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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.

骨骼肌分子药物靶点治疗运动诱导的心脏代谢健康运动训练的健康益处是巨大的，在身体活动指南中进行了总结。咨询委员会报告，并于2008年和2010年纳入美国人身体活动指南。和2018年。了解运动调节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具体临床需求定制锻炼计划- 个性化生活方式医学此外，它还将为新疗法的开发提供关键信息因为运动可以很好地治疗各种健康问题。很可能像许多环境一样，体细胞凋亡诱导表观遗传修饰，指导基因表达、蛋白质表达和代谢反应的目标器官，从而行使调解其影响。骨骼肌对运动训练可以使运动对健康产生许多益处。然而，这些有益的影响是如何中介很少被理解。本项目的目的是了解三个人的这些过程， STRRIDE队列包含广泛的七种不同的运动负荷-和非活动对照- 广泛的临床、生理数据以及血液和骨骼肌样本的生物储存库。的驱动这项工作的假设是，骨骼肌中的表观遗传修饰是一种中介，随着时间的推移，整合剂- DNA染色质甲基化-驱动一个主要的生物程序介导的改善在进行运动训练的人的心脏代谢健康方面。我们的工作将在三个具体的目标。1)确定运动训练和随后停止训练对人类骨骼肌表观基因组、转录组、蛋白质组和代谢组。这将被处理通过经典的联想建模。虽然我们知道一些DNA甲基化靶点和下游分子信号对一次运动有反应，我们不知道这些反应持续多久。修改持续存在;它们如何整合单一锻炼回合的反应，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。（二）确定运动量（剂量）、强度和方式对运动的特异性和差异性影响。人类骨骼肌甲基化和下游分子信号通路对重要的生理和临床结果。为了了解调节运动影响的途径，人类健康，重要的是要联系运动特征的分子决定因素的具体影响运动反应性的研究，重点是剂量-反应关系。这一目标将通过以下方式实现：一个团队科学的方法，涉及因果建模和监管电路和已知的监管网络-稳定动态网络-与已知文献生成一致。3)确定和测试推定的药物靶点模拟体外系统中的运动效果。我们将通过操纵候选节点来测试监管节点，我们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，细胞分子生理学的水平，导致新的治疗药物的目标。