Description du projet
Une dynamique multi-niveaux de l’hypertrophie adipocytaire
L’hypertrophie adipocytaire est une affection associée à des gouttelettes lipidiques (GL) plus grosses que la normale, les organites adipocytaires qui stockent l’énergie sous forme de triglycérides. L’hypertrophie adipocytaire est indépendante de la graisse corporelle et provoque un large éventail de conditions pathologiques, y compris les maladies cardiométaboliques. Le projet SPHERES, financé par l’UE, étudiera l’hypothèse selon laquelle des perturbations de l’interaction entre les protéines GL et la composition lipidique des GL conduisent à une hypertrophie adipocytaire. Dirigé par un réseau pluridisciplinaire d’experts, le projet développera des modèles et des méthodes de pointe pour étudier la formation et le maintien des grandes GL adipocytaires. Les travaux ouvriront la voie à une meilleure compréhension des mécanismes sous-jacents de l’hypertrophie adipocytaire, ainsi qu’à l’identification de stratégies thérapeutiques ciblant les adipocytes.
Objectif
The goal of SPHERES is to understand the dynamics and consequences of adipocyte hypertrophy (enlargement) through investigation of its large lipid droplet (LD). The adipocyte LD is a unique organelle specialized in storing energy in triglycerides (TGs). Its surface is composed of a phospholipid monolayer and specific LD-associated proteins (such as perilipins, CIDEs and lipases), which jointly regulate LD stability and TG turnover. Adipocyte hypertrophy due to an increase in LD size may, irrespective of body fat mass, cause a wide range of pathological conditions, notably cardiometabolic diseases. SPHERES PIs (Langin, Rydén, Antonny) postulate that disturbances in the interactions between LD proteins and LD lipid composition lead to adipocyte hypertrophy and its deleterious consequences. We have identified three fundamental unanswered questions: what determines the unique structure and dynamics of large LD; why does increased LD size alter the functional phenotype of the adipocyte; which factors cause inter-individual variations in LD size. To address these questions, SPHERES gathers expertise in clinical and cellular studies on human adipocytes, in/ex vivo investigations in mouse models, and biophysical analyses of LDs. At the core of this application is the development of beyond-state-of-the-art models and methods (spheroid cultures, native large LD preparation and reconstitution, proximity labelling of LD proteins, gene editing in cell and mouse models, and advanced LD imaging), only achievable through joint integrated effort of the PIs and co-workers. Spanning from molecular, cellular to the whole-body level, SPHERES will link new knowledge on the formation and maintenance of large adipocyte LDs to the deleterious impact of adipocyte hypertrophy. Altogether, SPHERES has a strong potential to discover novel pathogenic mechanisms, leading to a better understanding of highly prevalent diseases and identification of therapeutic strategies targeting adipocytes.
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ERC-SyG - Synergy grantInstitution d’accueil
31062 Toulouse Cedex 9
France