FFC#02/2014

A systems biology approach to the correction of Cystic Fibrosis: from building a network of proteostasis regulatory pathways to combinatorial targeting. (A rational approach to develop novel drugs for the treatment of Cystic Fibrosis)

FFC#02/2014

A systems biology approach to the correction of Cystic Fibrosis: from building a network of proteostasis regulatory pathways to combinatorial targeting. (A rational approach to develop novel drugs for the treatment of Cystic Fibrosis)

PRINCIPAL INVESTIGATOR

Alberto Luini (Consiglio Nazionale delle Ricerche, Dip. di Scienze Biomediche, Istituto di Biochimica delle Proteine, Napoli)

RESEARCHERS

5

CATEGORY

AREA 1 Therapies to correct the underlying defect

DURATION

2 years

GOAL

€ 80.000 €

RESULTS

Researchers developed a novel bionformatic method to identify genes that commonly are regulated by the corrector drugs of CFTR-F508del protein. 47 genes resulted involved in controlling proteostasis of the mutated protein and highlighted 8 signaling pathways/ networks. One of these pathway was deeply characterized and the protein MLK3 appeared to be the central component. The mechanism of MLK3 was investigated and it was found to control the endoplasmatic reticulum associated degradation of CFTR-F508del and also the plasma membrane quality control of CFTR-F508del. Additionally, small molecules mediated inhibition of the MLK3 pathway was observed to rescue CFTR-F508del and thus suggesting a potential pharmacological approach.

OTHER RESULTS

FFC #3/2024

Two molecules are effective in activating Heat Shock Proteins and enhancing the action of CFTR correctors with the F508del mutation in vitro.

FFC#5/2024

Some peptide nucleic acids (PNAs) re-sensitise Pseudomonas aeruginosa to the antibiotic meropenem in vitro and reduce its virulence.

FFC#1/2023

Tezacaftor, one of the components of Kaftrio, induces an accumulation of dihydroceramides both in vitro and in vivo in animal models