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Determinants of 5 Year Progression of Muscle Dysfunction and Inactivity in COPDGene Participants.

COPDGene 参与者肌肉功能障碍和不活动 5 年进展的决定因素。

基本信息

批准号：
10552666
负责人：
Alessandra Adami
金额：
$ 37.79万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA 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：
2020-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10552666
关键词：
Accelerometer Age American Ancillary Study Behavioral Biopsy Biopsy Specimen Body Composition Cardiovascular Diseases Cause of Death Cessation of life Characteristics Chronic Chronic Disease Chronic Obstructive Pulmonary Disease Clinical DNA DNA Methylation Data Diabetes Mellitus Diffusion Disease Disease Outcome Dual-Energy X-Ray Absorptiometry Enrollment Epigenetic Process Etiology Exercise Tolerance Exertion Exposure to Fluorometry Functional disorder Gases Gene Expression Genes Genetic Genetic Predisposition to Disease Genomics Health Hospitalization Hospitals Impairment Individual Inflammation Irritants Knowledge Light Lower Extremity Lung Lung diseases Measurement Measures Mediating Mediator Metabolic acidosis Methods Mitochondria Modification Muscle Muscle Mitochondria Muscle function Muscular Atrophy Nature Nuclear Obesity Outcome Parents Participant Patients Pharmaceutical Preparations Physical activity Predictive Factor Production Prognosis Pulmonary Emphysema Pulmonary Inflammation Quality of life RNA Resolution Risk Severities Shortness of Breath Skeletal Muscle Small RNA Smoker Smoking Spirometry Structure of parenchyma of lung Survival Rate Time Untranslated RNA Visit Work airway inflammation cigarette smoke cohort comorbidity deep sequencing disease diagnosis effective therapy epigenomics exercise capacity exercise intolerance exercise training follow-up functional decline gene discovery gene network genetic variant impaired capacity methylome mitochondrial dysfunction mitochondrial genome mortality muscle form never smoker novel therapeutic intervention physical inactivity predictive modeling premature prevent programs pulmonary function pulmonary rehabilitation quadriceps muscle reduce symptoms sedentary lifestyle symptomatic improvement transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is destruction of lung tissue and/or thickening of lung airways. It is the fourth leading cause of death in the USA. COPD is progressive and characterized by chronic inflammation and shortness of breath on exertion, which leads to physical inactivity and skeletal muscle dysfunction. Survival rate in COPD is more closely associated with exercise capacity than the severity of lung disease. A key determinant of exercise capacity is the ability of skeletal muscle mitochondria to sustain cellular energy delivery (termed, oxidative capacity). We recently applied a noninvasive near-infrared light-based method to assess muscle oxidative capacity in 245 smokers with and without COPD: the COPDGene ancillary Muscle Health Study. We showed that severe COPD patients have a 40% lower muscle oxidative capacity than smokers or never smokers with normal lung function. Yet, many questions remain about characteristics and mechanisms behind the loss of muscle oxidative capacity in COPD. The current proposal will follow-up with 200 of the Muscle Health Study participants to determine for the first time the rate of decline in lower limb skeletal muscle oxidative capacity over 5 years. Using the individual genetics, triaxial accelerometer measured daily physical activity, body composition measured by DXA, and 808 other clinical variables collected in the COPDGene parent study, we will identify clinical, behavioral and genetic variables that associate with the 5-year decline in skeletal muscle oxidative capacity. In addition, quadriceps muscle biopsy samples from 20 COPD patients with the fastest decline and 20 with the slowest decline in muscle oxidative capacity, identified by the near-infrared based noninvasive assessment, will be used to discover how gene expression is altered by the disease. DNA methylation and expression of small and large RNAs, including small non-coding RNAs from the mitochondrial genome (mitosRNAs), will be probed. These highly specific approaches will provide a detailed profile of mitochondrial and nuclear genes and/or gene networks underlying the causes of derangements in the lower limb skeletal muscles of COPD patients. The decline in muscle oxidative capacity impairs exercise tolerance and predisposes patients to chronic diseases such as cardiovascular disease, diabetes and obesity, each of which increases risk of premature death. The current proposal will be the first to determine how loss of muscle oxidative capacity progresses in COPD, and answer fundamental questions about the nature of the associations among mitochondrial dysfunction, sedentary lifestyle and poor outcomes in COPD patients. Our findings will guide efforts to create new therapeutic strategies to prevent skeletal muscle dysfunction, increase autonomy, hospital free survival and quality-of-life in COPD.

项目摘要慢性阻塞性肺疾病（COPD）是肺组织的破坏和/或肺气道的增厚。它是美国第四大死因慢性阻塞性肺病是一种进行性疾病，以慢性炎症为特征以及运动时呼吸短促，这导致身体活动不足和骨骼肌功能障碍。生存 COPD的发病率与运动能力的关系比肺部疾病的严重程度更密切。一个关键运动能力的决定因素是骨骼肌线粒体维持细胞能量传递的能力（称为氧化能力）。我们最近应用了一种基于近红外光的非侵入性方法来评估 245例COPD吸烟者和非COPD吸烟者的肌肉氧化能力：COPD基因辅助肌肉健康 Study.我们发现，重度COPD患者的肌肉氧化能力比吸烟者低40%，从不吸烟，肺功能正常。然而，许多问题仍然存在的特点和机制 COPD患者肌肉氧化能力丧失的背后。目前的建议将跟进200名肌肉健康研究首次确定参与者下肢骨骼肌氧化下降速度能力超过5年。使用个体遗传学，三轴加速度计测量每日身体活动，身体通过DXA测量的组成，以及在COPDGene母研究中收集的808个其他临床变量，我们将确定与骨骼肌5年衰退相关的临床、行为和遗传变量，氧化能力。此外，20例COPD患者的股四头肌活检样本中，下降和20与肌肉氧化能力下降最慢，确定了近红外为基础的非侵入性评估将用于发现基因表达如何被疾病改变。DNA 小和大RNA的甲基化和表达，包括来自线粒体的小的非编码RNA。基因组（mitosRNA），将被探测。这些高度具体的方法将提供一个详细的概况，线粒体和核基因和/或基因网络是下肢紊乱的原因 COPD患者的骨骼肌。肌肉氧化能力的下降损害了运动耐量，容易使患者患上慢性疾病，如心血管疾病、糖尿病和肥胖症，增加过早死亡的风险。目前的建议将是第一个确定如何损失肌肉氧化在COPD的能力进展，并回答有关之间的关联性质的基本问题，线粒体功能障碍、久坐不动的生活方式和COPD患者的不良结局。我们的发现将指导努力创造新的治疗策略，以防止骨骼肌功能障碍，增加自主性，医院 COPD患者的生存率和生活质量。