Phenotypes of Muscle Loss in Smokers

项目总结/摘要 慢性阻塞性肺病（COPD）是美国和世界范围内的主要死因。 肌肉质量下降在COPD中很常见，并与肺部疾病的严重程度、功能障碍， 全身性炎症和全因死亡率。无脂肪质量指数（FFMI），定义为全身 瘦肌肉和骨矿物质含量调整身高平方米，是一个公认的替代指标 全身肌肉质量的变化。FFMI与肺功能相关，是一个独立的预测因子， BMI正常的COPD患者的死亡率。然而，大多数评价COPD患者FFMI的研究 横截面，不检查FFMI随时间的变化。这些纵向研究对于识别 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在当前和以前的吸烟者与气流阻塞，定义为 1秒用力呼气量与用力肺活量之比（FEV 1/FVC）<0.70。然而，吸烟者没有 气流阻塞仍有肺气肿、呼吸道症状和呼吸道恶化的风险 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， 吸烟者不受气流阻塞状态的影响， 梗阻显示FFMI随时间显著降低。在这项研究中，我们将利用我们的良好- 特征性纵向队列的当前和既往吸烟者，有或无气流阻塞， 系列临床、生理和影像学数据，根据现成的双能X线确定的FFMI数据 吸收测定法（DXA）和库存血液样本，以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相关， 随着时间的推移与肺部疾病进展和功能障碍相关。在目标1中，我将确定 有和无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子。在目标2中，我将比较肺的纵向变化， 快速FFMI吸烟者之间的功能、肺气肿、功能状态和循环炎性蛋白 而吸烟者的FFMI没有快速下降。这项研究计划将提供重要的洞察自然 有或没有气流阻塞的吸烟者的肌肉损失史，并帮助建立特定的临床和 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进行有针对性的干预。 该培训计划，结合密切的指导和强大的研究环境，在大学 匹兹堡，将促进我过渡到一个指导职业发展奖，并最终， 作为一名独立的物理学家和科学家。

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.