The RAGE of COPD

Summary

Principal Investigator: John R Hoidal
Abstract: DESCRIPTION (provided by applicant): Abstract: Objective: To determine the pathogenic mechanisms of COPD and to define new ways to prevent or treat the disorder. Hypotheses: We propose a new paradigm for a central role of the receptor for advanced glycation end products (RAGE) and its ligands in the emphysema pathogenesis. We hypothesize that RAGE and its ligands through distinct signaling pathways that include NADPH oxidase(s) (Nox)-generated reactive oxygen species (ROS) activate key transcription factors including NF-B and EGR-1 to propagate the inflammation, apoptosis and lung destruction leading to emphysema. Background: Chronic obstructive pulmonary disease (COPD) is a devastating disorder characterized by chronic airflow limitation. It is among the most common discharge diagnoses from VA hospitals and will be the third leading cause of death worldwide by the year 2020. In part, due to the still poorly elucidated or undiscovered mechanisms causing COPD, treatment options are very limited. COPD is associated with chronic inflammation, apoptosis and emphysema. This proposal is aimed at defining the biochemical mechanisms for the inflammation, apoptosis and emphysema. Aims: Aim 1 will determine the ability of RAGE and its ligands to promote inflammation, apoptosis and lung destruction leading to the development of emphysema. It will test the hypothesis that advanced glycation end products (AGEs) or other ligands interact with RAGE to amplify the inflammatory response and apoptosis that mediate the lung destruction leading to the development of emphysema. Aim 2 will determine the role of signaling intermediates in RAGE-induced lung inflammation, apoptosis and destruction leading to the development of emphysema. It will test the hypothesis that RAGE and its ligands acting through Nox(s) and NF-B or Egr-1, cause synthesis and release of pro-inflammatory cytokines and additional RAGE ligands, which further perpetuate RAGE expression, inflammation, oxidative and/or proteinase stress and apoptosis with resulting lung destruction. Aim 3 will determine whether lung macrophage RAGE or alveolar epithelial cell RAGE is primarily responsible for propagating inflammation, apoptosis and lung destruction leading to the development of emphysema. These studies will take advantage of unique mouse models with mononuclear or alveolar epithelial cell specific deletion of RAGE to test the hypothesis that lung macrophage RAGE is the primary effector of RAGE-mediated inflammation and lung destruction. Research Design: We will study the expression of RAGE and its ligands during the development of emphysema using a model of cigarette smoke exposure to mice. Mutant mice exposed to cigarette smoke will be used to determine the importance of RAGE and specific signaling pathways in emphysema development. Studies in isolated cells exposed to cigarette smoke extract will complement those proposed in mouse models to aide in delineating signaling pathways. A particular focus will be the role(s) of RAGE expressed on lung macrophages and alveolar epithelium since these are the primary sources of RAGE expression in the lungs of cigarette smokers. Significance: Successful outcome of this proposal will transform basic understanding of the pathobiochemistry of emphysema by focusing on pathways currently only tangentially mentioned in discussions of the mechanisms for development of the disorder. It will impact our ability to prevent or reduce the enormous medical burden caused by cigarette smoking. Nowhere is the need for new approaches with clinical application more important in pulmonary diseases than in COPD.
Funding Period: 2013-04-01 - 2017-03-31
more information: NIH RePORT

Research Grants

  1. Mental Stress Ischemia: Prognosis and Genetic Influences
    Arshed A Quyyumi; Fiscal Year: 2013
  2. Biosynthesis and Function of Lactosaminyl Glycans in Hematopoiesis
    Robert Sackstein; Fiscal Year: 2013
  3. PATHOPHYSIOLOGY OF THE ENDOTHELIUM
    Francis W Luscinskas; Fiscal Year: 2013
  4. A TOLERANCE APPROACH TO XENOTRANSPLANTATION
    David H Sachs; Fiscal Year: 2013
  5. MULTIDISCIPLINARY STRUCTURES AT VASCULAR CELL SURFACES
    Timothy A Springer; Fiscal Year: 2013
  6. CHEMISTRY AND BIOLOGY OF HEPARAN SULFATE
    UMESH RAMANLAL DESAI; Fiscal Year: 2013
  7. MOLECULAR BIOLOGY OF HEMORRHAGIC SHOCK
    Timothy R Billiar; Fiscal Year: 2013
  8. TH17 Autoimmunity to Type V Collagen in Heart and Lung Transplant
    David S Wilkes; Fiscal Year: 2013
  9. Developmental Exposure Alcohol Research Center
    Linda Patia Spear; Fiscal Year: 2013
  10. Distinct and Overlapping Pathways of Fibrosis and Emphysema in Cigarette Smokers
    Augustine M Choi; Fiscal Year: 2013

Detail Information

Research Grants30

  1. Mental Stress Ischemia: Prognosis and Genetic Influences
    Arshed A Quyyumi; Fiscal Year: 2013
    ....
  2. Biosynthesis and Function of Lactosaminyl Glycans in Hematopoiesis
    Robert Sackstein; Fiscal Year: 2013
    ..This research effort should yield new treatments to improve marrow function in such conditions. (End of Abstract) ..
  3. PATHOPHYSIOLOGY OF THE ENDOTHELIUM
    Francis W Luscinskas; Fiscal Year: 2013
    ..g., heart attacks and strokes), as well as other organs and tissues of the body. These mechanistic insights may help identify novel therapeutic targets for the treatment of a broad spectrum of inflammatory diseases. ..
  4. A TOLERANCE APPROACH TO XENOTRANSPLANTATION
    David H Sachs; Fiscal Year: 2013
    ..abstract_text> ..
  5. MULTIDISCIPLINARY STRUCTURES AT VASCULAR CELL SURFACES
    Timothy A Springer; Fiscal Year: 2013
    ..Administrative (Springer) and Protein Expression (Lu) Cores enhance efficiency of the PPG. (End of Abstract) ..
  6. CHEMISTRY AND BIOLOGY OF HEPARAN SULFATE
    UMESH RAMANLAL DESAI; Fiscal Year: 2013
    ..End of Abstract) ..
  7. MOLECULAR BIOLOGY OF HEMORRHAGIC SHOCK
    Timothy R Billiar; Fiscal Year: 2013
    ..Based on our progress thus far, we are fully confident that our approach will continue to lead to productive collaboration and effective testing of a novel and important hypotheses. ..
  8. TH17 Autoimmunity to Type V Collagen in Heart and Lung Transplant
    David S Wilkes; Fiscal Year: 2013
    ..abstract_text> ..
  9. 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. ..
  10. 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 ..
  11. Integrating Structive Activity, Biokinetics and Response for ENP Risk Assessment
    Brian D Thrall; Fiscal Year: 2013
    ....
  12. Role of PPAR-gamma in Smoking-induced COPD Progression and Steroid Resistance
    Raju C Reddy; Fiscal Year: 2013
    ..It would also establish the feasibility of an innovative approach to restoring therapeutic glucocorticoid sensitivity, thereby promoting PPAR-g-glucocorticoid synergy, in COPD and potentially in other steroid-resistant diseases. ..
  13. Lung Endothelial Cell Apoptosis and Emphysema
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..These studies may result in development of more effective treatments for COPD. ..
  14. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..abstract_text> ..
  15. PPAR gamma as a therapeutic target in COPD
    Thomas J Mariani; Fiscal Year: 2013
    ....
  16. Role of ion channels in the development of COPD
    ESTELLE A CORMET-BOYAKA; Fiscal Year: 2013
    ..This proposal will also identify the role of CFTR in lung responses to cigarette smoking. These studies will identify new markers that could be targeted for therapy. ..
  17. Novel Anti-inflammatory Activities For ADAM8 In Pulmonary Emphysema
    Caroline A Owen; Fiscal Year: 2013
    ..Our studies may also identify ADAM8 as a novel target for developing therapeutic strategies to limit lung destruction and disease progression in patients with COPD. ..
  18. Cigarette Smoking Alters the Genomic Tone of Alveolar Macrophages
    Martha M Monick; Fiscal Year: 2013
    ..In addition, this could lead to an easily retrievable biomarker useful in tracking physiologically relevant smoke exposure and may be applicable to lung disease related to other inhaled toxicants. ..
  19. Cardiolipin, pneumonia, and a novel cardiolipin pump
    Rama K Mallampalli; Fiscal Year: 2013
    ..The model also implicitly predicts existence of a novel CL-binding protein(s) that may import this lipid from the alveolar or extracelular space as a salvage pathway to maintain lung homeostasis. ..
  20. Single Cell Analysis of EGFR Activity in Human Airway Cells Exposed to Pollutants
    RYAN MATTHEW PHILLIPS; Fiscal Year: 2013
    ..Understanding the details of this process will help protect human health and safety by guiding regulations for controlling air pollution. ..
  21. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  22. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  23. The Role of Complement in the Pathogenesis of Emphysema
    Carl Atkinson; Fiscal Year: 2013
    ....