Network Medicine Approaches to Cachexia in COPD

描述(申请人提供)：恶病质，以体重和肌肉的迅速减轻为特征，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)、癌症和艾滋病。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。作为我长期职业计划的第一步，开发一个关于复杂疾病中恶病质的网络医学方法的研究计划，我计划主要研究COPD患者群体中的恶病质。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。阐明COPD恶病质决定因素对公共健康的影响与我在网络医学部钱宁分部接受培训的时间不谋而合，在那里我可以接触到几个具有良好特征的COPD人群(NH5,300例COPD病例，采用纵向测量)。我们建议首次应用多阶段GWA术治疗任何疾病的恶病质。对慢性阻塞性肺疾病恶病质的研究将为其他慢性病的恶病质研究提供参考。网络医学应用系统生物学方法，如整合来自基因类型、基因表达水平和蛋白质-蛋白质相互作用的数据，试图了解系统中的扰动可能如何导致复杂的疾病。这项研究有三个具体目标。(1)我们将在三个典型的COPD群体(ECLIPSE、TESRA和COPD基因)中研究COPD恶病质的遗传学，并从COPD基因中研究COPD患者恶病质与全外显子测序(WES)变异的关系。我们将把常见基因变异的发现与蛋白质之间的相互作用结合起来，以识别新的和/或已知的疾病模块。(2)我们将招募一个新的COPD病例群体，以证明使用双X射线吸收测量仪(DXA)测量的无脂肪质量(FFM)与胸部计算机断层扫描(CT)测量的胸肌面积(PMA)之间存在相关性。此外，我们将测试基因表达签名与PMA和FFM之间的相关性。(3)我们将搜索与恶病质相关的基因表达特征，并生成差异共表达网络。这些发现将提高我们对COPD恶病质的病因和流行病学的了解。这将是一个长期计划的第一步，该计划旨在探索包括慢性阻塞性肺病、充血性心力衰竭、癌症和艾滋病在内的复杂疾病的恶病质网络医学图景。

DESCRIPTION (provided by applicant): ABSTRACT 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), cancer and AIDS. 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. For a first step in my long-term career plan to develop a research program on network medicine approaches to cachexia in complex disease, I plan to primarily study cachexia in COPD patient populations. 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. The public health impact of elucidating determinants of COPD cachexia coincides with my training in the Channing Division of Network Medicine where I have access to several well- characterized COPD populations (NH5,300 COPD cases with longitudinal measures). We propose the first application of a multi-stage GWAS to cachexia in any disease. Research on cachexia in COPD will inform cachexia research for other chronic diseases. Network medicine applies systems biology approaches, such as integration of data from genotypes, gene expression levels and protein-protein interactions, to try to understand how perturbations in the system may lead to complex diseases. This study has three specific aims. (1) We will investigate the genetics of COPD cachexia in three well-characterized COPD populations (ECLIPSE, TESRA and COPDGene) and we will investigate the association of whole-exome sequencing (WES) variants with cachexia in COPD cases from COPDGene. We will integrate findings from common genetic variants with protein-protein interactions to identify novel and/or known disease modules. (2) We will recruit a new COPD case population in order to demonstrate that fat-free mass (FFM) measure using Dual X- ray Absorptiometry (DXA) correlates with pectoralis muscle area (PMA) measured from chest computed tomography (CT) scans. Further, we will test for correlation between gene expression signatures with PMA and FFM. (3) We will search for gene expression signatures that are associated with cachexia and generate a differential co-expression network. These findings will improve our understanding of the etiology and epidemiology of cachexia in COPD. This will be the first step in a long term plan to probe the cachexia network medicine landscape of complex diseases including COPD, CHF, cancer and AIDS.