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COPD cachexia: deciphering the impact of antioxidants, iron and mitochondrial function using 'omics approaches

慢性阻塞性肺病恶病质：使用“组学方法”解读抗氧化剂、铁和线粒体功能的影响

基本信息

批准号：
10677563
负责人：
Merry-Lynn Noelle McDonald Donnelly
金额：
$ 64.22万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-10 至 2025-05-31
项目状态：
未结题

项目摘要

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 study has three specific aims: 1) To determine whether genomic variation associated with the absorption and regulation of Vitamin E is more common in COPD cachexia; 2) To assess whether plasma Vitamin E in subjects with COPD cachexia are associated with impaired mitochondrial function; Exploratory Aim) To test whether iron induced transcriptional dysregulation signatures in myoblasts are preserved in transcriptomics signatures associated with COPD cachexia in skeletal muscle biopsies. Elucidating mechanisms of mitochondrial dysfunction in COPD cachexia has the potential to aid the development of therapeutics targeting mitochondrial oxidative stress. As future research, we plan to test whether ‘omic regions and metabolites identified as associated with COPD cachexia directly effect pathways involved with Vitamin E and mitochondrial function using targeted assays in myoblasts or other appropriate systems.

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，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。这研究有三个具体目标：1）确定基因组变异是否与吸收相关，维生素E的调节在COPD恶病质中更常见; 2）评估受试者的血浆维生素E是否 COPD恶病质患者与线粒体功能受损相关;探索性目的）成肌细胞中铁诱导的转录失调标记保留在转录组学标记中与COPD恶病质相关。阐明线粒体 COPD恶病质中的功能障碍有可能帮助开发靶向线粒体的治疗方法氧化应激作为未来的研究，我们计划测试是否'组学区域和代谢物确定为与COPD恶病质直接影响途径涉及维生素E和线粒体功能使用成肌细胞或其它适当系统中的靶向测定。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Associations Between Muscle Weakness and Clinical Outcomes in Current and Former Smokers.

当前和以前吸烟者的肌肉无力与临床结果之间的关联。

DOI：
10.15326/jcopdf.2022.0365
发表时间：
2023
期刊：
Chronic obstructive pulmonary diseases (Miami, Fla.)
影响因子：
0
作者：
Zou,RichardH;Nouraie,SMehdi;Rossiter,HarryB;McDonald,Merry-Lynn;DeMeo,DawnL;Mason,Stefanie;Washko,GeorgeR;Saha,PunamK;Make,BarryJ;Casaburi,Richard;Regan,ElizabethA;Bon,Jessica;COPDGeneInvestigators
通讯作者：
COPDGeneInvestigators

NIRS-Based Muscle Oxygenation Is Not Suitable to Compute Convective and Diffusive Components of O 2 Transport at V̇O 2max.

基于 NIRS 的肌肉氧合不适合计算 VÌO 2max 下 O 2 传输的对流和扩散分量。