Network Medicine Approaches to Cachexia in COPD

恶病质以体重和肌肉的快速减少为特征，在许多复杂疾病中很常见，如慢性阻塞性肺疾病（COPD）、充血性心力衰竭（CHF）和癌症。无论原发疾病诊断如何，恶病质的存在与不良预后相关。同样重要的是，并不是每个被诊断患有复杂疾病（如慢性阻塞性肺病和慢性心力衰竭）的患者都会变成恶病质。这些信息促使我假设，在这些不同的复杂的慢性特征中，有共同的基因和途径影响恶病质。COPD是美国第三大死亡原因，据估计，高达20%的COPD病例发展为恶病质，然而由于对恶病质定义的限制，这一数字可能被高估了。恶病质的发展是死亡率的一个强有力的预测指标。本研究有三个具体目的：1)确定与慢性阻塞性肺病恶病质及相关特征相关的遗传和基因组变异；2) COPD患者胸肌面积（PMA）、无脂量（FFM）与基因表达数据的相关性检验；3)确定与慢性阻塞性肺病患者恶病质和PMA相关的基因表达特征。作为我的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物，如低PMA和BMI变化。然而，该领域需要对肌肉萎缩和恶病质表型的COPD病例进行研究。这样一个队列的开发是她申请R00阶段（目标2）的关键焦点，并将为她的第一个R01申请提供试点数据。

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.