CF is the most common lethal monogenic disease in Caucasians with F508del being the most common mutation (>80%). MicroRNA (miRNA) have emerged as key players in disease pathogenesis and are differentially expressed in the CF airway epithelium. Current in vitro models of CF do not represent the genetic background of individual patients and primary cells such as human bronchial and rectal epithelial cells are acquired by invasive procedures. Induced pluripotent stem cells (iPSC) represent an attractive tool to advance the understanding of CF given their capacity to generate large quantities of cells that can be shared, stored, gene-edited and differentiated into various cell types. Here, I propose to employ an iPSC model that reflects a patient’s unique genetic background, CF mutation and can be directed towards mini-lung organoids using established differentiation protocols to examine the role of miRNA in the pathogenesis of CF lung disease and ultimately advance molecular characterisation of CF. Key goals include, examination of differential miRNA expression in a patient derived CF and CF-corrected iPSC paediatric model of airway organoids and investigation of downstream miRNA:Target expression networks and their relationship to CFTR with a view to exploration of adjunct therapies to existing CFTR modulator drugs.
