Exploiting stem-cell derived epithelia to investigate pharmacological repair of bicarbonate transport in cystic fibrosis

The cystic fibrosis transmembrane conductance regulator (CFTR) anion channel mediates chloride and bicarbonate secretion across various epithelia in the body. Bicarbonate is essential for optimal function of various luminal secretions. As a result, people with cystic fibrosis (CF), i.e. people with little or no CFTR activity, suffer symptoms affecting many organ systems. The development of CFTR modulator drugs has transformed the care of many people with CF. These drugs are divided in two categories: (1) potentiators that improve the ion-channel function of CFTR, and (2) correctors that increase the amount of CFTR at the plasma membrane. So far, development of these has been driven by assays monitoring compound-induced changes in chloride permeation, whereas restoration of bicarbonate transport is seldom taken into account. However, it is conceivable that CF-causing mutations will have distinct consequences for chloride and bicarbonate transport, and that modulators have different effects on CFTR-mediated bicarbonate vs. chloride transport. Also, it is largely unclear whether CFTR modulators can restore bicarbonate secretion in all CF-affected tissues, in particular those that are rarely used as model systems in drug development (e.g. biliary epithelium). The aim of this project is to increase our knowledge of CFTR-dependent bicarbonate secretion, in the hope that a better understanding of its role in the pathophysiology of the disease may ultimately improve pharmacological treatment of people with CF. In this project, we will use advanced stem-cell, biochemical, molecular biology and genomics-based technologies to investigate epithelial bicarbonate secretion and luminal pH regulation, and use the organoid platform to develop new methods to assess (CFTR-dependent) bicarbonate secretion in CF-affected gastro-intestinal tissues, and to assess the effect of modulator therapy on CFTR function.

The PhD studentship is available to start in early 2023. Informal enquiries can be sent to Dr Marcel Bijvelds ([Email Address Removed]).

For more information see also https://www.erasmusmc.nl/en/research/departments/gastroenterology-hepatology

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