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.
Respiratory complications caused by O3 represent a significant public health burden in the United States and worldwide. Despite compelling evidence that pulmonary oxidative insults lead to systemic deleterious health outcomes, treatment options for environmentally-induced oxidative stress are limited and no significant changes have been made in improving the health of susceptible populations such as children, the elderly and allergic asthmatics. This research has the potential to identify a pathway that could be targeted by prevention or treatment of respiratory inflammation caused by exposure to inhaled environmental oxidants in susceptible individuals. Given the significant public health burden of respiratory diseases such as asthma and the lack of targeted therapeutics for oxidant-induced airway inflammation, the potential impact is great.
| Burbank, Allison J; Duran, Charity G; Pan, Yinghao et al. (2018) Gamma tocopherol-enriched supplement reduces sputum eosinophilia and endotoxin-induced sputum neutrophilia in volunteers with asthma. J Allergy Clin Immunol 141:1231-1238.e1 |
| Burbank, Allison J; Sood, Amika K; Kesic, Matthew J et al. (2017) Environmental determinants of allergy and asthma in early life. J Allergy Clin Immunol 140:1-12 |
| Duran, Charity G; Burbank, Allison J; Mills, Katherine H et al. (2016) A proof-of-concept clinical study examining the NRF2 activator sulforaphane against neutrophilic airway inflammation. Respir Res 17:89 |
| Angelon-Gaetz, Kim A; Richardson, David B; Marshall, Stephen W et al. (2016) Exploration of the effects of classroom humidity levels on teachers' respiratory symptoms. Int Arch Occup Environ Health 89:729-37 |
| Todoric, Krista; Bangdiwala, Shrikant; Vadlamudi, Anusha et al. (2015) Assessing asthma in African American children using the Asthma Control Test and the Childhood Asthma Control Test. Ann Allergy Asthma Immunol 114:342-4 |
| Todoric, Krista; Zhou, Haibo; Zhang, Hongtao et al. (2015) Body mass index correlates with pollutant-induced interleukin-1? in sputum and blood. Ann Allergy Asthma Immunol 114:251-3 |
| Aleman, Maria M; Mills, Katherine; Almond, Martha et al. (2015) Reply: To PMID 25195169. J Allergy Clin Immunol 135:836-7 |
| Hernandez, Michelle L; Mills, Katherine; Almond, Martha et al. (2015) IL-1 receptor antagonist reduces endotoxin-induced airway inflammation in healthy volunteers. J Allergy Clin Immunol 135:379-85 |
| Aleman, Maria M; Kesic, Matthew J; Mills, Katherine H et al. (2015) The IL-1 axis is associated with airway inflammation after O3 exposure in allergic asthmatic patients. J Allergy Clin Immunol 136:1099-101.e2 |
| Mills, K; Lay, J; Wu, W et al. (2014) Vitamin E, ?-tocopherol, diminishes ex vivo basophil response to dust mite allergen. Allergy 69:541-4 |
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