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: 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
• 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/10677563
• 关键词: Aminolevulinate; Antioxidants; Binding; Biological Assay; Biopsy; Body Weight decreased; Bronchoalveolar Lavage; Cachexia; Cancer Patient; Cardiovascular system; Cause of Death; Chronic Obstructive Pulmonary Disease; Citrate (si)-Synthase; Cytochromes; Data; Defect; Electron Transport; Enzymes; Etiology; Ferritin; Framingham Heart Study; Genes; Genetic; Genetic Transcription; Genetic Variation; Health Expenditures; Heart; Heme; Homeostasis; Impairment; Intake; Investigation; Iron; Iron Regulatory Protein 2; Jackson Heart Study; Life; Liver; 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 Factors; Role; Serum; Severities; Severity of illness; Skeletal Muscle; Smoke; Smoker; Smoking; System; Testing; Thinness; Toxic effect; Trans-Omics for Precision Medicine; Transcript; Translational Repression; 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; mRNA Translation; mitochondrial dysfunction; mortality; mortality risk; muscle form; patient population; preservation; public health relevance; recruit; therapeutic development; therapeutic target; transcriptome sequencing; transcriptomics; whole genome; Aminolevulinate; Antioxidants; Binding; Biological Assay; Biopsy; Body Weight decreased; Bronchoalveolar Lavage; Cachexia; Cancer Patient; Cardiovascular system; Cause of Death; Chronic Obstructive Pulmonary Disease; Citrate (si)-Synthase; Cytochromes; Data; Defect; Electron Transport; Enzymes; Etiology; Ferritin; Framingham Heart Study; Genes; Genetic; Genetic Transcription; Genetic Variation; Health Expenditures; Heart; Heme; Homeostasis; Impairment; Intake; Investigation; Iron; Iron Regulatory Protein 2; Jackson Heart Study; Life; Liver; 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 Factors; Role; Serum; Severities; Severity of illness; Skeletal Muscle; Smoke; Smoker; Smoking; System; Testing; Thinness; Toxic effect; Trans-Omics for Precision Medicine; Transcript; Translational Repression; 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; mRNA Translation; mitochondrial dysfunction; mortality; mortality risk; 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.

概括 慢性阻塞性肺疾病（COPD）是美国第四大死亡原因 随着死亡率继续上升，目的地在医学方面的进步。卡氏症是一种肌肉浪费的形式，是 使人衰弱的衰弱率随着COPD的严重程度而增加。但是，卡希克西亚仍然存在 COPD患有米勒病严重程度的患者。在癌症方面，最常见的是恶病质。然而， 根据人群的患病率，患有恶病质的COPD患者比恶病质患者多。然而 很少有研究调查COPD病原体的病因，强调了对 对COPD cachexia和减肥的研究。累积数据，包括我们自己的角色 COPD病原体病因的毒性。血红素是线粒体细胞色素的重要组成部分 提供免受活性氧（ROS）的保护。血红素生物合成中的缺陷导致自由产生 铁，ROS和线粒体功能障碍。自由铁的积聚导致铁毒性和ROS的产生 特别是在没有足够摄入抗氧化剂（例如维生素）的情况下。因此，我们的总体 假设是COPD恶病质中的铁毒性是由抗氧化剂和线粒体功能受损驱动的。这 研究具有三个具体目的：1）确定基因组变异是否与抽象相关 维生素E的调节在COPD恶病质中更为常见。 2）评估受试者中的血浆维生素E是否 与COPD cachexia有关线粒体功能受损而与之相关。探索目的）测试是否 铁诱导的成肌细胞中的转录失调特征保留在转录组学特征中 与骨骼肌活检中的COPD cachexia相关。阐明线粒体的机制 COPD恶病质功能障碍有可能帮助开发针对线粒体的治疗剂 氧化应激。随着未来的研究，我们计划测试“ OMIC区域和代谢物是否被确定为 与COPD CACHEXIA有关直接影响与维生素E和线粒体功能有关的途径 在成肌细胞或其他适当的系统中使用有针对性的测定。