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.
H4-Orphan Pharma (Dijon)
INFLECTIS BIOSCIENCES (Nantes)
Vaincre la Mucoviscidose
Amandine contre la Mucoviscidose
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 development2018 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
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