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    Team: Functional Pharmacology and Pathophysiology of Membrane Receptors

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    Team leader:

     

    The team, directed by Ralf Jockers, including a group led by Julie Dam, is interested in understanding the function of membrane receptors in metabolic diseases. Membrane receptors are at the interface between the extracellular and intracellular environment and are thus crucial for cell communication. They respond to a wide variety of extracellular stimuli and are the targets of most of the drugs prescribed for human diseases. Hormonal activation of these receptors leads to the activation of intracellular signaling events. However, the adequate response may vary depending on the genetic background and the disease state of individuals.

    Our objective is to understand the dysfunction of membrane receptors in metabolic diseases like obesity and diabetes among others. Both diseases constitute major public health problems with 1.5 billion people being over-weight, more than 500 million people being obese and more than 350 million people having diabetes worldwide. There is therefore an urgent need for innovative therapeutic approaches.                                                                                      

     

     

     

    Objectives

     

    We are interested in the investigation of the involvement of membrane receptors in metabolic diseases such as obesity and diabetes. We are particularly focusing our research on two membrane receptor families, the G protein-coupled receptor (GPCR) family and the cytokine receptor family to which the leptin receptor belongs. Among the various GPCRs studied the group has a major expertise on the melatonin receptor sub-family.

    We are employing cutting-edge biochemical, pharmacological, endocrinological and proteomic approaches to understand the function of these receptors and evaluate their therapeutic potential by developing innovative techniques such as Bioluminescence Resonance Energy Transfer (BRET), Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) and enzyme complementation. These methods are complemented with knock-out and knock-in mouse models.

    We are an international team of scientists coming from over ten different countries. Regular visiting PhD students, post-docs and senior scientists contribute to a highly cross-stimulating research environment. Established relationships with industrial partners allow the fast translation of our research results.

    Mental disorders and metabolic diseases (obesity and type 2 diabetes) are major public health problems that involve defects in membrane receptor function. Targeting of these receptors or their associated protein complexes are promising strategies for the treatment of these diseases. We are currently investigating two membrane receptor families in this regard: the melatonin receptor family (MT1, MT2, GPR50 subtypes) and other receptors belonging to the G protein-coupled receptor super-family (http://www.gdr3545.com/) and leptin receptors belonging to the cytokine receptor family.

    Our international team uses pharmacological, endocrinological and proteomic approaches to understand the function of melatonin and leptin receptors and evaluate their therapeutic potential by developing innovative techniques such as BRET (Bioluminescence Resonance Energy Transfer) and time-resolved fluorescence resonance energy transfer (TR-FRET). These methods are complemented by several lentiviral-based gene transfer techniques and in vivo animal models.


     

    Major Publications

    Wojciech S*, Ahmad R[FG1] *, Belaid-Choucair Z, Journé AS, Gallet S, Dam J, Daulat A, Ndiaye-Lobry D, Lahuna O, Karamitri A, Guillaume JL, Do Cruzeiro M, Guillonneau F, Saade A, Clément N, Courivaud T, Kaabi N, Tadagaki K, Delagrange P, Prévot V, Hermine O, Prunier C and Jockers R. The orphan GPR50 receptor promotes constitutive TGFβ receptor signaling and protects against cancer development. Nature Comm, 9:1216 (2018)
    INSERM Actualités du 10/04/2018
    Actualités scientifiques du CNRS 13/04/2018

    Vauthier V*, Roujeau C*, Chen P, Sarkis S, Migrenne S, Hoisi T, Ozawa K, Rouille Y, Foretz M, Mallet J, Launay JM, Magnan C, Jockers R, Dam J. Endospanin 1 affects oppositely body weight regulation and glucose homeostasis by differentially regulating central leptin signaling. Mol Metabolism, 6(1):159-172 (2016).

    Bonnefond A, Karamitri A, Jockers R, Froguel P. The Difficult Journey from Genome-wide Association Studies to Pathophysiology: The Melatonin Receptor 1B (MT2) Paradigm. Cell Metab. 2016 Sep 13;24(3):345 347

    Baba K*, Benleulmi-Chaachoua A*, Journé AS, Kamal M, Guillaume JL, Dussaud S, Gbahou F, Yettou K, Liu C, Contreras-Alcantara S, Jockers R*, Tosini G*. Heteromeric MT1/MT2 Melatonin Receptors Modulate Photoreceptor Function. Science Signaling, Oct 8;6(296):ra89, (2013)..
    Comment in: « Editor’s Choice » Science, 342 :535 (2013)

    Bonnefond A*, Clement N*, Fawcett K, Yengo L, Vaillant E, Guillaume JL, Dechaume A, Payne F, Roussel R, Czernichow S, Hercberg S, Hadjadj S, Balkau B, Marre M, Lantieri O, Langenberg C, Bouatia-Naji N, MAGIC, Charpentier G, Vaxillaire M, Rocheleau G, Wareham NJ, Sladek R, McCarthy MI, Dina C, Barroso I, Jockers R* & Froguel P*.  Rare MTNR1B variants impairing melatonin MT2 receptor function contribute to type 2 diabetes. Nat Genetics, 44:297-301 (2012)
    Press release : Highlight in « Faits scientifiques 2012 » of Inserm.

    (* equal contributions)

     

     Team news

    • Highlights

    A new duo for the protection of breast cancer: the heterodimer complex GRP50 – TβRI
    Free access article in Nat Comm (2018) 9:1216        

    Synthesis and characterization of first cell-impermeant and biased melatonin receptor ligands demonstrating functional expression of MT1 receptors in mitochondria
    https://vimeo.com/221003747); YouTube              


    Free access article in Br J Pharmacol 2017 174:2409-21   and Proc Natl Acad Sci U S A (2017) E7997-E8006

    Latest reference review on melatonin receptors: Update on melatonin receptors: IUPHAR Review 20
    Free access article in Br J Pharmacol (2016) 173:2702-25

    2017 Lab retreat

    some photos,  other photos......and more

    • Awards

    2017 Marie Sklodowska-Curie Actions Seal of Excellence awarded to Atsuro Oishi and our team

    2016 Best poster price for research engineers (INTERCHIM price) awarded to Marine Luka at the GDR-3545 meeting in Tours

    2015 Price of the Fondation Philippe Chatrier awarded to Erika Cecon

    The team obtained the label of Fondation pour la Recherche Médicale (FRM)- 2013[FG1] 

    Julie Dam, Laureate of the ANR Young Investigator program 2012

    • Networks

    Member of the Labex «Who am I ?». Who am I? is a large, cooperative and multi-disciplinary research project focusing on the fundamental question of the origin of identity (http://www.labex-whoami.fr/en/who-am-i)

    Member of the DHU (Département Hospitalo-Universitaire) AUTHORS « Autoimmune and hormonal diseases »

    Direction of the Groupement de Recherche GDR-3545  “RCPG-Physio-Med”. The GDR-3545 on “G Protein-coupled Receptors : from physiology to drugs (RCPG-Physio-Med)” was created in 2012 by the CNRS

    • Charity event participation

    2018 Running to support type1 diabetes

    2016/17 Several golf competition organized by Chatrier Fondation to support Alzheimer research

    2016 ODYSSÉA PARIS 2016 to support cancer research

    • Multimedia, Popular Science, Foundations

    Video production of article abstract of the team (Gbahou, Cecon et al. Br J Pharmacol, 2017) https://vimeo.com/221003747); YouTube (https://bcove.video/2t7ukwc)

    Photo shooting for France Alzheimer, May 2017 (1-2 example of the published photos?)

    Interview Journal Science & Avenir, « A chinese plant against obesity», July, 2015

    Participation in the “Nutrition Métabolisme » event organized on the occasion of the 50th anniversary of INSERM and "Les Chercheurs accueillent les Malades" (October 3rd, 2014).

    Participation in the visit of the« Conseil de surveillance » of the Fondation pour la Recherche Médicale (September, 2014).

    Interview for « HORIZON » Magazine  of the European Commission on « Obesity genes reveal why we eat too much « (J. Dam, R Jockers, EurOCHIP consortium Partner) (August, 2014). https://cordis.europa.eu/project/rcn/92511_en.html

    Pint of Science (J. Dam, R Jockers,(May 2014)

    • Visiting scientists

    Visiting PhD students:
    2013 Erika CECON (Brazil)
    2015 Sharon OWINO (USA)
    2017 Francesca PIAGGIO (Italy)
    2018 Ana DUARTE NOSEDA (Brazil)

    Visiting post-docs:
    2015 Min PARK (Singapore)
    2016 Atsuro OISHI (Japan)

    Visiting professors:
    2016 Gianluca TOSINI (USA) “Who Am I” Labex visiting professor
    2018 Toru HOSOI (Japan)

    • Useful links:

    Fondation pour la Recherche Médicale
    Fondation Philippe Chatrier 
    International diabetes federation

    Networks:
    GDR-3545
    Laboratory of Excellence "Who Am I?"
    Départements Hospitalo Universitaires (DHU) https://www.b2match.eu/system/dhudays/files/p12.pdf?1476370652

    Pharmacological targets (IUPHAR)
    GPCR database(GPCRdb)  
    Protein data bank(PDB) 

    Melatonin receptors: guide

    List of places / restau / co-working / leisure activities we “tested” in our 2017 lab retreats
    Escape Game Bordeaux
    Chateau Haut Brion 
    Co-working space Paris Cosy-corner
    Co-working space Bordeaux WIGI
    Co-working space Bordeaux Le Burro des Possibles  (also good option for lunch!)

     

    Financial supports