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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：
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.

项目总结