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: 10426201
• 负责人: Merry-Lynn Noelle McDonald Donnelly
• 金额: $ 64.37万
• 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/10426201
• 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; 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.

总结