Team C. Galés/JM. Sénard

Molecular and clinical determinants of cardiac architecture (ARCHI-CARD)

The physiologic response of an organ relies on a complex interplay between the different cell types structuring the tissue. At the cellular level, the response arises from the plasma membrane through different receptors, channels, pumps… that integrate and proceed the extracellular stimuli (chemical, mechanical). Alteration of the plasma membrane response is a hallmark of number of patho-physiological situations. Now, how the plasma membrane and the overall cell architecture behave in such pathologies, what is the impact on the surface organization and functions of the proteins inserted in the plasma membrane and more largely what is the impact on the neighboring cells still remain poorly understood.
In this context, the research program of our team focuses on understanding the clinical/molecular determinants of the cardiac architecture/function.
Our team is highly interdisciplinary integrating people from basic and medical research in pharmacology, cellular biology, cardiology and neurology. As a consequence, our approach also relies on a high interdisciplinarity starting from the identification of the molecular/cellular mechanisms to the integration in animal models but also in humans thanks to our collaboration with the Toulouse CHU hospital.

Team members

 
Tous / AllTeam leaderResearchersCliniciansStudentsTechnical staff
Team leader

Céline GALÉS

Co-team leader / PUPH

Jean-Michel SÉNARD

MCU-PH

Céline GUILBEAU-FRUGIER

Faculty investigator

Clément KARSENTY

Researcher, Inserm

Véronique PONS

Student

Ophélie HELISSEN

Engineer Assistant

Nicolas PATALUCH

Research Engineer

Amandine WAHART

Maire-Hélène SÉGUÉLAS
Technician, Inserm

Maire-Hélène SÉGUÉLAS

Clémentine VABRE
Student

Clémentine VABRE

Marc KERMORGANT
Clinical research associate

Marc KERMORGANT

Fabien DESPAS
Faculty investigator

Fabien DESPAS

Jean-Philippe MAURY
Faculty investigator

Jean-Philippe MAURY

Anne PAVY-LE TRAON
Faculty investigator

Anne PAVY-LE TRAON

Team leader

Céline GALÉS

Research director INSERM

Career path.
She received her PhD in Pharmacology (GPCRs) at Paul Sabatier University (Toulouse, France) in 2001, and completed her postdoctoral training (GPCRs) in the lab of Michel Bouvier at Montreal University (Canada). She got a permanent position at INSERM in 2005 as research PI, co-chairs the team Archi-Card since 2011 that she runs now since 2021.

Main domain of expertise
Pharmacology, G protein-coupled-receptors (GPCRs), Signaling, Biased agonism, Intracellular trafficking, cardiology, cardiomyocyte surface architecture, heart failure.

Email:celine.gales@inserm.fr

Tél/phone:+33(0)5 31 22 40 75

Co-team leader / PUPH

Jean-Michel SÉNARD

MD, PhD

Career path
JM Senard is Prof of Clinical Pharmacology at the school of Medicine of Toulouse University and a MD specialist in neurocardiology. He chaired the European Federation of Autonomic Societies and is the current chair of the SOOM1 IRB. He currently cochair with C Galés the team he founded in 2011.

Main domain of expertise
Pharmacology, autonomic nervous system.

MCU-PH

Céline GUILBEAU-FRUGIER

Medical Doctor, Physician-scientists doctor

Career path
Céline is a pathologist, a forensic medical doctor and the director of an electron microscopic platform. She obtained her PhD degree in pharmacology in 2012 at the university of Toulouse. She joined our team in 2013 wherein she developed the use of electron microscopy to explore the cardiac tissue.

Main domain of expertise
Myocardial morphology, electron microscopy, histology

Faculty investigator

Clément KARSENTY

Faculty investigator

Career path
Clement is a pediatric cardiologist. He received his Master degree in Biology option heart and circulation from the Paris Diderot University in 2015. He joined our team in 2015 as a master student, now finishing his thesis in the field of heart diseases.

Main domain of expertise: Pediatric cardiology, Cardiac postnatal development, Congenital heart defect, Heart failure, Animal experimentation.

Researcher, Inserm

Véronique PONS

INSERM researcher

Career path.
Sh
e received her PhD in Physiopathology at Toulouse University (2003) followed by a postdoctoral training in intracellular trafficking at Geneva University. In 2014, she got a permanent position at INSERM and joined the team to develop projects on GPCR pharmacology/biased agonism.

Main domain of expertise
Pharmacology, G protein-coupled-receptor, Signaling, Biased agonism, Intracellular trafficking

Student

Ophélie HELISSEN

PhD Student

Ophélie HELISSEN received her Master degree in Health Biology, option Cardiovascular Physiopathology and Pharmacology from the Angers University (France) in 2019. She joined our team in November 2019 as an PhD Student in the field of the heart-brain dialog.

Main domain of expertise
Animal experimentation, cardiovascular and cerebral physio/pathophysiology, autonomic nervous system, microgravity.

Email:ophelie.helissen@inserm.fr

Tél/phone:+33(0)628492832

Engineer Assistant

Nicolas PATALUCH

Engineer Assistant

Nicolas obtained his master degree in Biotechnologies options Neurology & Applied Physiology from the Faculty of Sciences of Nancy (France) in 2019. He Joined the team in September 2020 as an t Engineer Assistant in the field of cardiac imaging.

Main field of expertise
Animal experimentation, Biotechnologies, Tissue Clearing, Photonic microscopies, Physiology/animal experimentation.

Research Engineer

Amandine WAHART

Research Engineer

Her current research focuses on the study of the mechanisms responsible for the phenotype of smooth muscle cells during neoatherosclerosis in the context of restenosis during hyperglycemia.

Career path
Master in Biology (2014, Reims), Engineer in pre-clinical imaging (2014-2013, Reims), Thesis in biochemistry and cell biology (2015-2019, Reims), Post-doctoral fellow (2019-2022, Toulouse) in the team of Muriel Laffargue.

Main domains of expertise
Cell biology, Animal experimentation, Microsurgery, Pre-clinical imaging, histology.

Technician, Inserm

Maire-Hélène SÉGUÉLAS

INSERM technician

Main field of expertise: animal experimentation, primary culture of cardiomyocytes, histology

Student

Clémentine VABRE

PhD student

Career path 
Clémentine recently graduated as a PharmD at the faculty of pharmacy of Toulouse and obtained a Master degree in epidemiology from ISPED, university of Bordeaux. She started her PhD in the team in January 2021 and works on protein kinase inhibitors and their cardiovascular adverse effects.

Main domain of expertise : Pharmaco-epidemiology, anticancer drugs, protein kinase inhibitors

Clinical research associate

Marc KERMORGANT

Clinical research associate

Marc Kermorgant received his PhD in Biology and Health option Neurosciences, from the University of Western Brittany (Brest, France) in 2014. He joined our team in October 2014 as a clinical research associate in the field of neurophysiology and participates to the heart-brain communication project.

Main domain of expertise: Neurophysiology, autonomic nervous system, cardiovascular system, experimental surgery, microgravity

Email:marc.kermorgant@gmail.com

Tél/phone:+33(0)5531224075

Faculty investigator

Fabien DESPAS

Faculty Investigator

Career path
Fabien is a Pharmacist, MCU-PH of Pharmacology at the Faculty of Health of the University of Toulouse, specializing in the exploration of the autonomic nervous system. He joined the team in 2021 to develop the pharmacoepidemiology of the cardiovascular effects of anticancer drugs, in particular protein kinase inhibitors.

Main domain of expertise
Adverse drug reactions, anticancer drugs, cardiovascular pharmacology, protein kinase inhibitors

Email:fabien.despas@univ-tlse3.fr

Tél/phone:+33(0)56114595940

Faculty investigator

Jean-Philippe MAURY

Faculty Investigator

Career path
Jean-Philippe is Prof of Cardiology at the school of Medicine of Toulouse University and a MD specialist in interventional rhythmology. He is member of the electrophysiology working group of the french society of Cardiology. He joined our team in 2016 and develop in vivo rhythmology in mice.

Main domain of expertise
Electrophysiology, cardiac Arrhythmias

Faculty investigator

Anne PAVY-LE TRAON

Faculty Investigator

Career path
Anne is Associate Professor at the University Hospital of Toulouse. She holds an MD in Neurology, a PhD and a qualification to direct research and teaches space medicine. She joined our team in 2011 wherein she participates to the heart-brain communication project.

Main domain of expertise: Autonomic nervous system (assessment, cardiovascular regulation and disorders), Multiple system atrophy, Space medicine and physiology

Architecture of the lateral membrane of cardiomyocytes

 

Coordinators : Céline Galés & Jean-Michel Sénard

Defects in cardiomyocyte (CM) signaling are a hallmark of heart failure (HF) from all origins. However, most of the studies have focused on the end-stage pathology. Whether these modifications are causes or consequences still remain to be answered and are essential for the development of new efficient therapeutics. However, the intracellular signaling outcome of a cell is tightly dependent on its origin, i.e. the cell surface. How the architecture of the CM surface is temporally modified upon cardiac stresses and how this can impact the 3D heart structure, the CM response and the overall heart function remain fundamental questions in cardiology.

Thanks to high resolution microscopies (AFM, MET) we optimized during these last years, we previously reported and accurately characterized in the cardiac tissue the architectural organization of the lateral membrane of adult CMs with periodic crests related to the presence of subsarcolemmal mitochondria (SSM) whose role is unknown and that are rapidly lost after myocardial infarction before T-Tubule disorganization, a common HF hallmark. Our goal is now to better understand the crest loss: i/ is it specific or generic to all HF origins? ii/ what is the trigger? iii/ what are the crest determinants/ modulators?, iv/ how to prevent the crest loss?

Cardiac architecture and brain dialogs

 

Coordinators : Constandina Arvanitis & Jean-Michel Sénard

There is a dynamic relationship between the nervous system and heart. Data indicate that the burden of heart failure correlates with the high frequency of cognitive and mood disorders. This suggests a relationship between heart and brain (heart-to-brain axis) through vegetative afferences but that still remains poorly understood.

Our goal in cardioneurology is to better characterize this heart-brain dialog at the cellular/molecular/functional level. More specifically, we search to evaluate whether changes in cardiomyocyte architecture participate in the afferent reflex response and the ensuing modulation of the sympathetic autonomic system activity. We use a myriad of in vivo models including myocardial infarction, genetic knockouts and landbased microgravity research models. We apply physiology/electrophysiology, behavior assays and at the nanoscale, nanoparticle technologies and AFM.

G protein coupled receptor (GPCR) organization at the cell surface and its role in ligand efficacy

 

Coordinateur : Véronique Pons & Céline Galés

GPCRs represent the major pharmaceutical drug target. However, many drugs are associated with harmful side-effects and a poor clinical benefit-risk ratio that limit their use.
Recently, the concept of biased-agonism (ligand selecting some receptor-signaling pathways) paved the way for the development of pathway-specific drugs with higher efficacy and lower adverse events. Now, understanding the link between GPCR at the cell surface and the signaling/physiological outcome remains a major challenge for a more rational design of biased ligands.
By multiplexing high-resolution tools (FRET/BRET probes) to dissect and image the spatiotemporal GPCR signaling in living cells and 3D tissues, our goal is to identify the molecular basis underlying biased agonism/ligand efficacy at multiple cardiovascular GPCR drug targets (AT1-R, b2-AR, P2Y-R) by taking into account the existence of multiple receptor populations and different membrane architectures at the cell surface.

Selected publications

Cardiac sensory afferents modulate susceptibility to anxio-depressive behaviour in a mouse model of chronic heart failure. KERMORGANT M, BEN SALEM J, IACOVONI J, CALISE D, DAHAN L, GUIARD BP, LOPEZ S, LAIREZ O, LASBORIES A, NASR N, PAVY-LE TRAON A, BEAUDRY F, SENARD JM, ARVANITIS DN.  Acta Physiol (Oxf). 2021 Apr;231(4):e13601. doi: 10.1111/apha.13601. PMID: 33316126

Deciphering biased inverse agonism of cangrelor and ticagrelor at P2Y12 receptor. GARCIA C, MAUREL-RIBES A, NAUZE M, N’GUYEN D, MARTINEZ LO, PAYRASTRE B, SENARD JM, GALES C, PONS V. Cell Mol Life Sci. 2019 Feb;76(3):561-576. doi: 10.1007/s00018-018-2960-3. PMID: 30406277

Structural evidence for a new elaborate 3D-organization of the cardiomyocyte lateral membrane in adult mammalian cardiac tissues.GUILBEAU-FRUGIER C, CAUQUIL M, KARSENTY C, LAIREZ O , DAMBRIN C, PAYRE B, CASSARD H, JOSSE C, SEGUELAS MH, ALLART S,BRANCHEREAU M, HEYMES C, MANDEL F,  DELISLE MB, PATHAK A, DAGUE E, SENARD JM, GALES C.  Cardiovasc Res. 2018 Oct 17. doi: 10.1093/cvr/cvy256. PMID: 30329023 

Cardioprotective Angiotensin-(1-7) Peptide Acts as a Natural-Biased Ligand at the Angiotensin II Type 1 Receptor GALANDRIN S, DENIS C, BOULARAN C, MARIE J, M’KADMI C, PILETTE C, DUBROCA C, NICAISE Y, SEGUELAS MH, N’GUYEN D, BANÈRES JL, PATHAK A, SÉNARD JM, GALÉS C. Hypertension. 2016 Dec;68(6):1365-1374. doi: 10.1161/HYPERTENSIONAHA.116.08118. PMID: 27698068

Dual agonist occupancy of AT1-R-α2C-AR heterodimers results in atypical Gs-PKA signaling. BELLOT M, GALANDRIN S, BOULARAN C, MATTHIES HJ, DESPAS F, DENIS C, JAVITCH J, MAZÈRES S, SANNI SJ, PONS V, SEGUELAS MH, HANSEN JL, PATHAK A, GALLI A, SÉNARD JM, GALÉS C.  Nat Chem Biol. 2015 Apr;11(4):271-9. doi: 10.1038/nchembio.1766. PMID: 25706338

FUNDINGS

CNES

CNES

FFC

FFC

Indorsia

Indorsia

FRM

FRM

fondation bettencourt schueller

fondation bettencourt schueller

fondation d efrance

fondation d efrance

hopitaux de toulouse

hopitaux de toulouse

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