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A kinase-directed approach to rescue functionality of F508del CFTR
     
 
Author(s) : Venerando A, Villella VR, Cozza G, Esposito S, Maiuri L, Pinna LA
Address : University of Padova and CNR Institute of Neurosciences, European Institute for Research in Cystic Fibrosis.
Multiple Universities in Collaboration
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Background. CFTR F508 deletion (F508del) is the by far commonest mutation causative of Cystic Fibrosis (CF). F508delCFTR undergoes premature degradation subverting proteostasis regulation and generating fragments which have the potential to up-regulate the protein kinase CK2 that, in turn, can favour CFTR fragmentation and reduce CFTR stability. 

Hypothesis & Objectives. The project provide the rationale and proof-of-concept for the design of an original and novel therapeutic strategy that restores CFTR channel function by targeting the specific context in which the mutant CFTR channel fails to traffic to the cell surface. It focuses on the derailed CF proteostatic environment that is driven by the mutant channel, instead of on CFTR protein itself. Our strategy induces a self-sustained positive loop that ameliorates the CF phenotype by inhibiting protein cross linking that blocks autophagy and dampening overactive CK2. The workflow is summarized in the following tasks: 1) Identification and functional characterization of endogenous CK2 targets whose phosphorylation is altered by F508delCFTR; 2) In vivo confirmation of the CK2/CFTR functional link; 3) Analysis of known kinase modulators as a new class of molecules useful to rescue/stabilize F508del-CFTR;  4) In vivo validation of CK2/protein kinases modulators as reagents able to rescue CF phenotypes.  

 
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