Use of primary airway epithelial cells from children with cystic fibrosis to investigate novel anoctamin 1 activators (360G-Wellcome-203520_Z_16_Z)

Cystic fibrosis (CF) is the most common genetic life-limiting disease in the UK. Lifelong treatment burden is significant but despite this death occurs early in life due to respiratory failure. Dysfunctional CF transmembrane conductance regulator (CFTR) protein leads to defective apical airway chloride and bicarbonate transport, resulting in a dehydrated and acidic airway surface liquid (ASL), impaired mucociliary transport and progressive lung disease. Latest strategies directed at correcting dysfunctional CFTR will not benefit all people with CF and alternative approaches are required. Activation of an alternative apical chloride/bicarbonate channel, anoctamin 1 (ANO1), could bypass the effects of dysfunctional CFTR and mitigate subsequent ASL volume and pH abnormalities. To investigate this, I will characterise the electrophysiological profiles of paediatric human primary nasal (PBEC) and bronchial airway epithelial (PBEC) cells to further validate PNEC use as a paediatric CF drug discovery tool. Using these models, I will investigate ANO1 expression and the effects of novel small molecule ANO1 activators on electrophysiological profile, ASL height and pH. This fellowship will provide novel information regarding ANO1 activation using this airway epithelial model and help determine the role of these compounds as a potential CF therapeutic strategy. Keywords: Cystic fibrosis, Epithelium, Children, Airway, Anoctamin 1