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

• 批准号: 10209552
• 负责人: Merry-Lynn Noelle McDonald Donnelly
• 金额: $ 66.65万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10209552
• 关键词: Aminolevulinate; Antioxidants; Binding; Biological Assay; Biopsy; Body Weight decreased; Bronchoalveolar Lavage; Cachexia; Cancer Patient; Cardiovascular system; Cause of Death; Chronic Obstructive Airway Disease; Citrate (si)-Synthase; Cytochromes; Data; Defect; Electron Transport; Enzymes; Equilibrium; Etiology; Ferritin; Framingham Heart Study; Genes; Genetic; Genetic Transcription; Genetic Translation; Genetic Variation; Healthcare; Heart; Heme; Homeostasis; Impairment; Intake; Investigation; Iron; Iron Regulatory Protein 2; Jackson Heart Study; Life; Lung; Malignant Neoplasms; Mediating; Mediation; Medicine; Messenger RNA; Mitochondria; Multi-Ethnic Study of Atherosclerosis; Muscle; Muscular Atrophy; Myoblasts; National Heart, Lung, and Blood Institute; Oxidative Stress; Particulate Matter; Pathway interactions; Patients; Phenotype; Plasma; Population; Prevalence; Production; Proteins; Quantitative Trait Loci; Reactive Oxygen Species; Regulation; Research; Response Elements; Risk; Risk Factors; Role; Serum; Severities; Severity of illness; Skeletal Muscle; Smoke; Smoker; Smoking; System; Testing; Thinness; Tocopherols; Toxic effect; Trans-Omics for Precision Medicine; Transcript; Translations; United States; Variant; Vitamin E; Vitamins; Work; absorption; alpha-tocopherol transfer protein; cancer cachexia; cigarette smoke; cohort; comorbidity; genetic variant; genome wide association study; genomic variation; heme biosynthesis; mitochondrial dysfunction; mortality; muscle form; patient population; preservation; public health relevance; recruit; therapeutic development; therapeutic target; transcriptome sequencing; transcriptomics; whole genome

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.

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 这项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COPD恶病质中更常见；2)评估受试者血浆维生素E 患有COPD的恶病质与线粒体功能受损有关；探索性目的)测试 成肌细胞中铁诱导的转录失调信号保存在转录信号中 与骨骼肌活检中的慢性阻塞性肺疾病恶病质有关。阐明线粒体的作用机制 COPD恶病质的功能障碍有可能帮助开发针对线粒体的治疗方法 氧化应激。作为未来的研究，我们计划测试被鉴定为 与COPD相关的恶病质直接影响与维生素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分析。