Title: Investigating the effects of CFTR modulators on the epithelial sodium channel (ENaC) in the cystic fibrosis airway
Funder: The Academy of Medical Sciences

Abstract: Aims: 1. Understand the effects of CFTR modulators on the epithelial sodium channel (ENaC) in the paediatric cystic fibrosis (CF) airway to inform effective alternative pharmacological therapies. 2. Extend my training in ENaC physiology to support future intermediate fellowship applications that will focus on ENaC and its role in improving airway homeostasis in CF and other airway diseases. Objectives: 1. Investigate transcriptomic profiles of paediatric CF human bronchial epithelial cells treated with highly-effective CFTR modulators. 2. Characterise effects of highly-effective CFTR modulators on ENaC expression and function. Disordered airway surface liquid (ASL) homeostasis and progressive bronchiectasis are hallmarks of CF respiratory disease, arising from defects in the CF transmembrane conductance regulator (CFTR) protein. Recent development of CFTR modulator therapies has been a major breakthrough; however these only partially restore CFTR function and remain limited to specific CFTR genotypes. Improving ASL homeostasis via ENaC inhibition offers an alternative approach with capacity to benefit all people with CF. Ivacaftor is one such modulator that has shown potential to inhibit ENaC as well as improve CFTR function, but mechanisms are unclear. I hypothesise that ivacaftor and other modulators inhibit ENaC expression and function. I will extend my training in airway epithelial culture and electrophysiology to comprehensively investigate effects of CFTR modulators on ENaC function and acquire new skills in transcriptomic and proteomic analysis. This will generate novel data to 1) inform strategies to improve ASL homeostasis in the paediatric CF airway where early intervention is vitally important and 2) support my career development.

Lay abstract: Cystic fibrosis (CF) affects many organs in the body, especially the lungs. It occurs due to a faulty protein called CFTR. In CF the surface of the breathing tubes, or airways, becomes very dry. This makes it difficult to clear mucus and causes severe chest infections and lung damage. New treatments called ‘CFTR modulators’ will improve the health of many people with CF. However, these can’t completely correct CFTR and aren’t available for all people with CF because they only target specific faults in CFTR. ENaC is another protein in the airway which affects water balance. ENaC is overactive in CF and this makes the airway surface even more dry. Reducing the actions of ENaC could be a different way of treating CF that would be available for all people with CF. There is some evidence to show that CFTR modulators reduce ENaC activity as well as improving how CFTR works. However, there is very little research on whether and how this happens. In this project, I will use airway models in the lab to look at how CFTR modulators change the way ENaC works. These models have been developed by collecting cells that line the airways of children with CF and I have previously used these to look at how the airway surface is regulated. The overall aim of this project is to understand how existing treatments can be improved in children with CF, where starting treatment early in life will minimise effects of the disease.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS