The introduction of CFTR modulators brought remarkable progress to the therapeutic field but there is still margin for improvement, especially if we consider that even in patients under modulators, biomarkers do not achieve non-CF levels (e.g. sweat chloride does not lower to the ‘normal’ range). To that, we need to add those individuals with genotypes not eligible to current modulators. 

Here, the researchers propose to further dissect the complex mechanisms through which CFTR is regulated in the cell and, with that, to open the way for novel still unexplored therapeutic avenues.

The project will be focused on the cytoskeleton and how it cross-talks with cyclic AMP signaling in order to further characterize the mechanisms of CFTR membrane stability and to identify potential novel therapeutic targets. The crosstalk between the cytoskeleton and cyclic AMP is crucial for the regulation of CFTR and relies on multiple protein partners. Bringing together the correct partners at the right time requires the proper organization and function of the cytoskeleton and of cAMP signaling. The work proposed here has two general aims: 

1. to increase the stability of CFTR at the plasma membrane, a step in CFTR’s life which is still unexplored for its therapeutic potential; 
2. to improve the rescue of misfolded CFTR from its endoplasmic reticulum retention (that can be used to boost the effect of modulators in responsive mutations and to allow rescue of non-responsive ones). 

The mechanisms elucidated and the putative new targets may constitute novel therapeutic avenues that are likely to increase the rescue attained by modulators in individuals with genotypes that are eligible and allow the partial rescue of CFTR in individuals still without a causal therapy.

This is however a fundamental research project, and thus it will take time (after the scientific discoveries) before it can be translated into the clinic.