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.

项目概要/摘要 慢性阻塞性肺疾病（COPD）是美国和全世界的主要死亡原因。 肌肉质量减少在慢性阻塞性肺病中很常见，并且与肺部疾病的严重程度、功能障碍、 全身炎症和全因死亡率。无脂体重指数 (FFMI)，由全身体重总和定义 根据身高（以米为单位）调整的瘦肌肉和骨矿物质含量是公认的替代标记 COPD 患者的全身肌肉质量。 FFMI 与肺功能相关，是肺功能的独立预测因子 体重指数正常的慢性阻塞性肺病患者的死亡率。然而，大多数评估 FFMI 在 COPD 中的研究 横截面数据，不检查 FFMI 随着时间的推移发生的变化。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吸烟者的气流阻塞，定义为 1 秒用力呼气量与用力肺活量之比 (FEV1/FVC) <0.70。然而，吸烟者没有 气流阻塞仍面临肺气肿、呼吸道症状和呼吸道症状加重的风险 与一般人群相比。我们的初步数据表明，纵向肌肉质量的变化 吸烟者不会因气流阻塞状态而改变，并且有或没有气流的吸烟者的子集 阻塞表明 FFMI 随着时间的推移显着下降。在这项研究中，我们将利用我们良好的 对有或没有气流阻塞的当前和以前吸烟者进行纵向队列特征分析 系列临床、生理和放射学数据，从现成的双能 X 射线确定的 FFMI 数据 吸收测定法（DXA），并储存血液样本来测试我们的主要假设，即不同的轨迹 肌肉质量变化与特定的临床和分子表型相关，并且 FFMI 快速下降 随着时间的推移，与肺部疾病的进展和功能障碍相关。在目标 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因素。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 FFMI 下降。这项研究计划将为了解自然现象提供重要的见解 有或没有气流阻塞的吸烟者的肌肉损失史，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，以便在未来的研究中有针对性的干预措施。 该培训计划与大学的密切指导和强大的研究环境相结合 匹兹堡，将促进我过渡到指导职业发展奖，并最终过渡到 作为一名医师科学家的独立职业。