EMPAtHy · Endothelial Cell Molecular and Metabolic Heterogeneity in Pulmonary Arterial Hypertension
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-09-01 → 2021-08-31
- EU contribution
- €166,320
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Endothelial Cell Molecular and Metabolic Heterogeneity in Pulmonary Arterial Hypertension
The main role of the lung is to support blood oxygenation while removing carbon dioxide from the body. Appropriate blood circulation through the lungs, ensured by pulmonary blood vessels (arteries, capillaries and veins), is therefore crucial to support this organ’s function. In the context of pulmonary arterial hypertension (PAH), a dramatic increase in blood pressure in the pulmonary blood vessels ultimately results in right heart hypertrophy (corresponding to an abnormal enlargement of the cardiac muscle of the right heart ventricle, which pumps the blood to the lung), and heart failure, responsible for patients’ death. This disease is associated with a dysfunction of lung endothelial cells (ECs), which compose the innermost layer of blood vessels and regulate several key functions, such as vascular tone, blood vessel permeability, inflammation, etc. In PAH, lung EC dysfunction promotes an intense pulmonary vascular remodeling, imbalanced vascular tone, and inflammation. To date, with the exception of lung transplantation, this rare disease remains incurable with limited survival. A better understanding of the lung vasculature and of molecular processes underlying this disease is therefore necessary to propose new effective therapies. Since ECs are diverse in order to support different functions throughout the whole body and the lung vasculature, the main objective of this project was to provide an in-depth molecular characterization of the lung EC heterogeneity in health and disease, and highlight PAH-specific EC subtype(s) involved in vascular remodeling, if any. Since the host lab previously showed that EC metabolism is a cornerstone of EC function in health and disease, a second objective was to characterize the metabolic fingerprints of lung ECs and in particular of PAH-specific EC subtypes(s) associated with vascular remodeling.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- VIB VZW · ZWIJNAARDE - GENTCoordinatorBelgium
Links
Data: CORDIS, © European Union