Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene encoding a chloride and bicarbonate ion channel essential for mucociliary clearance. The absence or dysfunction of this channel causes dehydration of the mucus which then becomes the site of repeated infections, and the association with chronic inflammation, leads to the destruction of lungs. To date, although anti-inflammatory therapies remain limited, pharmacological molecules have been developed to enhance CFTR activity. However, all patients are not eligible to these drugs for which efficacy and toxicity need improvement, making the development of new treatments essential. In this aim our team focused its research on regulation of the CFTR gene expression and of inflammatory key genes, by determining the cis- and trans-regulatory elements acting on mRNAs 3'UTR end. We thus studied the tristetraprolin (TTP) protein expression, mainly known for its anti-inflammatory effect (in its dephosphorylated form) through pro-inflammatory cytokines mRNA decay. We validated its destabilizing action on the mRNAs of IL6, IL8 and TNFα in CF cultures, as well as a stabilizing effect on CFTR gene expression. In CF models, we also observed a decrease in the level of TTP mRNA as well as an accumulation of the phosphorylated TTP protein (inactive form of TTP). Recent works showed the growing interest in stabilizing the amount of TTP protein as an anti-inflammatory therapy. We applied an oligonucleotide-based strategy to stabilize the TTP mRNA level. We showed that oligonucleotides incubation induced an increase in the TTP mRNA and protein level associated with a decrease in the pro-inflammatory cytokines’ expression in CF bronchial cells. In inflammatory context, the positive effect of TTP overexpression has been also observed in M1 macrophages. This study defines a new role for TTP RNA-BP as well as proposes a new strategy to participate in inflammatory resolution in CF.
- Étude de l’expression et de la régulation de la tristetraproline, une protéine anti-inflammatoire dans la mucoviscidose
- Solenne Bleuse - 33UDM_INST___HR10S01106
- Magali TaulanPrisca Boisguerin [Président]Pascale Fanen [Rapporteur]Loïc Guillot [Rapporteur]Christine BrunFrédéric Velard
- École doctorale Sciences Chimiques et Biologiques pour la Santé (Montpellier ; 1992-....); Doctoral
- Doctoral, École doctorale Sciences Chimiques et Biologiques pour la Santé (Montpellier ; 1992-....)
- 99189434609311
- Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp
- French
- Dissertation
- tel-05443684