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Endothelial Cell Molecular and Metabolic Heterogeneity in Pulmonary Arterial Hypertension

Project description

Identifying the cellular perpetrator behind pulmonary hypertension

Most people likely think about blood pressure cuffs when hypertension is mentioned, but the large arteries carrying de-oxygenated blood from the heart to the lungs are also susceptible. Pulmonary arterial hypertension (PAH) is a rare progressive disorder for which there is treatment but no cure. The exact cause is unknown but research points to endothelial cells lining the small blood vessels of the lung and a role in vascular remodelling. The EU-funded EMPAtHy project is studying differences in metabolic gene expression among subpopulations of endothelial cells in PAH. Comparing effects of a new metabolic therapy on patients and on these subsets of cells could provide a clue as to which cells do what when it comes to PAH.

Objective

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.

Coordinator

VIB VZW
Net EU contribution
€ 166 320,00
Address
SUZANNE TASSIERSTRAAT 1
9052 ZWIJNAARDE - GENT
Belgium

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Region
Vlaams Gewest Prov. Oost-Vlaanderen Arr. Gent
Activity type
Research Organisations
Links
Total cost
€ 166 320,00