Group 4 : KCNK3, NMDAR & ionic channel pathways

Fabrice Antigny and Sylvia Cohen-Kaminsky

The pathophysiology of PAH involve the remodelling the pulmonary arteries and the right heart. The functions of pulmonary vascular cells and right ventricular cells are regulated by many ion channels. We are studying different families of ion channels (K+, Ca2+ and Cl−), their regulatory mechanisms and their functions at the pulmonary vascular and cardiac levels, in order to understand their implication in the pathophysiology of PAH, and to explore their potential as new therapeutic targets for PAH.

Work in progress in the group

Our group studies the cellular and molecular consequences of dysfunctions of KCNK3, ABCC8, CFTR, SOC channels, and NMDAR in the development of PAH, in order to explore their therapeutic potentials in PAH. We characterize their respective roles and their interactions in the pulmonary vascular system (contraction / relaxation, proliferation / apoptosis, cell migration) as well as their involvement in the right ventricular dysfunction in PAH.

Our objective are:

(1) To decipher the role of KCNK3 in the pathophysiology of PAH, and to identify a therapeuticapproach targeting KCNK3 (https://anr.fr/Projet-ANR-18-CE14-0023)

Principal investigator: Fabrice Antigny

Researcher involved: Hélène Le Ribeuz, Véronique Capuano, Angèle Boet, Catherine Rucker-Martin

Internal collaborators : David Montani, Maria-Rosa Gighna

External collaborators: Alexandre Hinzpeter (INSERM U1151), Boris Manoury (INSERM U1180)

(2) To understand the role of SUR1/Kir6.2 in the pathophysiology of PAH and to determine if these SUR1/Kir6.2 channels could be a potential therapeutic target

Principal investigator: Fabrice Antigny

Researchers involved: Hélène Le Ribeuz, Véronique Capuano, Angèle Boet, Yan Ruchon

Internal collaborators: David Montani, Maria-Rosa Gighna

External collaborators : Wendy Cheng (Colombia University)

(3) To decipher the role of SOC in the pathophysiology of PAH, and to develop a multicellular therapy for PAH targeting SOCs

Principal investigator: Fabrice Antigny and Véronique Capuano

Researchers involved: Angèle Boet, Yan Ruchon

Internal collaborators: David Montani, Barbara Girerd

External collaborators: Jessica Sabourin (INSERM U1180), Maud Freiden (Geneva University), Claude Férec et Emmanuel Masson (INSERM U1078), Trangenic platform University of Nantes (Ignacio Anegon)

(4) To identify the of the CFTR channel in the development of PAH

Principal investigator: Fabrice Antigny, David Montani

Researchers involved: Hélène LeRibeuz, Catherine Rucker-Martin, Fabrice Antigny

Internal collaborators:, Frédéric Perros, Olaf Mercier, Maria-Rosa Gighna

External collaborators : Frédéric Becq (University of Poitiers), Clémence Martin and Pierre-Régis Burgel (Institut Cochin), Boris Manoury (INSERM U1180), Isabelle Sermet and Charles-Henry Cottart (INSERM U1151)

(5) To study the impact of ICaT-related signaling on the initiation and the progression of PAH in experimental models

Principal investigator: Véronique Capuano

Researchers involved: , Fabrice Antigny, Yan Ruchon

Internal collaborators: Frédéric Perros, David Montani

(6) To explore the role of NMDAR in the pathophysiology of PAH, its genetic implication in PAH, its cross-talk with the GCN2 and KCNK3 pathways and its potential as a new therapeutic target in PAH, particularly in subgroups like pulmonary veno-occlusive disease

Principal investigator: Sylvia Cohen-Kaminsky

Researchers involved: Firmin Akoumia

Internal collaborators: David Montani, Barbara Girerd, Frederic Perros, Fabrice Antigny

External collaborators: Nick Morrell, Stefen Graaf (University of Cambridge, UK), Florent Soubrier, Melanie Eyries (INSERM UMR S1166)

(7) To develop new NMDAR antagonists as therapeutic tools for the treatment of PAH (NUTS-Mat SATT Paris Saclay, https://satt-paris-saclay.fr/vitrine-technologique/nuts-mat/)

Principal investigator: Sylvia Cohen-Kaminsky

Researchers involved: Firmin Akoumia

Internal collaborators: Frederic Perros, David Montani

External collaborators: Mouad Alami (BioCis, CNRS UMR 8076), Alain Pruvost (LEMM, SMArt-MS, CEA)

(8) To study the impact of the pulmonary microbiota in vascular remodeling in PAH, by focusing on its metabolites capable to modulate ion channels: to develop innovative biotherapeutic targets (ANR LUMI, https://anr.fr/Projet-ANR-18-CE14-0043).

Principal investigator: Sylvia Cohen-Kaminsky

Researchers involved: Firmin Akoumia, Sofiane Remani

Internal collaborators: Frederic Perros, Fabrice Antigny

External collaborators: Genevieve Hery-Arnaud (INSERM UMR_S 1078, UBO), Nicolas Lapaque (MICALIS, INRA)