Joshua D. Chandler, PhD
 |
Assistant Professor, Division of Pulmonary Medicine, Department of Pediatrics, School of Medicine
Graduate Programs
- Full Member - Biochemistry, Cell and Developmental Biology
- Full Member - Molecular and Systems Pharmacology
Education
PhD, University of Colorado, Anschutz Medical Campus, 2014BA, Drury University, 2009
Contact Information
Email: joshua.chandler@emory.edu
Phone: 404-727-3536
Address:
Emory Children's Center, Room 350
2015 Uppergate Drive
Atlanta, GA 30322
Inflammation, or white blood cell infiltration into bodily tissues and activation of immune functions, impacts a range of human illnesses. Understanding the molecular basis of inflammatory tissue injury is key to preventing and resolving pathological outcomes. However, such mechanisms are complex, multifactorial, and change with time.
The Chandler Laboratory focuses on elucidating the biochemical and metabolic causes and consequences of inflammatory pathology by utilizing a suite of small molecule, redox, metabolic, and biochemical-focused techniques. We also design experiments to test rational pharmacological interventions against inflammation that could improve human health.
To date, we have placed major emphasis on myeloperoxidase (MPO), a heme enzyme, and its role in early-stage pathogenesis of cystic fibrosis. Neutrophils, the most abundant white blood cells in humans, secrete mature MPO after infiltrating tissues. MPO utilizes hydrogen peroxide to produce a range of oxidants, including hypochlorous acid (chlorine bleach) and a weaker, more selective oxidant, hypothiocyanous acid. Notably, changing the abundance of MPO substrates changes its output of oxidants, and differences in oxidant reactivity change the impacted biochemicals wherever MPO is present. Therefore, MPO substrates can be targeted as a means of controlling its activity and shifting oxidation reactions to different targets, a process I call "oxidant switching". My lab's research program is designed to build on previous successes in leveraging oxidant switching to improve lung health.[1-3]
Due to the complexity of immune effector molecules, particularly promiscuous oxidants like hypochlorous acid, we use high-resolution, accurate-mass mass spectrometry to conduct metabolomics experiments (attempting to measure as many small molecules in a biological system as possible with a relatively unbiased method). This allows us to (1) quantify hundreds of validated compounds; (2) annotate and quantify hundreds more according to MS/MS fragmentation; and (3) potentially detect and quantify undiscovered compounds, all via nontargeted analysis of a single experiment. We also use stable isotope flux analysis to identify metabolic pathway activity and aid structure elucidation of novel compounds. Experiments can be set up to both generate and test hypotheses, depending on extent of a priori knowledge.
Combining metabolomics and traditional biochemistry, we partnered with international colleagues to study bronchoalveolar lavage from clinically stable toddlers with cystic fibrosis. These samples are very difficult to acquire, and using them we determined that MPO is active in the earliest stages of cystic fibrosis, contributes to metabolite oxidation, and is closely associated with lung damage.[4, 5] Ongoing funded research aims to determine if it is also an important factor in disease risk, as well as the fate(s) and molecular impact of the MPO protein in the context of neutrophilic airway inflammation. Additional lines of research are focused on the ability to non-invasively monitor important metabolites in CF, and on the metabolic rewiring and metabolic signaling of neutrophils epithelial cells and circulating metabolites in cystic fibrosis and cystic fibrosis-related diabetes.[6]
Citations
1. Chandler, J.D. and B.J. Day, Biochemical mechanisms and therapeutic potential of pseudohalide thiocyanate in human health. 2015. 49(6): p. 695-710.
2. Chandler, J.D., et al., Antiinflammatory and Antimicrobial Effects of Thiocyanate in a Cystic Fibrosis Mouse Model. American Journal of Respiratory Cell and Molecular Biology, 2015. 53(2): p. 193-205.
3. Chandler, J.D., et al., Selective Metabolism of Hypothiocyanous Acid by Mammalian Thioredoxin Reductase Promotes Lung Innate Immunity and Antioxidant Defense. 2013. 288(25): p. 18421-18428.
4. Chandler, J.D., et al., Myeloperoxidase oxidation of methionine associates with early cystic fibrosis lung disease. European Respiratory Journal, 2018. 52(4): p. 1801118.
5. Horati, H., et al., Airway profile of bioactive lipids predicts early progression of lung disease in cystic fibrosis. J Cyst Fibros, 2020. 19(6): p. 902-909.
6. Chandler, J.D., et al., Determination of thiocyanate in exhaled breath condensate. Free Radical Biology and Medicine, 2018. 126: p. 334-340.
7. Kim S.O., et al, Substrate-dependent metabolomic signatures of myeloperoxidase activity in airway epithelial cells: Implications for early cystic fibrosis lung disease. Free Radic Biol Med, 2023. S0891-5849(23)00508-7
The Chandler Laboratory focuses on elucidating the biochemical and metabolic causes and consequences of inflammatory pathology by utilizing a suite of small molecule, redox, metabolic, and biochemical-focused techniques. We also design experiments to test rational pharmacological interventions against inflammation that could improve human health.
To date, we have placed major emphasis on myeloperoxidase (MPO), a heme enzyme, and its role in early-stage pathogenesis of cystic fibrosis. Neutrophils, the most abundant white blood cells in humans, secrete mature MPO after infiltrating tissues. MPO utilizes hydrogen peroxide to produce a range of oxidants, including hypochlorous acid (chlorine bleach) and a weaker, more selective oxidant, hypothiocyanous acid. Notably, changing the abundance of MPO substrates changes its output of oxidants, and differences in oxidant reactivity change the impacted biochemicals wherever MPO is present. Therefore, MPO substrates can be targeted as a means of controlling its activity and shifting oxidation reactions to different targets, a process I call "oxidant switching". My lab's research program is designed to build on previous successes in leveraging oxidant switching to improve lung health.[1-3]
Due to the complexity of immune effector molecules, particularly promiscuous oxidants like hypochlorous acid, we use high-resolution, accurate-mass mass spectrometry to conduct metabolomics experiments (attempting to measure as many small molecules in a biological system as possible with a relatively unbiased method). This allows us to (1) quantify hundreds of validated compounds; (2) annotate and quantify hundreds more according to MS/MS fragmentation; and (3) potentially detect and quantify undiscovered compounds, all via nontargeted analysis of a single experiment. We also use stable isotope flux analysis to identify metabolic pathway activity and aid structure elucidation of novel compounds. Experiments can be set up to both generate and test hypotheses, depending on extent of a priori knowledge.
Combining metabolomics and traditional biochemistry, we partnered with international colleagues to study bronchoalveolar lavage from clinically stable toddlers with cystic fibrosis. These samples are very difficult to acquire, and using them we determined that MPO is active in the earliest stages of cystic fibrosis, contributes to metabolite oxidation, and is closely associated with lung damage.[4, 5] Ongoing funded research aims to determine if it is also an important factor in disease risk, as well as the fate(s) and molecular impact of the MPO protein in the context of neutrophilic airway inflammation. Additional lines of research are focused on the ability to non-invasively monitor important metabolites in CF, and on the metabolic rewiring and metabolic signaling of neutrophils epithelial cells and circulating metabolites in cystic fibrosis and cystic fibrosis-related diabetes.[6]
Citations
1. Chandler, J.D. and B.J. Day, Biochemical mechanisms and therapeutic potential of pseudohalide thiocyanate in human health. 2015. 49(6): p. 695-710.
2. Chandler, J.D., et al., Antiinflammatory and Antimicrobial Effects of Thiocyanate in a Cystic Fibrosis Mouse Model. American Journal of Respiratory Cell and Molecular Biology, 2015. 53(2): p. 193-205.
3. Chandler, J.D., et al., Selective Metabolism of Hypothiocyanous Acid by Mammalian Thioredoxin Reductase Promotes Lung Innate Immunity and Antioxidant Defense. 2013. 288(25): p. 18421-18428.
4. Chandler, J.D., et al., Myeloperoxidase oxidation of methionine associates with early cystic fibrosis lung disease. European Respiratory Journal, 2018. 52(4): p. 1801118.
5. Horati, H., et al., Airway profile of bioactive lipids predicts early progression of lung disease in cystic fibrosis. J Cyst Fibros, 2020. 19(6): p. 902-909.
6. Chandler, J.D., et al., Determination of thiocyanate in exhaled breath condensate. Free Radical Biology and Medicine, 2018. 126: p. 334-340.
7. Kim S.O., et al, Substrate-dependent metabolomic signatures of myeloperoxidase activity in airway epithelial cells: Implications for early cystic fibrosis lung disease. Free Radic Biol Med, 2023. S0891-5849(23)00508-7
Atlanta Society of Mentors (ASOM), 2017
Diversity: Inclusion in the Modern Workplace, 2021
Unconscious Bias Training, 2023
Sarah Mansour
Biochemistry, Cell and Developmental Biology
Entrance Year: 2019
Topic: Metabolomics of Early Cystic Fibrosis Bronchoalveolar Lavage Fluid Reveals Biomarkers to Track and Predict Neutrophil-Driven Pediatric Lung Disease
Joseph Shapiro
Molecular and Systems Pharmacology
Entrance Year: 2022
Sue Kim
Biochemistry, Cell and Developmental Biology
PhD, 2023
"SUBSTRATE-DEPENDENT EFFECTS OF MYELOPEROXIDASE-DERIVED OXIDANTS ON THE METABOLOME AND TRANSCRIPTOME OF HUMAN AIRWAY EPITHELIAL CELLS "
