Research project

The major interest of my laboratory is to study cholesterol homeostasis and the regulatory pathways responsible for its export or storage under healthy and pathological conditions. We use transgenic animals as well as cultured mammalian cells to identify specific abnormalities in these pathways that lead to inflammatory diseases such as atherosclerosis and neurodegeneration.

Our work has identified that the lipoprotein receptor, the LDL receptor-related protein (LRP1), its ligand the apolipoprotein E, TGFb, and the platelet-derived growth factor (PDGF-bb) receptor cooperate in the remodeling of the vascular wall, and protects against atherosclerosis.

We also pioneered investigations into the role of Wnt signaling as essential to maintain cholesterol homeostasis. LRP1 drives a Wnt5a signaling pathway that prevents cholesterol and cholesterol-esters intracellular accumulation, vascular smooth muscle cells (VSMCs) plasticity, foam cell formation and atherosclerosis. We found that Wnt5a functions as member of the nutrient/energy/stress sensor mTORC1 scaffolding complex that promotes lysosomal cholesterol egress, cool down inflammation, and protects against the accumulation of deleterious biological materials within lysosome of multiple cell types.

Moreover, LRP1 is necessary for the nuclear translocation of transcriptional modulators that activate the chondrogenic program and vascular calcification. Although not as fully developed, there are considerable evidences that LRP1 signaling, through the adaptor protein ShcA and Wnt, promotes chondrogenic hypertrophic commitment, vascular calcification, and osteoarthritis.

Our goal is to understand how LRP1, ShcA, and Wnt signaling cooperate in maintaining cholesterol homeostasis and promotes lysosomal function. We develop cell repair and immunotherapy approaches against new therapeutic targets that impact cholesterol homeostasis and the medical problems of atherosclerosis, osteoarthritis, and neurodegeneration, all major health risks in France and several countries.

Collaborations

– Nationals :

Catherine Tomasetto/Fabien Alpy, IGBMC, Université de Strasbourg

Mustapha Oulad-Abdelghani, IGBMC, Université de Strasbourg

Xavier Collet, I2MC, Université de Toulouse

Laura Harsan, iCube, Université de Strasbourg

Xavier Houard, INSERM S_938, Sorbonne Université, Paris

Guillaume Mabilleau, GEROM, Université d’Angers

Carmen M Martinez, SOPAM, INSERM 1063, Université d’Angers

– Internationals:

Joachim HERZ, University of Texas, Southwestern Medical Center, Dallas, TX

Ute A. HELLMICH, Membrane Biochemistry, Johannes Gutenberg-University Mainz

Andreas NIEMEIER, Department of Orthopaedics and Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg -Eppendorf, Germany

Arnaud Scherberichand Andrea BARBERO, Department of Biomedecine, University of Basel, Switzerland

Katey J Rayner, University of Ottawa Heart Institute, Canada

Lina Badimon Maestro, Research Institute Hospital de la Santa Creu i Sant Pau-Autonomous University of Barcelona, Spain

Funding

  • Fondation de France
  • Satt Conectus
  • ERA-CVD