Functional characterization of complexes regulation chloride and muscus transport and their significance in disease

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Functional characterization of complexes regulating chloride and mucus transport and their significance in disease

Publication . Simões, Filipa Bica; Kunzelmann, Karl; Amaral, Margarida

Mucus hyperproduction is a feature of several pulmonary diseases, such as cystic fibrosis (CF). CF is caused by mutations in the Cl-/HCO3- channel CFTR, which result in airway mucus obstruction, bacterial infections, chronic inflammation, and epithelial remodelling. A possible therapy is the activation of alternative Cl- channels, such as TMEM16A, that can compensate for the absence of functional CFTR. However, some studies describe a role of Cl- channels in mucus hyperproduction, inflammation and differentiation, although the mechanisms behind these processes are still unclear. Thus, the aim of this work was to understand the importance of Cl- channels for mucus production, epithelial differentiation and airway inflammation. In the first chapter, we showed that, although essential for airway hydration, TMEM16A is not required for mucus production. Particularly, our results show that TMEM16A is upregulated by interleukin-4 (IL-4) due to an increase in cell proliferation that is independent of mucus hyperproduction. Hence, we conclude that TMEM16A is a promising drug target for CF. In the second chapter, we generated a novel CF airway basal cell line and observed that dysfunctional CFTR is sufficient to impair epithelial differentiation, even in the absence of bacterial infection or inflammation. This cell line is the first in vitro model allowing the study of the CFTR-dependent differentiation, thus contributing to the understanding of CF pathogenesis. In the third chapter, we studied the interaction between inflammatory mediators and the airway epithelium. Our results describe differential responses according to the inflammatory stimuli in terms of mucus production, expression of Cl- channels and epithelial differentiation. These findings may help to design novel cytokine-specific therapies to solubilise mucus secretions for the treatment of pulmonary diseases. Altogether, these results contribute to the understanding of how mucus hyperproduction, ion transport and epithelial differentiation are regulated, particularly upon airway inflammation

2021-07Tese de doutoramento

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Fundação para a Ciência e a Tecnologia

Programa de financiamento

OE

Número da atribuição

PD/BD/131008/2017