们知道一些 DNA 甲基化目标和下游分子信号传导对单次运动有反应，我们不知道这些运动会持续多久修改仍然存在；他们如何整合单次锻炼的反应，以及它们如何与表观基因组、转录组、蛋白质组和代谢组水平的其他下游分子靶点。 2）确定运动量（剂量）、强度和模式对运动的具体和差异影响人类骨骼肌甲基化组及其下游分子信号通路对重要生理和临床结果。为了了解介导运动影响的途径对于人类健康来说，将运动特征对分子决定因素的具体影响联系起来非常重要运动反应性，重点关注剂量反应关系。这一目标将通过涉及因果建模和调节回路以及已知调节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) 确定和测试假定的药物靶点在体外系统中模拟运动效果。我们将通过操纵候选节点来测试监管节点我们的肌肉器官芯片微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利用这些知识制定针对个人健康目标的个性化锻炼计划，并了解细胞分子生理学的水平达到导致新的治疗药物靶标的水平。