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：
10339339
负责人：
Alessandra Adami
金额：
$ 37.86万
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10339339
关键词：
Accelerometer Age American Ancillary Study Behavioral Genetics 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 Diffuse Disease Disease Outcome Dual-Energy X-Ray Absorptiometry Enrollment Epigenetic Process Etiology Exercise Tolerance Exertion Exposure to Fluorometry Functional disorder Gases Gene Expression Genetic Genetic Predisposition to Disease Genomics Health Hospitalization Hospitals Impairment Individual Inflammation Irritants Knowledge Light Lower Extremity Lung Lung diseases Measurement Measures Mediating Mediator of activation protein 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 Structure of parenchyma of lung Survival Rate Time Untranslated RNA Visit Work airway inflammation base 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 improved 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 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.

项目概要慢性阻塞性肺病（COPD）是肺组织破坏和/或肺气道增厚。它是美国第四大死因。慢性阻塞性肺病是进行性的，其特征是慢性炎症劳累时呼吸短促，导致身体缺乏活动和骨骼肌功能障碍。生存慢性阻塞性肺病的发病率与运动能力的关系比与肺部疾病的严重程度的关系更为密切。一把钥匙运动能力的决定因素是骨骼肌线粒体维持细胞能量输送的能力（称为氧化能力）。我们最近应用了一种基于近红外光的无创方法来评估 245 名患有和不患有慢性阻塞性肺病 (COPD) 的吸烟者的肌肉氧化能力：COPDGene 辅助肌肉健康学习。我们发现，严重 COPD 患者的肌肉氧化能力比吸烟者或吸烟者低 40% 肺功能正常、从不吸烟的人。然而，关于特征和机制仍然存在许多问题慢性阻塞性肺病患者肌肉氧化能力丧失的背后原因。目前的提案将跟进 200 的肌肉健康研究参与者首次确定下肢骨骼肌氧化下降速度 5年以上的能力。利用个体遗传学，三轴加速度计测量日常身体活动、身体通过 DXA 测量的成分，以及 COPDGene 母研究中收集的 808 个其他临床变量，我们将识别与骨骼肌 5 年下降相关的临床、行为和遗传变量氧化能力。此外，还对 20 名 COPD 患者的股四头肌活检样本进行了最快的检测。通过基于近红外的方法确定肌肉氧化能力下降最慢的 20 名非侵入性评估将用于发现疾病如何改变基因表达。脱氧核糖核酸小RNA和大RNA的甲基化和表达，包括来自线粒体的小非编码RNA 基因组（mitosRNA）将被探测。这些高度具体的方法将提供详细的概况导致下肢紊乱的线粒体和核基因和/或基因网络 COPD 患者的骨骼肌。肌肉氧化能力下降会损害运动耐量使患者容易患上心血管疾病、糖尿病和肥胖等慢性疾病，这些疾病增加过早死亡的风险。目前的提案将首先确定肌肉氧化损失如何慢性阻塞性肺病的能力进展，并回答有关之间关联性质的基本问题线粒体功能障碍、久坐的生活方式和慢性阻塞性肺病患者的不良预后。我们的研究结果将指导努力创造新的治疗策略来预防骨骼肌功能障碍，增加自主权，医院 COPD 患者的自由生存和生活质量。