Down-regulation of oxidant-induced airway inflammation though modulation of NRF2

Summary

Principal Investigator: Michelle Hernandez
Abstract: DESCRIPTION (provided by applicant): This proposal outlines a 3 year K23 Mentored Patient-Oriented Research Career Development Award (K23) designed to refine the candidate's training as a physician scientist and to prepare for a multidisciplinary, translational research program focused on the development of therapies against airway oxidative stress. The goal of this proposal is to provide support, training in drug discovery/development, and guidance in intervention-based proof of concept studies as the candidate applies experience in basic science and clinical research to the development of an independent translational research project. Recent evidence from this group and others has emphasized the role of intracellular antioxidant enzymes in exacerbation of O3-induced airway inflammation. Healthy volunteers lacking the antioxidant enzyme, Glutathione S Transferase Mu 1 (GSTM1), suffered from increased neutrophilic airway inflammation after chamber exposure to 0.4 parts per million (ppm) ozone (O3). GSTM1 and numerous other phase II antioxidant enzymes (NQO1, GSTP1, HO-1) are regulated by the master transcription factor NF-E2- related factor 2 (NRF2). Murine models and studies of patients with chronic obstructive pulmonary disease suggest that defects in NRF2 are associated with oxidant-mediated lung injury. Therefore, NRF2 is a strong candidate to modulate in protection against airway inflammation caused by ubiquitous inhaled oxidants such as O3. The intent here is to use sulforaphane (SFN), an antioxidant compound derived from specially bred broccoli that was found to upregulate expression of NRF2 and NRF2-regulated Phase II enzymes (GSTM1, GSTP1, HO1, and NQO1), to examine if NRF2 induction with oral SFN supplementation will reduce O3-induced airway inflammation in normal volunteers. Second, cultured differentiated nasal epithelial cells derived from mild-moderate persistent allergic asthmatics will be used to examine if SFN treatment of these epithelial cells modifies O3-induced inflammatory responses. The candidate will acquire experience in the drug discovery process of pharmacologic agents that can target oxidative stress processes through the proposed didactic coursework as well as with the completion of these aims with the assistance of the mentoring team. The mentoring team consists of three individuals with extensive experience in mentoring young scientists and in developing translational research programs: Dr. David Peden, a translational scientist with expertise on environmental pollution, oxidative stress, and lead mentor;Dr. Wesley Burks, a translational researcher focused on phase I/II clinical trial interventions against food allergy;and Dr. Angela Kashuba, the director f the clinical pharmacology fellowship at UNC with extensive experience in clinical pharmacokinetic and pharmacodynamic studies.
Funding Period: 2012-08-16 - 2015-07-31
more information: NIH RePORT

Top Publications

  1. pmc Vitamin E, γ-tocopherol, reduces airway neutrophil recruitment after inhaled endotoxin challenge in rats and in healthy volunteers
    Michelle L Hernandez
    Center for Environmental Medicine, Asthma, and Lung Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27516, USA
    Free Radic Biol Med 60:56-62. 2013

Research Grants

Detail Information

Publications2

  1. pmc Vitamin E, γ-tocopherol, reduces airway neutrophil recruitment after inhaled endotoxin challenge in rats and in healthy volunteers
    Michelle L Hernandez
    Center for Environmental Medicine, Asthma, and Lung Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27516, USA
    Free Radic Biol Med 60:56-62. 2013
    ..These results suggest that γT is a potential therapeutic candidate for prevention or treatment of neutrophilic airway inflammation in diseased populations...

Research Grants30

  1. Novel approaches for vaccine design
    Michel C Nussenzweig; Fiscal Year: 2013
    ..abstract_text> ..
  2. Airway Inflammation and Airway Remodeling
    David H Broide; Fiscal Year: 2013
    ..An lOFM Core is also proposed as requested by the RFA. ..
  3. CHEMISTRY AND BIOLOGY OF HEPARAN SULFATE
    UMESH RAMANLAL DESAI; Fiscal Year: 2013
    ..End of Abstract) ..
  4. Cigarette Smoke and Susceptibility to Influenza Infection
    Terry L Noah; Fiscal Year: 2013
    ..abstract_text> ..
  5. Azithromycin to prevent BPD in ureaplasma-infected preterms.
    Ken B Waites; Fiscal Year: 2013
    ....
  6. TOXIC SUBSTANCES IN THE ENVIRONMENT
    Martyn T Smith; Fiscal Year: 2013
    ..The program will be overseen and coordinated by an Administration core (A). ..
  7. Integrating Structive Activity, Biokinetics and Response for ENP Risk Assessment
    Brian D Thrall; Fiscal Year: 2013
    ....
  8. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  9. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013
    ..A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources. ..
  10. 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 ..
  11. Consortium for AIDS Vaccine Research in Nonhuman Primates
    R Paul Johnson; Fiscal Year: 2013
    ....
  12. Host and Viral Determinants of Infant and Childhood Allergy and Asthma
    Ray Stokes Peebles; Fiscal Year: 2013
    ..Further, in Project 3, we will use RSV strains isolated from ReSPIRA in Project 2 to determine the generalizability of PGI2 as a therapeutic target. ..
  13. 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. ..
  14. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..abstract_text> ..