Transports Ioniques et Dynamiques Membranaire de l’Epithélium, Mucoviscidose (TIME) (Epithelial Ion Transports and Membrane Dynamics, Cystic Fibrosis)

Thématique:

Study of the epithelial ion transport in physiology and human diseases (cystic fibrosis) caused by dysfunction of ion channels (channelopathies)

Axe de recherche 1:

Study of novel F508del-CFTR modulators (pharmacological correctors, potentiators and inhibitors)

Axe de recherche 2:

Study of calcium homeostasis and water-transport in CFTR- and F508del-expressing cells and epithelia

Axe de recherche 3:

Study of lipointoxication and autophagy in yeast, in CFTR- and F508del-expressing epithelial cells

 

Responsable :  Frédéric Becq

Membres de l’équipe: 

Frédéric Becq (Pr), Marianne BERNARD (MCU),  Thierry BERGES (Pr), Matthieu REGNACQ (MCU), Clarisse VANDEBROUCK (MCU),  Pierre VOISIN (DR CNRS), Jenny COLAS  (AJT, 50%), Sandra MIRVAL (T), Arnaud BILLET, PhD, (Post-doc CF-TRUST, 2015-2019), Lionel FROUX, PhD, (Post-doc VLM, 2015-2017 ; H4 Orphan Pharma, 2018-2019), Jodie LLINARES (doc MESR, 2016-2019),  Chloé GREBERT (doc VLM, 2016-2019).

 

Mots Clefs : CFTR, cystic fibrosis, epithelial ion transport, calcium homeostasis, water transport, pharmacology, channelopathies, electrophysiology, lipointoxication, autophagy

We are developing our research activities in three complementary directions. The first one is the study of the pharmacology of CFTR and other chloride (Cl) channels (TMEM16A, LRRC8…) and channelopathies (cystic fibrosis, CF), including search for novel F508del-CFTR modulators (direct binders, channel potentiators and inhibitors, proteostasis modulators). The second one is the study of calcium homeostasis and ion channel-dependent water transport in epithelial cells. The third is the study of autophagy and plasma membrane dynamics in yeast and epithelial cells related to ion channel activity and to the control of the biogenesis of misfolded proteins.

In particular, our objectives are to elucidate the molecular and cellular mechanisms causing CF and to study several ion channels (CFTR, ClC, CaC, TMEM16A, TRPV6) in CF and non-CF cells. We are specialized in the study of the epithelial Cl channel CFTR (cystic fibrosis transmembrane conductance regulator), its regulation, biogenesis and pharmacology. The CFTR protein is an apical membrane protein functioning as a Cl channel regulating transepithelial Cl transport in secretory organs (lung, pancreas). A dysfunction of this protein affects Cl, Na+, Ca2+, HCO3 and water transports in epithelial tissue leading to thick and viscous secretions, a hallmark of CF tissues.

Cystic fibrosis is a lethal monogenic disease caused by mutations in the CFTR gene that entails the (diagnostic) increase in sweat electrolyte concentrations, progressive lung disease with chronic inflammation and recurrent bacterial infections, pancreatic insufficiency, and male infertility. The most common mutation in CF patients is the deletion of a phenylalanine at position 508 (F508del) in the first nucleotide-binding domain (NBD1) of the CFTR protein. This mutation occurs in 90 % of the CF patients, while 50 to 70 % of them have two copies of the F508del allele. The F508del-CFTR mutation is primarily classified as a class II mutation, which affects CFTR processing, causing its misfolding, retention in the endoplasmic reticulum (ER), accelerated degradation and impaired channel gating.

Whereas the features of Cl transport by the CFTR protein are relatively well defined, studies directly addressing calcium homeostasis and water transport in epithelial physiology and in human pathologies (such as cystic fibrosis) are both still at an early stage. Our research is thus primarily dedicated to Cl channels and Cl channelopathies with a special interest to CFTR and cystic fibrosis but we are also studying other ionic channels (TRPV6, TMEM16A, acid-activated chloride channels, CLC) and epithelial aquaporins (AQP3, AQP9), their physiological and physiopathological roles in epithelia. Finally, we also addressed questions related to lipid membrane composition, lipointoxication of CF cells and autophagy. Defective autophagy is also one of the hallmarks of cells homozygous for F508del that exhibits an impressive derangement of cellular proteostasis.

Partenariats

H4-Orphan Pharma (Dijon)

INFLECTIS BIOSCIENCES (Nantes)

LFEL (Bordeaux)

BioAlternatives (Gencay)

ConicMeds (Poitiers)

 

CF-TRUST

Vaincre la Mucoviscidose

MucoVie

Amandine contre la Mucoviscidose

ABCF2

Dernières publications
1.

Modulating the cystic fibrosis transmembrane regulator and the development of new precision drugs. Froux L, Billet A, Becq F.

Expert Review of precision medicine and drug development 2018 in press

 

Update on the cellular and molecular aspects of cystic fibrosis transmembrane conductance regulator (CFTR) and male fertility. M. Yefimova, N. Bourmeyster, F. Becq, A. Burel, M.-T. Lavault, G. Jouve, S. Vea, C. Pimentel, B. Jégou, C. Ravel.

Morphologie 2018 in press

 

Modulation of cellular membrane properties as a potential therapeutic strategy to counter lipointoxication in obstructive pulmonary diseases. Kadri L, Ferru-Clément R, Bacle A, Payet LA, Cantereau A, Hélye R, Becq F, Jayle C, Vandebrouck C, Ferreira T.

Biochim Biophys Acta Mol Basis Dis. 2018 Sep;1864(9 Pt B):3069-3084.

 

In cellulo analyses of the p.Val322Ala mutation on the CFTR protein conformation and activity. Farhat R, El-Seedy A, Sari AIP, Norez C, Pasquet MC, Becq F, Kitzis A, Ladevèze V.

C R Biol. 2017 Aug;340(8):367-371.

 

Bioactive natural product and superacid chemistry for lead compound identification: case study of selective hCA III and L-type Ca2+ current inhibitors for hypotensive agent discovery. Carreyre H, Carre G, Ouedraogo M, Vandebrouck C, Bescond J, Supuran CT and,  Thibaudeau S.

Molecules. 2017 May 31;22(6) Review

 

Development of Automated Patch Clamp Technique to Investigate CFTR Chloride Channel Function. Billet A, Froux L, Hanrahan JW, Becq F.

Front Pharmacol. 2017 Apr 7;8:195.

 

Calumenin contributes to ER-Ca2+ homeostasis in bronchial epithelial cells expressing WT and F508del mutated CFTR and to F508del-CFTR retention. Philippe R, Antigny F, Buscaglia P, Norez C, Huguet F, Castelbou C, Trouvé P, Becq F, Frieden M, Férec C, Mignen O.

Cell Calcium. 2017 Mar;62:47-59.

 

The Pig: A Relevant Model for Evaluating the Neutrophil Serine Protease Activities during Acute Pseudomonas aeruginosa Lung Infection. Chevaleyre C, Riou M, Bréa D, Vandebrouck C, Barc C, Pezant J, Melo S, Olivier M, Delaunay R, Boulesteix O, Berthon P, Rossignol C, Burlaud Gaillard J, Becq F, Gauthier F, Si-Tahar M, Meurens F, Berri M, Caballero-Posadas I, Attucci S.

PLoS One. 2016 Dec 16;11(12):e0168577.

 

Myelinosomes act as natural secretory organelles in Sertoli cells to prevent accumulation of aggregate-prone mutant Huntingtin and CFTR. Yefimova MG, Béré E, Cantereau-Becq A, Harnois T, Meunier AC, Messaddeq N, Becq F, Trottier Y, Bourmeyster N.

Hum Mol Genet. 2016 Oct 1;25(19):4170-4185.

 

Targeting surface voids to counter membrane disorders in lipointoxication-related diseases.

Ferru-Clément R, Spanova M, Dhayal S, Morgan NG, Hélye R, Becq F, Hirose H, Antonny B, Vamparys L, Fuchs PF, Ferreira T.

J Cell Sci. 2016 Jun 15;129(12):2368-81.

 

Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis. Meijer L, Nelson DJ, Riazanski V, Gabdoulkhakova AG, Hery-Arnaud G, Le Berre R, Loaëc N, Oumata N, Galons H, Nowak E, Gueganton L, Dorothée G, Prochazkova M, Hall B, Kulkarni AB, Gray RD, Rossi AG, Witko-Sarsat V, Norez C, Becq F, Ravel D, Mottier D, Rault G.

J Innate Immun. 2016;8(4):330-49.

 

Régnacq M, Voisin P, Héchard Y, Bergès T, Braquart-Varnier C, Samba-Louaka A. Identification of Atg8 from Acanthamoeba castellanii by genetic complementation in Saccharomyces cerevisiae.

Mol Biochem Parasitol. 2016 Nov – Dec;210(1-2):55-57.

 

Régnacq M, Voisin P, Sere YY, Wan B, Soeroso VM, Bernard M, Camougrand N, Bernard FX, Barrault C, Bergès T. Increased fatty acid synthesis inhibits nitrogen starvation-induced autophagy in lipid droplet-deficient yeast. Biochem Biophys Res Commun. 2016 Aug 12;477(1):33-9.

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