Phenotypes of Muscle Loss in Smokers

吸烟者肌肉损失的表型

基本信息

批准号：
10463996
负责人：
Richard Hang Zou
金额：
$ 7.92万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10463996
关键词：
Applications Grants Biological Markers Blood Banks Blood specimen Body Composition Body mass index Body measure procedure Bone Mineral Contents C-reactive protein Cause of Death Chronic Obstructive Pulmonary Disease Clinical Cohort Analysis Complex Cross-Sectional Studies Data Data Store Disease Disease Progression Dual-Energy X-Ray Absorptiometry Early Intervention Environment Evaluation Fatty acid glycerol esters Foundations Future General Population Goals Height Impairment Individual Inflammatory Interleukin-6 Intervention K-Series Research Career Programs Longitudinal Studies Longitudinal cohort Lung diseases Measures Mentors Mentorship Methodology Modeling Molecular Morbidity - disease rate Muscle Muscular Atrophy Natural History Outcome Phenotype Physicians Physiological Positioning Attribute Proteins Pulmonary Emphysema Pulmonary Function Test/Forced Expiratory Volume 1 Quality of life Research Respiratory Signs and Symptoms Risk Risk Factors Role Scientist Severity of illness Smoker Subgroup Sum Surrogate Markers TNF gene Testing Thinness Time TimeLine Training United States Universities Vital capacity Walking airway obstruction base career clinical phenotype clinical risk cohort comorbidity demographics disease phenotype disorder risk exercise intolerance experience former smoker functional decline functional disability functional status health related quality of life high risk population indexing inflammatory marker insight lean body mass meter molecular phenotype mortality multilevel analysis muscle form pulmonary function radiological imaging reduced muscle mass respiratory systemic inflammatory response trend

项目摘要

PROJECT SUMMARY/ABSTRACT Chronic obstructive pulmonary disease (COPD) is a leading cause of death in the United States and worldwide. Decreased muscle mass is common in COPD and associates with lung disease severity, functional impairment, systemic inflammation, and all-cause mortality. Fat free mass index (FFMI), defined by the sum of whole-body lean muscle and bone mineral content adjusted for height in meters squared, is an accepted surrogate marker of whole-body muscle mass in COPD. FFMI associates with lung function and is an independent predictor of mortality in individuals with COPD who have normal BMI. However, most studies evaluating FFMI in COPD are cross-sectional and do not examine changes in FFMI over time. These longitudinal studies are critical to identify the clinical and molecular phenotype of individuals at greatest risk for disease morbidity and mortality. Additionally, most studies focused primarily on current and former smokers with airflow obstruction, defined by a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) <0.70. Yet, smokers without airflow obstruction remain at risk for emphysema, respiratory symptoms, and respiratory exacerbations compared with the general population. Our preliminary data show that longitudinal muscle mass changes in smokers are not modified by airflow obstruction status, and that a subset of smokers both with and without airflow obstruction demonstrates a significant decrease in FFMI over time. In this study, we will leverage our well- characterized longitudinal cohort of current and former smokers with and without airflow obstruction who have serial clinical, physiologic, and radiographic data, FFMI data determined from readily available dual energy x-ray absorptiometry (DXA), and banked blood samples to test our primary hypotheses that distinct trajectories of muscle mass change are associated with specific clinical and molecular phenotypes and that rapid FFMI decline correlates with lung disease progression and functional impairments over time. In Aim 1, I will determine trajectories of FFMI change in smokers with and without airflow obstruction and identify important baseline clinical and molecular predictors of muscle loss trajectories. In Aim 2, I will compare longitudinal changes in lung function, emphysema, functional status, and circulating inflammatory proteins between smokers with rapid FFMI decline and smokers without rapid FFMI decline. This study proposal will provide important insight into the natural history of muscle loss in smokers with and without airflow obstruction and help establish specific clinical and molecular phenotypes associated with rapid muscle mass decline for targetable interventions in future studies. This training plan, combined with close mentorship and a robust research environment at the University of Pittsburgh, will facilitate my transition to a mentored Career Development Award and, ultimately, to an independent career as a physician-scientist.

项目摘要/摘要慢性阻塞性肺疾病（COPD）是美国和全球的主要死亡原因。肌肉质量降低在COPD中常见，并且与肺部疾病严重程度，功能障碍相关，系统性炎症和全因死亡率。全身之和定义的无脂质质量指数（FFMI）瘦肌肉和骨矿物质含量以平方为单位的高度调整为一个公认的替代标记 COPD中的全身肌肉质量。 FFMI与肺功能相关，是患有BMI正常的COPD患者的死亡率。但是，大多数评估COPD中FFMI的研究是横截面，不会随着时间的推移检查FFMI的变化。这些纵向研究对于确定疾病发病率和死亡风险最大的个体的临床和分子表型。此外，大多数研究主要集中于当前和以前的气流阻塞的吸烟者，由强迫呼气量在1秒内与强制生命力（FEV1/FVC）的比率<0.70。但是，吸烟者没有气流阻塞仍处于肺气肿，呼吸道症状和呼吸系统加剧的危险中与一般人群相比。我们的初步数据表明，纵向肌肉质量变化吸烟者不会因气流阻塞状态而修改，并且有或没有气流的吸烟者障碍物随着时间的推移表明FFMI显着下降。在这项研究中，我们将利用我们的福祉表征有和没有气流阻塞的当前和前吸烟者的纵向队列串行临床，生理和射线照相数据，FFMI数据可从随时可用的双能X射线确定吸收率（DXA）和存放的血液样本来检验我们的主要假设，这些假设不同肌肉质量变化与特定的临床和分子表型有关，FFMI快速下降随着时间的流逝，与肺部疾病进展和功能障碍相关。在AIM 1中，我将确定有或没有气流阻塞的吸烟者的FFMI变化轨迹，并确定重要的基线肌肉损失轨迹的临床和分子预测指标。在AIM 2中，我将比较肺的纵向变化 FFMI快速吸烟者之间的功能，肺气肿，功能状态和循环炎性蛋白衰落和吸烟者而没有快速FFMI下降。该研究建议将为自然提供重要的见解吸烟者有或没有气流阻塞的吸烟者肌肉损失的病史，并有助于建立特定的临床和在未来的研究中，与肌肉质量快速下降有关的分子表型。该培训计划，结合了大学的密切指导和强大的研究环境匹兹堡，将促进我过渡到指导的职业发展奖，并最终向作为医师科学家的独立职业。