The Role of Mitochondrial DNA Mutations in Oxidant-Mediated Lung Injury

EPA Grant Number: R825702C008
Subproject: this is subproject number 008 , established and managed by the Center Director under grant R825702
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Environmental Lung Disease Center (National Jewish Medical and Research Center)
Center Director: Mason, Robert J.
Title: The Role of Mitochondrial DNA Mutations in Oxidant-Mediated Lung Injury
Investigators: Day, Brian
Institution: National Jewish Medical and Research Center
EPA Project Officer: Chung, Serena
Project Period: February 16, 1998 through February 28, 2003 (Extended to February 28, 2004)
RFA: Environmental Lung Disease Center (National Jewish Medical and Research Center) (1998) RFA Text |  Recipients Lists
Research Category: Targeted Research

Objective:

The objective of this project is to explore the role of somatic mitochondrial DNA (mtDNA) mutations in the etiology of oxidant-induced lung injury. Oxidative damage in post mitotic tissues such as the brain, heart and skeletal muscle are thought to account for the increased mutations in mtDNA that accumulate with age. The mitochondria generate high levels of reactive oxygen species on the inner mitochondrial membrane that can damage the nearby mtDNA. Recent data suggests that manganese superoxide dismutase (MnSOD) is a critical antioxidant enzyme that controls superoxide levels in the mitochondria and is an enzyme that declines with age. The relationships between oxidative damage, the accumulation of somatic mtDNA mutations and mitochondrial dysfunction in the pathogenesis of lung disease is virtually unexplored. It is hypothesized that chronic oxidative stress causes an accumulation of somatic mtDNA mutations which results in mitochondrial dysfunction in cell copulations vital to the maintenance of the of the lung. To test this hypothesis, proposed studies will: I) evaluate the role of oxidative stress in the production of somatic mtDNA mutation events and fibroproliferative responses in cultured fibroblasts; 2) study the role of somatic mtDNA mutations in the etiology of oxidatant-induced lung injury in mice that are genetically deficient in mitochondrial MnSOD. These studies have the potential to further define the etiology of oxidant-induced lung injury and may insight to risk factors associated injury responses in the lung.

Supplemental Keywords:

Health, Scientific Discipline, Health Risk Assessment, Risk Assessments, Disease & Cumulative Effects, Biochemistry, Biology, health effects, antioxidants, lung disease, airway disease, enzymes, DNA mutations, oxidants, etiology, human exposure, lung dysfunction, mitochondrial membrane, human health risk

Progress and Final Reports:

  • 1998
  • 1999
  • 2000
  • 2001
  • 2002
  • 2003
  • Final

  • Main Center Abstract and Reports:

    R825702    Environmental Lung Disease Center (National Jewish Medical and Research Center)

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R825702C001 SP-A and SP-D in Environmental Lung Disease
    R825702C003 Adaptation to Nitrogen Dioxide: Role of Altered Glycolytic Pathway Enzyme Expression and NF-κB-Dependent Cellular Defenses Against Apoptosis
    R825702C005 Inhalation of Particulate Matter Alters the Allergic Airway Response to Inhaled Allergen
    R825702C006 Particle-Induced Lung Inflammation and Extracellular EC-SOD
    R825702C007 Indoor-Outdoor Relationships of Airborne Particle Count and Endotoxin Concentrations
    R825702C008 The Role of Mitochondrial DNA Mutations in Oxidant-Mediated Lung Injury
    R825702C009 Immunopathogenesis of Hypersensitivity Pneumonitis in the Mouse
    R825702C010 Activation of Natural T Lymphocytes by Diesel Exhaust Particulates Leads to Their Production of Interleukin-4 and TH2 Lymphocyte Differentiation to Allergen
    R825702C011 Latex Antigen Levels During Powdered and Powderless Glove Use
    R825702C012 Adjuvant Effects of Ozone in a Model of Allergen-Induced Airway Inflammation and Hyperresponsiveness
    R825702C013 Acute Exposure to Particulate Air Pollution in Childhood Asthma
    R825702C014 Mechanisms of Ozone Toxicity to the Lung