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

总结 慢性阻塞性肺疾病（COPD）是美国第四大死亡原因 尽管医学进步了，但死亡率仍在上升。恶病质是肌肉萎缩的一种形式， 使人衰弱的合并症，其患病率随着COPD的严重程度而增加。但是，恶病质仍然发生在 病情较轻的COPD患者。恶病质最常被认为与癌症有关。然而，在这方面， 从人群患病率来看，COPD恶病质患者多于癌症恶病质患者。然而 很少有研究调查COPD恶病质的病因，强调需要 COPD恶病质和体重减轻的研究。积累的数据包括我们自己的数据都指出了铁的作用 毒性在COPD恶病质病因学中的作用。血红素是线粒体细胞色素的重要组成部分 提供对活性氧物质（ROS）的保护。血红素生物合成的缺陷导致游离血红素的积累， 铁、ROS和线粒体功能障碍。游离铁的积累导致铁毒性和ROS的产生 特别是在缺乏足够的抗氧化剂如维生素E摄入的情况下。因此，我们的总体 一种假说是COPD恶病质中的铁毒性是由受损的抗氧化剂和线粒体功能驱动的。这 补充将在父R01的目标1上扩展。1)为了确定基因组变异是否与 维生素E的吸收和调节在COPD恶病质中更常见，我们将进行整体分析， 来自All of Us招募的受试者和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.