Phenotypes of Muscle Loss in Smokers

吸烟者肌肉损失的表型

• 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
• 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

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)是美国和世界范围内的主要死亡原因。 肌肉质量减少在COPD患者中很常见，并与肺部疾病的严重程度、功能损害、 全身性炎症和全因致死。脱脂体重指数(FFMI)，由全身的总和定义 瘦肌肉和骨矿物质含量根据身高调整，以米为单位，是一个被接受的替代标记 慢性阻塞性肺病患者全身肌肉质量的变化。FFMI与肺功能有关，是一项独立的预测因子 体重指数正常的COPD患者的死亡率。然而，大多数评估COPD患者FFMI的研究都是 横断面分析，不检查FFMI随时间的变化。这些纵向研究对于确定 疾病发病率和死亡率风险最高的个体的临床和分子表型。 此外，大多数研究主要集中在现在和以前有气流障碍的吸烟者，定义为 1秒用力呼气量与用力肺活量的比率(FEV1/FVC)&0.70。然而，吸烟者没有 气流阻塞仍然存在肺气肿、呼吸道症状和呼吸恶化的风险。 与普通人群相比。我们的初步数据显示，纵向肌肉质量在 吸烟者不会因气流障碍状态而改变，并且吸烟者的子集在有气流和没有气流的情况下都是如此 梗阻显示随着时间的推移，FFMI显著降低。在这项研究中，我们将充分利用- 有气流障碍和无气流障碍的现任和前任吸烟者的特征纵向队列 一系列临床、生理和放射学数据，FFMI数据由现成的双能x射线确定 吸光度(DXA)，和银行血液样本来测试我们的主要假设，不同的轨迹 肌肉质量变化与特定的临床和分子表型以及FFMI的快速下降有关 随着时间的推移，与肺部疾病的进展和功能损害相关。在目标1中，我将确定 有无气流障碍吸烟者的FFMI轨迹变化及重要基线识别 肌肉丧失轨迹的临床和分子预测指标。在目标2中，我将比较肺部的纵向变化 快速FFMI吸烟者之间的功能、肺气肿、功能状态和循环炎症蛋白 下降和吸烟者没有快速的FFMI下降。这项研究建议将提供对自然界的重要见解 有和没有气流阻塞的吸烟者肌肉损失的病史有助于建立特定的临床和 与肌肉质量快速下降相关的分子表型在未来研究中用于有针对性的干预。 这一培训计划与密歇根大学的密切指导和强大的研究环境相结合 匹兹堡，将促进我向导师职业发展奖的过渡，并最终向 作为一名独立的内科科学家职业。