Parkin in mitochondrial dysfunction and airway inflammation of obese asthma

Information

  • Research Project
  • 10264924
  • ApplicationId
    10264924
  • Core Project Number
    R01AI152504
  • Full Project Number
    5R01AI152504-02
  • Serial Number
    152504
  • FOA Number
    PA-19-056
  • Sub Project Id
  • Project Start Date
    9/16/2020 - 3 years ago
  • Project End Date
    8/31/2025 - a year from now
  • Program Officer Name
    MINNICOZZI, MICHAEL
  • Budget Start Date
    9/1/2021 - 2 years ago
  • Budget End Date
    8/31/2022 - a year ago
  • Fiscal Year
    2021
  • Support Year
    02
  • Suffix
  • Award Notice Date
    7/28/2021 - 2 years ago
Organizations

Parkin in mitochondrial dysfunction and airway inflammation of obese asthma

Project Summary/Abstract The goal of this R01 application is to determine the mechanisms by which mitochondrial dysfunction in obese asthma exacerbates airway inflammation. Nearly 40% of asthmatics in the U.S. are obese. Obese (vs. lean) asthmatics experience more frequent exacerbations, poorer response to inhaled corticosteroids and worse asthma control. There is an unmet need to study the novel pathogenesis of obese asthma. We have found mitochondrial dysfunction in obese asthma airway epithelium, including increased respiration, glycolytic rates, reactive oxygen species, and greater numbers of dysfunctional mitochondria. We discovered up-regulation of Parkin (Park2) in obese asthma airway epithelium. Parkin is an E3 ubiquitin ligase that regulates mitophagy by degrading defective mitochondria. We further observed increased levels of mitochondrial DNA (mtDNA) and palmitic acid (PA) levels in obese asthma bronchoalveolar lavage fluid and serum samples. Moreover, type 2 cytokine IL-13, type 1 cytokine IFN-g and palmitic acid (PA, a saturated fatty acid increased in obese asthma) increased airway epithelial Parkin levels. Parkin is essential to IL-13-mediated mtDNA release and airway neutrophilic and eosinophilic inflammation in mice and in human airway epithelial cells. We hypothesize that Parkin is up-regulated in obese asthma airways with dysfunctional mitochondria, which is amplified by the type 1 or type 2 cytokine milieu, enhancing mitochondrial DNA release and exaggerating airway inflammation. In Aim 1, we will determine the mechanisms by which Parkin is up-regulated in obese asthma by measuring Parkin, PA, mitophagy, type 1 and type 2 cytokines, and nitric oxide (NO), and performing human airway epithelial cell and precision-cut lung slice cultures to determine if IFN-g, IL-13 and PA increase Parkin in part by reducing transcriptional repressor THAP11. We then test if restoring NO bioavailability reduces Parkin activity. In Aim 2, we will determine how Parkin enhances airway mtDNA release and neutrophilic inflammation. By using Parkin, TLR9 and STAT1 knockout human airway epithelial culture and mouse models, we will test if excessive Parkin in a type 1 cytokine setting of obese asthma promotes mtDNA release, and amplifies neutrophilic inflammation through the TLR9/STAT1 signaling axis. In Aim 3, we will determine the mechanisms by which Parkin enhances airway eosinophilic inflammation. We will test if Parkin-mediated mtDNA release in a type 2 cytokine setting amplifies STAT6 signaling and pro-eosinophilic cytokine (e.g. eotaxin) production. Research findings from our proposed studies will likely provide several key targets (e.g. Parkin, TLR9) to treat obese asthma, a heterogenous disease currently without specific therapies.

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    R01
  • Administering IC
    AI
  • Application Type
    5
  • Direct Cost Amount
    578089
  • Indirect Cost Amount
    153315
  • Total Cost
    731404
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
  • Funding ICs
    NIAID:731404\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    NATIONAL JEWISH HEALTH
  • Organization Department
  • Organization DUNS
    076443019
  • Organization City
    DENVER
  • Organization State
    CO
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    802062761
  • Organization District
    UNITED STATES