Mitochondrial Bioenergetic Dysfunction and Chlorine Toxicity

Summary

Principal Investigator: Sadis Matalon
Abstract: DESCRIPTION (provided by applicant): Chlorine (Cl2) is a highly irritant and reactive gas produced in large quantities throughout the world and used extensively for pulp bleaching, waste sanitation and in the manufacturing of various pharmaceuticals. It also poses a significant threat to public health when inhaled. Exposure to Cl2, released into the atmosphere during transportation and industrial accidents, as well as acts of terrorism resulted in significant morbidity and mortality to both humans and animals. There is no safe exposure to Cl2: Even domestic exposure to low levels of Cl2 may result in wheezing and exacerbate the clinical outcome of asthma and chronic obstructive pulmonary disease. When inhaled, Cl2 first reacts with antioxidants in the lung epithelial lining fluid (ELF);when antioxidants are depleted, it fors relatively stable adducts with proteins, components of the extracellular matrix and unsaturated fatty acids which then proceed to prolong the toxicity of the initial Cl2 exposure and contribute t the long term pathology. In this proposal we will test the hypothesis that these secondary reactive species target the mitochondrion and so decrease mitochondrial quality and cause bioenergetic dysfunction which delays tissue recovery and repair. Based upon these data we hypothesize that mitochondria are a critical target for Cl2 toxicity in lung epithelial cells and te combined strategy of preventing mitochondrial oxidative damage by mitochondrial targeted antioxidants (such as MitoQ) with enhancing mitophagy (by rapamycin and trehalose), will be beneficial in ameliorating Cl2 toxicity. This hypothesis will be tested by completing the in vitro and in vivo studies highlighted in these two highly integrated specific aims: SA-1: Determine the mechanisms and physiological sequelae of mitochondria injury and autophagy following exposure of human airway cells to Cl2 in vitro. SA-2: Determine if post Cl2 administration of MitoQ, rapamycin and trehalose in mice decreases Cl2 induced mortality and lung injury and improves mitochondrial bioenergetics function. Completion of these experiments will provide the rational basis for additional studies to establish effective therapies for a major environmental and public health threat to humans.
Funding Period: 2013-09-24 - 2015-08-31
more information: NIH RePORT

Research Grants

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
  2. TOXIC SUBSTANCES IN THE ENVIRONMENT
    Martyn T Smith; Fiscal Year: 2013
  3. DEVELOPMENT AND CONTROL OF PULMONARY ALVEOLAR STABILITY
    Samuel Hawgood; Fiscal Year: 2013
  4. PPG - Gene Therapy for Cystic Fibrosis Lung Disease
    Paul B McCray; Fiscal Year: 2013
  5. Physically-Based Biodosimetry for Triage After a Large Radiation Incident
    Harold M Swartz; Fiscal Year: 2013
  6. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
  7. MPD RESEARCH CONSORTIUM
    Ronald Hoffman; Fiscal Year: 2013
  8. Developmental Exposure Alcohol Research Center
    Linda Patia Spear; Fiscal Year: 2013
  9. M. D. Anderson Cancer Center SPORE in Multiple Myeloma
    ROBERT ZYGMUNT ORLOWSKI; Fiscal Year: 2013
  10. Growth Control in Multiple Myeloma
    Bart Barlogie; Fiscal Year: 2013

Detail Information

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. TOXIC SUBSTANCES IN THE ENVIRONMENT
    Martyn T Smith; Fiscal Year: 2013
    ..The program will be overseen and coordinated by an Administration core (A). ..
  3. DEVELOPMENT AND CONTROL OF PULMONARY ALVEOLAR STABILITY
    Samuel Hawgood; Fiscal Year: 2013
    ..abstract_text> ..
  4. PPG - Gene Therapy for Cystic Fibrosis Lung Disease
    Paul B McCray; Fiscal Year: 2013
    ..The discoveries from this PPG will accelerate the development of gene-based medicine for patients who suffer from this devastating disease...
  5. Physically-Based Biodosimetry for Triage After a Large Radiation Incident
    Harold M Swartz; Fiscal Year: 2013
    ..abstract_text> ..
  6. INNATE AND ADAPTIVE IMMUNE RESPONSES IN TH2-HIGH ASTHMA
    John V Fahy; Fiscal Year: 2013
    ..Including studies in human biospecimens in a PPG that promises to advance understanding of airway TH2 inflammation in ways that are highly relevant to patients with asthma. ..
  7. MPD RESEARCH CONSORTIUM
    Ronald Hoffman; Fiscal Year: 2013
    ..abstract_text> ..
  8. Developmental Exposure Alcohol Research Center
    Linda Patia Spear; Fiscal Year: 2013
    ..Thus, the DEARC will serve as a nexus of alcohol research in Central New York and as a beacon for national activities. ..
  9. M. D. Anderson Cancer Center SPORE in Multiple Myeloma
    ROBERT ZYGMUNT ORLOWSKI; Fiscal Year: 2013
    ..abstract_text> ..
  10. Growth Control in Multiple Myeloma
    Bart Barlogie; Fiscal Year: 2013
    ..This work will be accomplished with access to 5 shared resource cores. ..
  11. Program Project Grant - Genetics and Ankylosing Spondylitis (AS) Pathogenesis
    JOHN DUFFIN REVEILLE; Fiscal Year: 2013
    ..abstract_text> ..
  12. Caloric Restricted Rodent Colony
    RICK MORIN; Fiscal Year: 2013
    ..The purpose of this project is to develop, maintain and distribute a standing colony ofaged, calorically restricted rodents ofdefined strains for use by investigators in studies of aging. ..
  13. MECHANISMS AND MODULATION OF ACCELLULAR HbA TOXICITY
    Joel M Friedman; Fiscal Year: 2013
    ..Olson, leader);Core D, Chemical, Cellular, And Animal Toxicity Evaluations (FDA, Alayash leader) ..
  14. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
    ..Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases. ..
  15. GENE THERAPY USING HEMATOPOIETIC STEM CELLS
    Donald B Kohn; Fiscal Year: 2013
    ..The Project and Core leaders have complementary expertise in the relevant areas of experimental hematology, gene therapy, immunology, and signal transduction and have a long-standing record of interactive collaborations. ..
  16. Neutralizing Antibody &AAV FIX Gene Therapy
    Richard J Samulski; Fiscal Year: 2013
    ..The long-term objective of this PPG is to advance basic understanding of vector-cell-animal model interactions for safe gene delivery. ..
  17. Elucidating Risks: From Exposure and Mechanism to Outcome
    James A Swenberg; Fiscal Year: 2013
    ..This Program is highly relevant to Superfund by addressing high-priority chemicals and by focusing on mechanisms underlying health effects, exposure assessment, and remediation to mitigate exposure and toxicity. ..
  18. BIOMARKERS OF EXPOSURE TO HAZARDOUS SUBSTANCES
    Bruce D Hammock; Fiscal Year: 2013
    ..abstract_text> ..
  19. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
    ..A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF. ..
  20. Superfund Metal Mixtures, Biomarkers and Neurodevelopment
    David C Bellinger; Fiscal Year: 2013
    ..Aim 4- To promote rapid dissemination of significant research findings;and Aim 5- Compliance- To ensure compliance with NIH requirements for data and resource-sharing and the human and animal institutional review board requirements ..
  21. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  22. Vascular Subphenotypes of Lung Disease
    Mark T Gladwin; Fiscal Year: 2013
    ..vascular disease Project 3: Pulmonary vascular-targeted NO therapeutic strategies Core A: Administrative core Core B: Pre-Clinical Models of PAH Core C: Translational Vascular Phenomics, Genomics and Epidemiology Core ..
  23. Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers
    Augustine M Choi; Fiscal Year: 2013
    ..4) Clinical Outcomes and Molecular Phenotypes in Smokers with Parenchymal Lung Disease Cores: 1) Administrative Core 2) Respiratory Computational Discovery Core 3) Clinical Biorepository Core 4) Murine Models and Molecular Analysis Core ..
  24. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
    ..Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease. ..
  25. Neuro-Circulatory Function in Chronic Heart Failure
    Irving H Zucker; Fiscal Year: 2013
    ..The role of exercise training in modulating ROS generation and antioxidant enzymes in animals with CHF will also be investigated in this project. ..