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Eric HONORE
Chef d'équipe

L'EQUIPE

Ajroud

Arhatte

Bernier

Berthieux

Douguet

Glogowska

Honore

Patel
LES PUBLICATIONS

 
 Douguet D. et al. (2019). Piezo Ion Channels in Cardiovascular Mechanobiology. Trends Pharmacol Sci

 Douguet D. and Honore E. et al. (2019). Mammalian Mechanoelectrical Transduction: Structure and Function of Force-Gated Ion Channels. Cell

 Arhatte M. et al. (2019). TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells. Nat Commun

 Douguet D. et al. (2019). Structure and function of polycystins: insights into polycystic kidney disease. Nat Rev Nephrol

 Ma S. et al. (2018). Common PIEZO1 Allele in African Populations Causes RBC Dehydration and Attenuates Plasmodium Infection. Cell

 Retailleau K. et al. (2016). Arterial Myogenic Activation through Smooth Muscle Filamin A. Cell Rep

CONTACTS
Eric HONORE
Chef d'équipe, 04 93 95 77 45

Virginie BERTHIEUX
Gestionnaire, 04 93 95 77 64
 

Equipe du Dr Eric Honor
Mcanobiologie molculaire et intgrative

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expert

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MOLECULAR AND INTEGRATIVE MECHANOBIOLOGY

Activités de l'équipe

OUR RESEARCH

Mechanobiology concerns the role of force in development, physiology, and diseases (1, 2). Our team focuses on the molecular mechanisms by which cells sense and respond to mechanical signals. Some cells in the body are specialized for sensing a specific type of mechanical input: for instance touch sensitive sensory dorsal root ganglion neurons or hair cells in the inner ear. However, all cells of the organism (even non-specialized cells) are mechanosensitive (MS) and can respond to mechanical stress by adaptive responses. A variety of molecular players are involved in cellular mechanotransduction including: the extracellular matrix, adhesion molecules, ion channels,  cytoskeletal elements, nuclear proteins, transcription factors, enzymes, as well as numerous other molecular structures and signaling molecules. It is now well recognized that changes in cellular mechanotransduction significantly contribute to the development of severe pathologies, including atherosclerosis, heart failure and cancer. Notably, mechanotherapy is being progressively introduced for clinical use, as for instance in reconstructive medicine.

 
Collectively cells respond to local mechanical stress by activation of specific molecular pathways resulting in macroscopic changes at the organ level. For instance resistance arteries (small diameter) respond to hypertension by a major structural remodeling caused by the repositioning of arterial smooth muscle cells (SMCs) around a smaller lumen diameter (inward eutrophic remodeling). Hypertensive arterial remodeling allows a normalization of the parietal tension because of an increase in wall thickness (although without hypertrophy) and a reduced arterial diameter. Thus, wall tension is restored to a normal level, despite an increase in luminal pressure [Laplace’s law]. We aim at identifying the sensors and effectors that are involved in these specific adaptive responses to chronic mechanical stress [although these can become maladaptive when hypertension is maintained](3, 4).

Our group has been focusing on the role of ion channels in cellular mechanotransduction for the last 20 years. MS ion channels are conserved throughout evolution and are already present in microbes, yeast and plants. For instance, osmotic down-shock opens bacterial MS ion channels, such as the large non-selective conductance MscL, allowing osmolyte efflux, relieving pressure and preventing cell lysis (5).
Additional studies performed on bacterial MS channels have provided strong evidence that its conformation is directly dependent on tension in the lipid bilayer (for review (6)). Our team members discovered, for the first time, the molecular identity of a mammalian MS ion channel (7) (and for review (8)). We reported that the K2P channel TREK-1 is a MS K+-selective ion channel, directly activated by force generated in the lipid bilayer, as confirmed by more recent structural data and reconstitution experiments (7-31). Opening of TREK/TRAAK channels in response to mechanical stress (shear stress, membrane stretch or cell swelling) causes cell hyperpolarization leading to a decrease in cell excitability (for review (8)).
The identity of the non-selective depolarizing MS cationic channels was discovered in 2010 by the Patapoutian group (32-42). Piezo1 is a large trimeric complex, with an N-terminal mechanotransduction module followed by a C-terminal ionic pore (35, 43). Functional reconstitution experiments with purified Piezo1, as well as electrophysiological recordings indicate that membrane tension is the common activating force acting on Piezo1 gating (36, 39, 40, 44). Piezo1 was shown by our group and others to be required for vascular development, flow-mediated dilatation and arterial remodelling (4, 33, 34, 45), while Piezo2 plays a key role in mechanosensory transduction, in particular light touch sensitivity and proprioception (46-51). Recent findings also indicate that Piezo1 is involved in epithelial cell overcrowding/confinement-sensing and cell extrusion (52, 53). Moreover, mechanical stretch triggers rapid epithelial cell division through Piezo1 opening (54).
Notably, Piezo1/2 are implicated in a variety of rare genetic disorders, including xerocytosis (dominant Piezo1 gain-of-function mutations; GOF), lymphatic dysplasia (recessive Piezo1 loss-of-function mutations; LOF), arthrogryposis (dominant Piezo2 GOF) and muscular atrophy with scoliosis and perinatal respiratory distress (recessive Piezo2 LOF)(55-62).

We are currently focusing on four different projects concerning the role of Piezo1 in: 1) obesity; 2) pulmonary hypertension; 3) nephropathies; 4) genetic resistance to malaria.
 
Expected global outcomes:
Our project is intrinsically pluridisciplinary and aggregates state-of-the-art biophysics, molecular and cellular biology, stem cells research, physiology and bio-engineering. This rationalized and integrated collection of experimental data should allow us to gain important new insights into the basic mechanisms of mechanobiology. We expect that our findings will pave the way for the discovery and development of new strategies, based on the pharmacological and/or mechanical modulation of Piezo1 (mechanotherapy).

Projet 1: L'obésité sous pression

PROJECT 1: OBESITY UNDER PRESSURE
The increase in the prevalence of overweight/obese people worldwide has reached epidemic proportions, with at least 600 million clinically obese adults (WHO, 2014). Numbers are expected to further increase, particularly promoted by the demographical change towards the elderly. Obesity is multifactorial and constitutes a substantial risk factor for type 2 diabetes, cardiovascular diseases, cancer and a variety of additional disorders, thus presaging tremendous burdens for the public health care system. Efficient and safe pharmacological treatments against obesity with significant long-term success are still critically needed. Thus, there is an urgent need to better understand the basic mechanisms of adipose tissue expansion, in view of designing effective strategies against obesity.

Projet 2: Piezo1 dans le remodelage artériel

PROJECT 2: PIEZO1 IN ARTERIAL REMODELING
The pulmonary circulation is a low-pressure low resistance system allowing the whole cardiac output to cross the lung (85-87). Pulmonary hypertension (PH) is characterized by increased pulmonary artery (PA) pressure and resistance, which negatively impacts the right ventricular (RV) function because of enhanced afterload. It may appear as idiopathic pulmonary arterial hypertension but may also be associated with a variety of conditions, including chronic hypoxemia (88). In PH, increased arterial reactivity and structural remodeling occur with a thickening of the medial layer of small muscular PAs (85-87). PA SMCs hypertrophy is a characteristic pathological feature of PH that involves muscularized arteries (ranging between 70 and 500 μm in diameter), and precapillary vessels (below 70 μm in diameter) (85-87). The mechanisms underlying the thickening of the pulmonary vascular medial layer are also linked to enhanced SMCs proliferation (hyperplasia). Several arguments point to an important role for mechanical stress in PH. First, PA remodeling is associated with a prolonged vasoconstriction of muscular PAs, as occurring during hypoxemia at high altitude or secondary to chronic hypoxic pulmonary diseases (85-87). Second, patients with heart dysfunctions leading to an increase in PA pressure also develop pathological remodeling of the pulmonary vessels (85-87). Third, stretch stimulates hypertrophy and hyperplasia of cultured PA SMCs (89, 90).

 Projet 3: Mécano-néphropathies

PROJECT 3: MECHANO-NEPHROPATHIES
In the kidney, important progress has recently been made in the understanding of flow sensing by tubular epithelial cells (91, 92). Bending of the primary cilium at the apical side of tubular cells induced by the flow of intraluminal urine activates the ciliary polycystin complex (Polycystin-1; PC1 and Polycystin-2; PC2 which are mutated in autosomal dominant polycystic kidney disease, ADPKD), resulting in a calcium influx through the transient receptor potential (TRP) channel PC2 (for reviews: (2, 93-95)). Kidney epithelial cells also respond to changes in intraluminal pressure (2, 94). Normal pressure at rest within the renal pelvis and ureter is in the range of 0-10 mm Hg. However, peristaltic pressures generated by rhythmic papillary contractions required for the transport of urine vary between 15 and 45 mm Hg (2). When a renal tubule is subjected to intraluminal pressure, both apical and basolateral membranes are stretched (96). This physiological transient elevation in pressure is transmitted back to the tubular lumen and leads to repetitive tubular distension and cell stretching. Intraluminal pressure can also be dramatically elevated in kidney disease states (2). Indeed, obstructive uropathy is associated with a major increase in intratubular pressure, in excess of 60 mm Hg, leading to tubular circumferential stretch (97-101). Stretching, as well as compression of renal epithelial cells also occurs in PKD patients (2). Abnormal fluid accumulation in renal cysts causes the cyst wall to stretch (102-104). Moreover, growing cysts compress neighboring tubules with upstream accumulation of urine leading to increased intratubular pressure. Stretch of epithelial cells has been proposed to impact on cell proliferation, fibrosis, as well as apoptosis (28,97-101,104). Thus, pressure-induced stretch of tubular epithelial cells is relevant to both physiological and diseased kidney conditions (2).

Projet 4: Piezo1 érythrocytaire et paludisme

PROJECT 4: OPENING PIEZO1 IN RED BLOOD CELLS TO FIGHT MALARIA
In our group, Dominique Douguet develops computational methods and creates databases for virtual screening and de novo molecular design, drug re-purposing and knowledge-based design of drug-like compounds (LEA3D suite of tools). We are analyzing the current FDA approved drug chemical space from various dimensions: chemical structures, privileged structures, physicochemical properties, pharmacodynamic and pharmacokinetic properties (our own database e-Drug3D http://chemoinfo.ipmc.cnrs.fr/edrug3d.html; Inter Deposit Digital Number IDDN.FR.001.240001.000.S.P.2017.000.31235). Such structure-activity/property collections allow retrospective analyses of past successes and to foster the development of improved predictive methods relevant to the drug discovery and optimization process and, in particular, methods for assessing pharmacokinetic properties directly from molecular structures. These knowledge-based models and guidelines are associated with conventional ligand- and structure-based virtual screening methods (fingerprint, pharmacophore, shape-matching, docking…) to optimally identify and optimize bioactive small molecules.
 
 

Collaborations et réseaux scientifiques

ONGOING COLLABORATIONS AND SCIENTIFIC NETWORKS

Our group is a member of the “Défi mécanobiologie CNRS”, Human Frontier Science Program (EH PI), CNRS pre-maturation (Dominique Douguet and Kai Wengelnik, co-PIs) and ANR networks.

Current collaborators:
 
Serge ADNOT
Institut Mondor de Recherche Biomédicale, Créteil (France)
Jonathan MARCHANT
University of Minnesota, MN (USA)
Ez-Zoubir AMRI
Institut de Biologie Valrose, University of Nice Sophia Antipolis
(France)
Pierre NASSOY
Laboratoire Photonique Numérique et Nanosciences, Bordeaux (France)
Chih-Cheng CHEN
Academia Sinica, Taipei
(Taïwan)
Stefan OFFERMANNS
Max Planck Institute for Heart and Lung Research, Bad Nauheim(Germany)
Christian DANI
Institut de Biologie Valrose, University of Nice Sophia Antipolis
(France)
Ardem PATAPOUTIAN
The Scripps Research Institute, La Jolla, CA
(USA)
Dennis DISCHER
University of Pennsylvania, Philadelphia, PA (USA)
Alexander PFEIFER,
University of Bonn (Germany)
Valérie DOYE
Institut Jacques Monod, Paris (France)
Olivier ROSSIER and Grégory GIANNONE
Interdisciplinary Institute for Neuroscience, Bordeaux (France)
Carsten GRASHOFF
Max Planck Institute for Biochemistry, Martinsried (Germany)
Pierre SENS
ESCPI, Paris (France)
Daniel HENRION
Université d’Angers (France)
Jean-François TANTI, Mireille CORMONT and Philippe GUAL
C3M Inserm Nice (France)
Benoît LADOUX
Institut Jacques Monod, Paris
(France)
Kai WENGELNIK
Dynamique des Interactions Membranaires Normales et Pathologiques, Montpellier (France)
Christophe LAMAZE
Centre de Recherche Institut Curie, Paris (France)
Robet WILKINSON
University of Sheffield, (UK)
Cheng-Chang LIEN
National Yang-Ming University, Taipei (Taïwan)
Aimin XU
The Hong Kong University (China)

 

Conseil consultatif scientifique

SCIENTIFIC ADVISOSY BOARD

Human Frontier Science Program Grant (PI: Eric Honoré - CV, Partners: Carsten Grashoff, Dennis Discher, Aimin Xu)

Charmain of the SAB:
  • Professor Paul M. VANHOUTTE
M.D., PhD, DHC
http://www.pharma.hku.hk/web2/staffweb/pmvanhoutte/index.php
Invited Professor
Department of Pharmacology and Pharmacy
The University of Hong Kong
Li Ka Shing Faculty of Medicine
21 Sassoon Road
Hong Kong, China

Members of the SAB:
  • Professor Bernd NILIUS
M.D., Ph.D.
http://www.ae-info.org/attach/User/Nilius_Bernd/CV/nilius_bernd_cv_2011.pdf
http://www.kuleuven.be/fysio/trp/
http://de.wikipedia.org/wiki/Bernd_Nilius

Emeritus Professor
Dept Molecular Cell Biology
Faculty of Medicine
KU Leuven
Campus Gasthuisberg,
Herestraat 49,
B-3000 Leuven, Belgium
  • Dr. Emmanuel CANET
M.D. PhD.
http://www.servier.fr/
President of Research and Development
Servier Laboratories Limited
Laboratoires Servier
50 Rue Carnot, 92284 Suresnes, France
  • Dr. Roberto BRUZZONE
M.D.
http://www.hkupasteur.hku.hk/index.php/research/roberto_
Co-Director of HKU-Pasteur Research Pole
Division of Public Health Laboratory Sciences
7/F Hong Kong Jockey Club Building for Interdisciplinary Research, 5 Sassoon Road, Hong Kong, China
  • Dr. Bart STAELS
PhD
http://www.insulinresistance.us/bio/StaelsBart.pdf
http://www.u1011.lille.inserm.fr/

Director
Group « Nuclear receptors in the gastrointestinal system » INSERM U1011 – Institut Pasteur de Lille-Université Lille Nord de France – EGID
1 rue Calmette, BP245, 59019 Lille, France

Financements

FUNDING
 

                                      
 
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INSTITUT DE PHARMACOLOGIE MOLECULAIRE ET CELLULAIRE

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