Respiratory diseases such as cystic fibrosis (CF) are characterized by a cascade of pathophysiological changes starting with dehydration of mucus secretions and proceeding to impaired mucociliary clearance, chronic airway inflammation, and subsequent lung injury. Effective biomarkers of these changes are urgently needed to monitor disease progression, identify exacerbations, and evaluate the efficacy of existing and novel therapies. The goal of this career development application is to provide Dr. Charles Esther with the skills needed to identify and assess candidate biomarkers in exhaled breath condensate (EBC), an airway sample that can be collected simply and non-invasively even in young children. Dr. Esther plans to overcome the challenges of analyzing the low concentration, variable dilution EBC through application of liquid-chromatography-tandem mass spectrometry (LC-MS/MS). This technology represents a highly sensitive and flexible methodology that permits simultaneous measurement of multiple small molecule biomarkers as well as urea as a dilution marker. In this research proposal, Dr. Esther will use mass spectrometry to identify and test simple and non-invasive EBC biomarkers of two critical aspects of CF airways pathophysiology: neutrophilic airway inflammation and dehydration of airway mucus secretions. Potential biomarkers identified based on both targeted analyses of established biomarkers and metabolomic studies of in vitro models of neutrophilic inflammation and mucus dehydration. Measurement protocols will be developed using LC-MS/MS, and promising biomarkers assessed in a cohort of children and adults with to determine their reliability and relationship to accepted markers of disease pathophysiology and to identify potential confounders. Successful completion of the research plan outlined in this proposal will not only generate important tools for future research on the pathophysiology and therapeutic options for CF, but will also provide Dr. Esther with the skills and experiences necessary to develop a career in identification and testing of non-invasive biomarkers of respiratory disease.

Public Health Relevance

Cystic fibrosis is characterized by disease related changes within the lung, and Dr. Esther proposes to develop simple and non-invasive methods to detect these changes using the cutting edge technologies of mass spectrometry and exhaled breath condensate collection. Development of these methods will provide invaluable tools for clinical management and research in cystic fibrosis and other lung diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-R (F1))
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Tigno, Xenia
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Esther Jr, Charles R; Hill, David B; Button, Brian et al. (2017) Sialic acid-to-urea ratio as a measure of airway surface hydration. Am J Physiol Lung Cell Mol Physiol 312:L398-L404
Giddings, Olivia; Esther Jr, Charles R (2017) Mapping targetable inflammation and outcomes with cystic fibrosis biomarkers. Pediatr Pulmonol 52:S21-S28
Donoghue, Lauren J; Livraghi-Butrico, Alessandra; McFadden, Kathryn M et al. (2017) Identification of trans Protein QTL for Secreted Airway Mucins in Mice and a Causal Role for Bpifb1. Genetics 207:801-812
Esther Jr, Charles R; Turkovic, Lidija; Rosenow, Tim et al. (2016) Metabolomic biomarkers predictive of early structural lung disease in cystic fibrosis. Eur Respir J 48:1612-1621
Esther Jr, Charles R; Coakley, Raymond D; Henderson, Ashley G et al. (2015) Metabolomic Evaluation of Neutrophilic Airway Inflammation in Cystic Fibrosis. Chest 148:507-515
Esther Jr, Charles R; Boucher, Richard C; Johnson, M Ross et al. (2014) Airway drug pharmacokinetics via analysis of exhaled breath condensate. Pulm Pharmacol Ther 27:76-82
Cholon, Deborah M; Quinney, Nancy L; Fulcher, M Leslie et al. (2014) Potentiator ivacaftor abrogates pharmacological correction of ?F508 CFTR in cystic fibrosis. Sci Transl Med 6:246ra96
Esther Jr, Charles R; Olsen, Bonnie M; Lin, Feng-Chang et al. (2013) Exhaled breath condensate adenosine tracks lung function changes in cystic fibrosis. Am J Physiol Lung Cell Mol Physiol 304:L504-9
Patel, Kavita; Davis, Stephanie D; Johnson, Robin et al. (2013) Exhaled breath condensate purines correlate with lung function in infants and preschoolers. Pediatr Pulmonol 48:182-7
Esther Jr, Charles R; Lazaar, Aili L; Bordonali, Elena et al. (2011) Elevated airway purines in COPD. Chest 140:954-960

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