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.

概括慢性阻塞性肺疾病（COPD）是美国第四大死因尽管医学取得了进步，但死亡率仍在持续上升，恶病质（一种肌肉萎缩）是一种疾病。使人衰弱的共病，其患病率随着慢性阻塞性肺病的严重程度而增加，但恶病质仍然存在于其中。然而，病情较轻的慢性阻塞性肺病患者恶病质通常被认为与癌症有关。从人群患病率来看，患有恶病质的慢性阻塞性肺病患者多于患有恶病质的癌症患者。很少有研究调查 COPD 恶病质的病因，强调需要对慢性阻塞性肺病恶病质和减肥的研究不断积累，包括我们自己的观点，表明铁的作用。慢性阻塞性肺病恶病质的病因学中的毒性血红素是线粒体细胞色素的重要组成部分。提供保护，防止血红素生物合成缺陷导致游离氧积累。铁、ROS 和线粒体功能障碍导致铁毒性和 ROS 的产生。特别是在缺乏足够的抗氧化剂（例如维生素 E）摄入的情况下。因此，我们的首要任务是假设慢性阻塞性肺病恶病质中的铁毒性是由抗氧化和线粒体功能受损引起的。研究有三个具体目标：1）确定基因组变异是否与吸收和维生素 E 的调节在慢性阻塞性肺病 (COPD) 恶病质中更为常见；2) 评估受试者血浆维生素 E 是否存在变化；慢性阻塞性肺病恶病质是否与线粒体功能受损有关；探索性目的）测试是否成肌细胞中铁诱导的转录失调特征保留在转录组学特征中骨骼肌活检中与慢性阻塞性肺病恶病质相关的线粒体机制。慢性阻塞性肺病恶病质的功能障碍有可能有助于开发针对线粒体的疗法作为未来的研究，我们计划测试“组学区域和代谢物是否被确定为” 与慢性阻塞性肺病（COPD）恶病质相关，直接影响与维生素 E 和线粒体功能有关的通路在成肌细胞或其他适当的系统中使用靶向测定。

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：
发表时间：
2023-01-25
期刊：
影响因子：
0
作者：
Zou, Richard H;Nouraie, S Mehdi;Rossiter, Harry B;McDonald, Merry;DeMeo, Dawn L;Mason, Stefanie;Washko, George R;Saha, Punam K;Make, Barry J;Casaburi, Richard;Regan, Elizabeth A;Bon, Jessica;COPDGene Investigators
通讯作者：
COPDGene Investigators

NIRS-Based Muscle Oxygenation Is Not Suitable to Compute Convective and Diffusive Components of O 2 Transport at V̇O 2max : Response to Manferdelli, Barstow, and Millet.

基于 NIRS 的肌肉氧合不适合计算 VÌO 2max 时 O 2 传输的对流和扩散分量：对 Manferdelli、Barstow 和 Millet 的响应。

DOI：
发表时间：
2023-11-01
期刊：
影响因子：
4.1
作者：
Porcelli, Simone;Pilotto, Andrea M;Rossiter, Harry B
通讯作者：
Rossiter, Harry B

Selective androgen receptor modulation for muscle weakness in chronic obstructive pulmonary disease: a randomised control trial.

选择性雄激素受体调节慢性阻塞性肺疾病肌无力：一项随机对照试验。

DOI：
发表时间：
2023-03
期刊：
影响因子：
10
作者：
Mohan, Divya;Rossiter, Harry;Watz, Henrik;Fogarty, Charles;Evans, Rachael A;Man, William;Tabberer, Maggie;Beerahee, Misba;Kumar, Subramanya;Millns, Helen;Thomas, Sebin;Tal;Russell, Alan J;Holland, Marie Claire;Akinseye, Chika;N
通讯作者：
N

Inventing the wheel: understanding heterogeneity of response to skeletal muscle dysfunction interventions in women with COPD.

发明轮子：了解慢性阻塞性肺病女性骨骼肌功能障碍干预措施反应的异质性。