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About

2002-2013. For 11 years in the PhyCell lab (INSERM U1003), I have actively studied the cold/menthol receptor, TRPM8, I discovered and characterized new TRPM8 isoforms. 4TM-TRPM8 isoforms expressed in mitochondria-associated membranes in ER where they participate in the calcium channeling between the two organelles. On the other hand, non-channel short TRPM8 isoforms act as negative regulatory subunits of the canonical cold receptor. We demonstrated that the suppression of their regulatory subunits induced apoptosis of prostate cancer cells in vitro and in vivo.

2013-2015. In PHLAM laboratory, by a combination of cutting-edge photonics, automated image correlation spectroscopy and multivariate statistics, we achieved the biophysical characterization of the dynamics of the association of positive elongation factor (PTEF-b) with RNA polymerase II. In order to do, we developed FICS (FRET-FLIM image correlation spectroscopy) in order to quantify the microdomains in which proteins interacted. Finally, we also studied and modelled how protein-protein interaction shift the diffusion properties of oligomers.

2015-present.

1) System biology of cardioprotection.

In one hand, we dusted off ischemic-post-conditioning (IPOC), an old-fashion method to decrease the severity of myocardial infarction, and have started studying mechanisms behind the scene and developed novel methods to track these mechanisms in a mouse model of myocardial infarction and in human samples from STEMI patients as well.

In the other hand, therapeutic hypothermia (TH) has been used in clinical care for decades. TH decreases ischemia-reperfusion injuries in extra-corporal circulation practice, in transplant preservation, in myocardial infarction and stroke. However, molecular mechanisms behind the protective effect of TH are not understood. It is usually assumed that its protective effect would be mediated by the decreased metabolism rate, this latter declines of about 0.6 fold at 32°C as defined by Arrhenius law. We confirmed that at the mitochondrial level, 32°C did not modified the metabolism and we found that Ca-uptake by MCU was the most sensitive mechanism being mainly inhibited between 25-32°C. By contrast, a strong inhibition of respiration and ROS production requires to decrease temperature below 20°C if not 15°C. This latter range of temperature is however of importance for our project to improve graft preservation at mild temperature. At 32°C, I hypothesized that TRM8 could initiate a positive cascade of molecular even triggering protection against ischemia-reperfusion that we and others observed in ex vivo and in vivo animal models. We are thus investigating the mechanisms by which TRPM8 could trigger the TH-mediated protective effect.

Finally, as a more explanatory way to investigate TH mechanism, we initiated a comparative analysis between Csa treatment or IPOC combined with TH in order to identify parts of the molecular networks being specific of one or the other cardioprotective method. The ultimate objective will be to assess the protective effect trigged by a synergistic combination of therapeutics targeting different mechanisms. This work is prolonged by an extensive characterization of patients samples in order to figure out whether patients are already too much protected without any hope to improve the treatments any further.

2) TRPM8 isoforms as targets for a therapy of heart failure with preserved ejection fraction (HFpEF).

Menthol diet in animal has been reported to trigger non-shivering thermogenesis in BAT and is thought to be a good fat-burning strategy. Along this line, KO of TRPM8 have been shown to be resistant to High Fat Diet-induced insulin-resistance. Because I have cloned an characterized more than 30 TRPM8 isoforms, I have developed a KO line in which all channel-like TRPM8 isoforms are inactivated. Because these isoforms can be expressed in cell types deprived in the canonical TRPM8 receptor, knocking-out this sole receptor will ne mandatorily trigger same effects as knocking-out all isoforms.

In our TRPM8i^-/- line, we identified metabolic pathways repressed or induced. We hypothesized that these features could offer a protection against metabolic syndrome and HFpEF and have started to investigate it.

Administrative duties

• Steering committee member of the CNRS workshop for “functional microscopy” (MIFOBIO).
• Scientific committee member of the French scientific network for microscopy (GDR IMABIO).
• Steering committee of iXplora platform (in vivo exploration of ischemia-reperfusion), Lyon.
• Scientific committee of Lymic platform (3 microscopy plateforms), Lyon.
• CarMeN director’s substitute at steering committee of the Research Laboratory federation in Lyon (SFR Santé).
• Editorial Board: Cells, International Journal of Molecular Science (2020-present)
• Reviewer for peer-reviewed journals: Basic Research in Cardiology, Biochimica et Biophysica Acta – Molecular cell research, Cell death & diseases, Journal of physiology and biochemistry, Plos One, Spinger Plus, Theranostics..

Prix reçus

• Research grant of the French National Research Agency (Jan 2006) Associated with University of Lille 1

5 major publications:

within the 5 last years:

• Neven Stevic, Jennifer Maalouf, Laurent Argaud, Noëlle Gallo-Bona, Lo Grasso Mégane, Claire Crola Da Silva, Ferrera René, Michel Ovize, Martin Cour, Gabriel Bidaux. Cooling Uncouples Differentially ROS Production from Respiration and Ca2+ Homeostasis Dynamic in Brain and Heart Mitochondria. Accepted 2022-03-11.
• Leboube S, Paccalet A, Da Silva CC, Hayek A, Derimay F, Bonnefoy-Cudraz E, Ovize M, Mewton N, Bidaux G, Bochaton T. Soluble C-Met as a Biomarker of Clinical Outcomes After STEMI. J Am Coll Cardiol. 2021 May 11;77(18):2348-2350. doi: 10.1016/j.jacc.2021.03.015.PMID: 33958133.
• Yves Gouriou et al. ANT2-Mediated ATP Import into Mitochondria Protects against Hypoxia Lethal Injury. Cells, Published: 25 November 2020.
• Zeina Harhous et al. Critical Appraisal of Mitochondrial STAT3 in Adult Cardiomyocytes. J Mol Cell Cardiol, 2019 Apr 22; PMID: 31022374.
• Samuel Blanquart, Anne-sophie Borowiec, Philippe Delcourt, Martin Figeac, Christopher A. Emerling, Andrea S. Meseguer, Morad Roudbaraki and Gabriel Bidaux. Evolution of the human cold and menthol receptor gene: TRPM8. Mol Phylogenet Evol. 2019 April 10.

5 most important publications in career:

• Leboube S, Paccalet A, Da Silva CC, Hayek A, Derimay F, Bonnefoy-Cudraz E, Ovize M, Mewton N, Bidaux G, Bochaton T. Soluble C-Met as a Biomarker of Clinical Outcomes After STEMI. J Am Coll Cardiol. 2021 May 11;77(18):2348-2350. doi: 10.1016/j.jacc.2021.03.015.PMID: 33958133.
• Gabriel Bidaux et la. Epidermal TRPM8 channels isoform controls the balance between keratinocyte proliferation and differentiation in a cold-dependent manner. Proc Natl Acad Sci U S A. 2015 Jun 30;112(26) ; PMID: 26080404.
• C Dubois et al. Remodeling of Channel-Forming ORAI Proteins Determines an Oncogenic Switch in Prostate Cancer. Cancer cell. 2014 Jul 14;26(1):19-32; PMID: 24954132.
• Charbel El Boustany et al. Hepatology. 47: 6. 2068-2077 Jun; PMID: 18506892.
• Gabriel Bidaux et al (2007). Prostate cell differentiation status determines transient receptor potential melastatin member 8 channel subcellular localization and function. J Clin Invest. 117: 6. 1647-1657 Jun; PMID: 17510704.