Description du sujet de thèse

Cholesterol homeostasis is a central process in cell biology, involving a complex network of organelles specialized in its synthesis, transport, storage, and degradation. Under normal conditions, cholesterol is mainly synthesized in the endoplasmic reticulum (ER) or taken up through endocytosis of lipoproteins at the lysosomes. Its correct distribution among cellular compartments—such as the Golgi apparatus, plasma membrane, lysosomes, and lipid droplets (LDs)—is essential for maintaining cellular function. This thesis will investigate intracellular cholesterol trafficking pathways, with a particular focus on: the transport routes of free and esterified cholesterol between the ER, Golgi, lysosomes, and LDs; inter-organelle contact sites (membrane contact sites, MCSs) such as ER–LD, lysosome–LD, and Golgi–LD connections, which mediate rapid, non-vesicular lipid exchange; key regulatory proteins including oxysterol-binding proteins (ORPs), STARDs, Rab GTPases, and tethering factors like VPS13 and SNX14; the mechanisms of esterified cholesterol storage in LDs via acyl-CoA:cholesterol acyltransferases (ACATs/SOATs), and its mobilization according to cellular needs; and finally, the consequences of disrupted cholesterol trafficking in pathological contexts such as lysosomal storage diseases (e.g., Niemann-Pick type C, Gaucher disease), atherosclerosis, and metabolic disorders linked to obesity.

Contexte de travail

This PhD project will take place at the Laboratoire de Physique de l'École Normale Supérieure (LPENS), located at 24 rue Lhomond, 75005 Paris, within the Physics Department of ENS-PSL. LPENS is a leading fundamental research laboratory operating at the interface of physics, biology, mathematics, and cognitive sciences.

The project will be carried out in a highly interdisciplinary research environment, bringing together expertise in membrane biophysics, cell biology, advanced imaging, and quantitative modeling. The PhD candidate will benefit from access to cutting-edge technological platforms (including high-resolution microscopy, lipid mass spectrometry, and functional genomics), as well as from a multidisciplinary mentoring team that fosters interaction between physicists, biologists, and chemists.

Contraintes et risques

Biology