COPD Cachexia: Deciphering the Impact of Antioxidants, Iron and Mitochondrial Function Using 'Omics Approaches

摘要 慢性阻塞性肺疾病(COPD)是美国第四大死因 尽管医学取得了进步，但死亡率仍在继续上升。恶病质是肌肉萎缩的一种形式，是一种 衰弱的共病，其患病率随着COPD的严重程度而增加。但是，恶病质仍在 疾病严重程度较轻的COPD患者。恶病质最常被认为是与癌症有关的。然而， 从人群患病率来看，COPD患者合并恶病质的人数多于癌症患者合并恶病质的人数。还没有 很少有研究探讨COPD恶病质的病因，强调有必要 慢性阻塞性肺疾病恶病质与减肥的调查。积累数据，包括我们自己对铁的作用 慢性阻塞性肺疾病恶病质病因学的毒性。血红素是线粒体细胞色素的重要组成部分 提供对活性氧物种(ROS)的保护。血红素生物合成缺陷导致游离 铁、ROS和线粒体功能障碍。游离铁的积聚导致铁中毒和ROS的产生 尤其是在缺乏维生素E等抗氧化剂的情况下，我们最主要的 假说认为COPD恶病质中铁毒性是由抗氧化剂和线粒体功能受损引起的。这 补充将在父R01的Aim1上展开。1)确定基因组变异是否与 维生素E的吸收和调节在COPD恶病质中更为常见，我们将对其进行整体分析。 来自我们所有受试者和Trans Omics for Precision参与者的基因组序列数据 医学(TOPMed)倡议。

SUMMARY Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of death in the United States with mortality continuing to rise despite advances in medicine. Cachexia, a form of muscle wasting, is a debilitating co-morbidity whose prevalence increases with severity of COPD. But, cachexia still occurs among COPD patients with milder disease severity. Cachexia is most often thought of with respect to cancer. However, by population prevalence there are more COPD patients with cachexia than cancer patients with cachexia. Yet there have been few studies investigating the etiology of COPD cachexia underscoring the need for investigations of COPD cachexia and weight-loss. Accumulating data including our own points to a role for iron toxicity in the etiology of COPD cachexia. Heme is an essential component of mitochondrial cytochromes providing protection from reactive oxygen species (ROS). Defects in heme biosynthesis cause buildup of free iron, ROS and mitochondrial dysfunction. Buildup of free iron leads to iron toxicity and production of ROS particularly in the absence of adequate intake of antioxidants such as Vitamins E. As such, our overarching hypothesis is iron toxicity in COPD cachexia is driven by impaired antioxidant and mitochondrial function. This supplement will expand on Aim1 of the parent R01. 1) To determine whether genomic variation associated with the absorption and regulation of Vitamin E is more common in COPD cachexia we will perform analysis of whole- genome sequence data from subjects recruited from All of Us and participants in the Trans Omics for Precision Medicine (TOPMed) Initiative.