Mitchell, Arthur; (2024) An integrated in vitro and in silico approach to developing airway hydration strategies for cystic fibrosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cystic fibrosis (CF) is a genetic disorder characterised by loss-of-function mutations affecting the cystic fibrosis transmembrane regulator (CFTR). CFTR is an anion channel, crucial for maintaining the hydration of the airway surface liquid (ASL). ASL dehydration in CF patients contributes to recurrent airway infections, irreversible damage to the lungs, and significant alterations in mucus rheology. This thesis presents an integrated theoretical and experimental investigation into new approaches for restoring ASL dehydration in CF. The initial part of this research introduces a mathematical model of ion transport in the airways, validated against in vitro experiments. Utilising a novel optimisation approach and data from the literature, the model estimates transport parameters and sheds light on how ASL composition and depth can be controlled by manipulating apical membrane permeabilities. The model thus identifies potential therapeutic targets to ameliorate airway hydration in CF. The subsequent chapter delves into in vitro measurements of ASL depth and transepithelial potential difference in CF and non-CF cell cultures, testing some of the ideas derived from modelling. The results highlight the possibility of utilizing the BK channel as a therapeutic target to restore airway hydration in CF. In the final chapter, this thesis explores changes in mucus rheology in CF and the impact of drugs modulating ion channels on this rheology. Surprisingly, it reveals that alterations in airway hydration do not consistently correlate with some of the expected changes in mucus rheology, suggesting the involvement of other factors beyond hydration alone. This chapter synthesises findings from all three research methods, providing an overview of how existing CF therapies and potential new targets can influence ASL hydration and mucus rheology. This thesis makes the following contributions. It improves our understanding of the intricate relationship between CFTR dysfunction, ASL dehydration, and the consequent health implications in CF patients. This thesis introduces a mathematical model and experimental data which contribute new insights into potential therapeutic interventions aimed at mitigating the effects of ASL dehydration and improving the overall health outcomes of individuals with cystic fibrosis. Finally, it contributes new insights into mucus in CF and how current leading therapies alter its rheology.

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