FFC#7/2019

Targeting the signalling network controlling proteostasis and inflammation to rescue F508del-CFTR

FFC#7/2019

Targeting the signalling network controlling proteostasis and inflammation to rescue F508del-CFTR.

PRINCIPAL INVESTIGATOR

Alberto Luini (Istituto di Biochimica delle Proteine, Dip. Scienze Biomediche CNR, Napoli)

Partner

Anna Tamanini (Azienda Ospedaliera Universitaria Integrata Verona, Lab. di Patologia Molecolare, UOC Lab. Analisi); Monica Borgatti (dip. di Scienze della vita e biotecnologie, Università degli Studi di Ferrara)

RESEARCHERS

12

CATEGORY

AREA 1 Therapies to correct the underlying defect

DURATION

1 year

GOAL

€ 60.000 €

RESULTS

The researchers report that hydrogen peroxide (H2O2) has a strong proteostasis action on the CFTR-F508del. The thesis that inflammation accelerates the degradation of mutated CFTR is confirmed by the action of hydrogen peroxide, a mediator of inflammation. Tests on cell lines obtained from bronchial epithelium from CF patients (CFBE) treated with H2O2 showed a decrease in the levels of the mutated protein. The degradation action of the mutated CFTR given by H2O2 was also found on CFBE cells treated with VX-809 (the lumacaftor modulator) which acts as a corrector facilitating the maturation and transport of the protein. To understand the molecular pathway through which hydrogen peroxide acts, experiments were conducted on MAP-kinases (MAPK), key enzymes for many cellular functions that are sensitive to stress (also caused by exposure to hydrogen peroxide). Researchers have shown that reducing the levels of MLK3 kinase and BAG3 strongly rescued H2O2 induced reduction in F508del-CFTR levels, indicating MAPK as possible therapeutic targets for cystic fibrosis.

OTHER RESULTS

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