Description du projet
Identifier le coupable cellulaire à l’origine de l’hypertension pulmonaire
La plupart des personnes pensent probablement au tensiomètre lorsqu’elles entendent le terme «hypertension», mais les grandes artères transportant du sang désoxygéné du cœur jusqu’aux poumons sont également concernées. L’hypertension artérielle pulmonaire (HTAP) est une maladie progressive rare pour laquelle il existe un traitement, mais aucun remède. La cause exacte est méconnue, bien que les recherches indiquent que les cellules endothéliales recouvrant les petits vaisseaux sanguins des poumons et leur rôle dans le remodelage vasculaire pourraient y être impliqués. Le projet EMPAtHy, financé par l’UE, étudie les différences dans l’expression génétique métabolique des sous-populations de cellules endothéliales atteintes d’HTAP. Comparer les effets d’un nouveau traitement métabolique chez les patients et chez ces sous-ensembles de cellules pourrait fournir un indice sur le comportement des cellules lorsqu’il s’agit de l’HTAP.
Objectif
BACKGROUND: Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by a dramatic increase in pulmonary arterial pressure and an intense remodeling of small intrapulmonary arteries. With the exception of the lung replacement therapy, PAH remains an incurable disease with poor survival. Recent studies have shown that in PAH, rewiring of the metabolism of the lung endothelial cells (ECs) promotes vascular remodeling. However, these studies overlooked that lung ECs are exposed to diverse microenvironments in vivo (various hemodynamic forces and stimuli), which might result in their phenotypic and metabolic heterogeneity, though this has never been investigated. OBJECTIVES & EXPERIMENTAL APPROACH: In order to characterize, for the 1st time, the lung EC heterogeneity in PAH, identify EC subsets, and determine in an unbiased way the metabolic gene expression profiles of these EC subsets, I will use single-cell RNA-sequencing (scRNA-seq) on freshly isolated lung ECs from PAH patients and from an animal model of PH. As proof-of-concept, I will evaluate the effects of a new metabolic therapy on these EC subsets, in vivo, in comparison to a clinically-used, ameliorative but not curative, PAH therapy. This approach, already validated in the host lab, promises to lay the foundation of a new paradigm in PAH where lung ECs are phenotypically and metabolically heterogeneous. It will yield novel insights into PAH pathophysiology, identify specific EC subpopulations driving the vascular remodeling process as well as new potential metabolic targets. CAREER DEVELOPMENT: Combining my expertise on PAH (PhD thesis) together with state-of-the-art frontline technology (scRNA-seq) and innovative science (EC metabolism) (within the host lab) in a multi-disciplinary project and international research environment will ensure successful achievement of the project goals, enhance my scientific output and offer me a highly competitive basis for my future career in academia.
Champ scientifique
Programme(s)
Régime de financement
MSCA-IF-EF-ST - Standard EFCoordinateur
9052 ZWIJNAARDE - GENT
Belgique