Role of SLC26A9 chloride transporter in mucociliary clearance in health and chronic inflammatory airways diseases
Scientific interest within the context of the graduate college:
The airway mucosa represents the first line of defense of the respiratory system against pathogens, pollutants, and irritants that are constantly inhaled during tidal breathing. Elimination of these potentially harmful stimuli by mucociliary clearance is an important innate defense mechanism of the lung, which operates through the coordinated function of (i) the motile cilia, (ii) the airway surface liquid layer, and (iii) the mucus layer. Abnormalities in mucociliary clearance contribute to the pathogenesis of a spectrum of chronic lung diseases, such as cystic fibrosis, where the underlying ion and fluid transport defect results in viscous, thick mucus that can not be cleared properly from the lungs. Recent evidence suggests that the SLC26A9 chloride transporter plays important roles in coordinated epithelial ion and fluid transport and is crucial for the maintenance of airway mucus clearance during inflammation.1 Furthermore, genetic association studies demonstrated a link between SLC26A9 and lung function in health, as well as in chronic lung diseases, suggesting that SLC26A9 is an attractive therapeutic target to improve mucociliary clearance.2 However, the cellular and molecular mechanisms that maintain proper mucociliary clearance upon pro-inflammatory stimuli, and the role of SLC26A9 upregulation in this process, are poorly understood.
Project description:
In our lab, we use patient-derived, highly differentiated airway epithelial cultures to model key aspects of airway physiology and mucosal defense.3 The aim of this translational research project is to utilize this model system to investigate the coordinated regulation of SLC26A9-mediated chloride transport and mucociliary clearance in health and during inflammation, to identify physiologic changes that adapt mucociliary clearance to environmental challenges, as well as changes that promote disease development. For this purpose, airway epithelial cultures from healthy donors and cystic fibrosis patients will be challenged with pro-inflammatory cytokines and proteases, and will be studied in vitro under near physiological air-liquid-interface conditions. This will include studies on (i) epithelial ion transport, (ii) airway mucus characteristics, and (iii) mucociliary transport. Further, to identify molecules and signaling pathways that may serve as therapeutic targets to enhance mucociliary clearance, we will conduct RNA sequencing and proteome analysis. This experimental MD thesis will apply complex primary cell culture methods, basic molecular biology techniques, electrophysiology assays and state of the art live cell microscopy imaging to obtain mechanistic insights into the pathobiology of chronic inflammatory airway diseases.
WP1: Effect of inflammatory mediators and proteases on ion transport properties of the airway epithelium
WP2: Effect of inflammatory mediators and proteases on mucus properties of the airway epithelium
WP3: Effect of inflammatory mediators and proteases on mucociliary transport of the airway epithelium
WP4: Molecular signatures and therapeutic targeting of airway epithelial inflammation
References
- Balázs A, Mall MA. Role of the SLC26A9 Chloride Channel as Disease Modifier and Potential Therapeutic Target in Cystic Fibrosis. Front Pharmacol. 2018; 9:1112. doi: 10.3389/fphar.2018.01112.
- Gong J, He G, Wang C, […], Ratjen F, Rommens JM, Strug LJ. Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease. NPJ Genom Med. 2022; 7:28. doi: 10.1038/s41525-022-00299-9.
- Balázs A, Millar-Büchner P, Mülleder M, […], Röhmel J, Ralser M, Mall MA. Age-Related Differences in Structure and Function of Nasal Epithelial Cultures From Healthy Children and Elderly People. Front Immunol. 2022; 13:822437. doi: 10.3389/fimmu.2022.822437.