The epigenetics of exercise and physical activity in COPD

慢性阻塞性肺疾病（COPD）在美国退伍军人中非常普遍，是一个重要的疾病。 发病率和死亡率来源。COPD患者经常有运动能力降低（定义为 作为患者执行工作的最大能力）和身体活动水平（一个经常用于 描述患者典型的日常活动水平）。运动能力和体力活动减少 与显著的临床结局相关，如残疾、全因死亡率和医疗保健利用 rates.重要的是，运动能力和体力活动是潜在的可改变的风险因素， 慢性阻塞性肺病运动训练，通常在结构化肺康复的环境中进行 该计划目前得到了全球阻塞性肺病倡议（GOLD）指南的认可， 是COPD非药物治疗的重要组成部分， 症状和健康相关的生活质量，同时减少医疗保健利用。除了正式 肺康复，新的计划，重点是改善日常体力活动，可提供 类似的好处。除了上述疾病特异性益处外，运动训练和增加体力 活性也与全身变化如改善的常量营养素代谢有关， 增加肌肉质量和减少全身炎症。然而，COPD患者在以下方面差异很大： 他们对运动干预的反应。我们对决定运动的机制的理解 能力和对训练的反应是不完整的;我们的假设是，表观遗传机制，如 DNA甲基化与基线运动能力和系统重编程相关， 发生在训练中。我们建议检查2个人血液中的全基因组DNA甲基化模式， 现有的基于VA-波士顿的COPD受试者队列，具有关于运动能力和 和日常体力活动。分析第一个队列，一个横断面队列，包括受试者， 广泛的功能限制，将有助于建立基线运动的表观遗传决定因素 能力和体力活动（目标1）。在第二个队列中，我们将确定 使用收集的配对样品，在干预增加日常体力活动后进行甲基化 参与Every Step Counts试验（目标2）前后。最后，由于传统 肺康复计划通常涉及比每天目标为 体力活动（如每一步都很重要），我们建议从以下人群中重新收集样本： COPD受试者参考VA波士顿肺康复计划以描述变化 与高强度训练相关（目标3）。除了提供关于 锻炼和增加身体活动的好处，我们的建议有可能有助于 为COPD患者开发风险分层和个性化治疗方案的算法。

Chronic obstructive pulmonary disease (COPD) is highly prevalent among U.S. Veterans and is a significant source of morbidity and mortality. Patients with COPD frequently have reduced exercise capacity (defined as a patient's maximal capacity to perform work) and levels of physical activity (a term frequently used to describe a patient's typical daily level of activity). Reduced exercise capacity and physical activity are correlated with significant clinical outcomes, such as disability, all-cause mortality, and healthcare utilization rates. Importantly, exercise capacity and physical activity represent potentially modifiable risk factors in COPD. Exercise training, which is typically performed in the setting of a structured pulmonary rehabilitation program, is currently endorsed by the Global Initiative for Obstructive Lung Diseases (GOLD) guidelines as an essential component of the non-pharmacological management of COPD and has been shown to improve symptoms and health-related quality of life while reducing healthcare utilization. In addition to formal pulmonary rehabilitation, novel programs which focus on improving daily physical activity may provide similar benefits. In addition to the disease-specific benefits above, exercise training and increased physical activity have also been associated with systemic changes such as improved macronutrient metabolism, increased muscle mass, and decreased systemic inflammation. However, COPD patients vary widely in their responses to exercise interventions. Our understanding of the mechanisms which determine exercise capacity and the response to training is incomplete; our hypothesis is that epigenetic mechanisms such as DNA methylation are associated with both baseline exercise capacity and the systemic reprogramming that occurs with training. We propose to examine genome-wide DNA methylation patterns in blood from 2 existing VA-Boston based cohorts of COPD subjects with detailed, objective data on both exercise capacity and daily physical activity. Analysis of the first cohort, a cross-sectional cohort which includes subjects with a broad range of functional limitation, will help to establish the epigenetic determinants of baseline exercise capacity and physical activity (Objective 1). In the second cohort, we will determine longitudinal changes in methylation following an intervention to increase daily physical activity using paired samples collected before and after participation in the Every Step Counts trial (Objective 2). Finally, because traditional pulmonary rehabilitation programs typically involve higher intensity training than programs which target daily physical activity (such as the Every Step Counts program), we propose to collect de novo samples from COPD subjects referred to the VA Boston Pulmonary Rehabilitation program to characterize changes associated with higher intensity training (Objective 3). In addition to providing mechanistic insights on the benefits of exercise and increased physical activity, our proposal has the potential to assist in the development of algorithms for risk stratification and personalized treatment programs for COPD patients.