Network Medicine Approaches to Cachexia in COPD

恶病质的特征是体重和肌肉迅速减轻，是许多复杂疾病的常见症状，如慢性阻塞性肺疾病(COPD)、充血性心力衰竭(CHF)和癌症。不管最初的疾病诊断是什么，恶病质的存在都与预后不良有关。同样重要的是，观察到并不是每个被诊断为患有慢性阻塞性肺疾病和充血性心力衰竭等复杂疾病的患者都会出现恶病质。这一信息促使我假设，在这些不同的复杂、慢性特征中，存在影响恶病质的共同基因和途径。COPD是美国第三大死因，据估计，高达20%的COPD病例会发展为恶病质，但由于与定义恶病质相关的限制，这个数字可能被高估了。恶病质的发展是死亡率的有力预测因素。这项研究有三个具体目的：1)确定与COPD患者恶病质及相关特征相关的遗传和基因组变异；2)测试COPD患者的胸肌面积(PMA)、脱脂重量(FFM)与基因表达数据之间的显著关系；3)确定COPD患者中与恶病质和PMA相关的基因表达特征。作为我K99分析的一部分，我利用了几个具有良好特征的COPD人群的可用性，以调查肌肉萎缩和恶病质的标志，如低PMA和BMI的变化。然而，该领域需要对COPD病例队列进行重点调查，这些病例表现为肌肉萎缩和恶病质。这样一个队列的发展是她的应用程序(目标2)R00阶段的一个关键重点，并将为她的第一个R01应用程序提供试点数据。

Cachexia, featuring rapid loss of weight and muscle, is common to many complex diseases such as chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF) and cancer. Regardless of the primary disease diagnosis, the presence of cachexia is associated with poor prognosis. Equally important is the observation that not every patient diagnosed with a complex disease such as COPD and CHF becomes cachectic. This information motivated me to hypothesize that there are common genes and pathways influencing cachexia in these different complex, chronic traits. COPD is the third leading cause of death in the United States and it has been estimated that as high as 20% of COPD cases develop cachexia, however this number may be overestimated due to limitations associated with defining cachexia. The development of cachexia is a strong predictor of mortality. This study has three specific aims: 1) Identify genetic and genomic variants associated with cachexia and related traits in COPD; 2) Test for significant relationships between pectoralis muscle area (PMA), fat-free mass (FFM) and gene expression data in COPD cases; 3) Identify gene expression signatures associated with cachexia and PMA in COPD cases. As part of my K99 analyses, I took advantage of the availability of several well-characterized COPD populations in order to investigate markers of muscle wasting and cachexia such as low PMA and change in BMI. However, the field is in need of investigations focused on cohorts of COPD cases phenotyped for muscle wasting and cachexia. The development of such a cohort is a key focus of the R00 phase of her application (Aim 2) and will lead to pilot data for her first R01 applications.