DEFINING AND EXPLOITING ENDOTHELIAL CELL HETEROGENEITY IN THE PULMONARY VASCULATURE IN MOUSE AND HUMAN

Pulmonary hypertension is a rare but severe remodeling of the distal lung vasculature. The endothelium is very important in the early responses to pulmonary hypertension and the subsequent remodeling of blood vessels. Here, we study this cell type, its response to hypoxia at the single cell level in models of disease and patient samples to understand the cellular responses in vivo and derive new therapeutic approaches.
Proposed Aims: (1) To understand at the molecular and cellular level the underpinning responses to hypoxia that drive these substantial changes in the transcriptome using inhibitors of hypoxia and associated metabolic pathways. (2) To understand the relevance of these findings to human lung vasculature using samples of endothelial cells freshly isolated from human lung in patients with pulmonary arterial hypertension and blood outgrowth endothelial cells from patients and controls using 10X single cell systems and associated bioinformatics. (3) To assess novel drivers of pathological endothelial changes observed above in the mouse hypoxic model (genetic, small molecule based) for influence of pulmonary vascular disease in mice. These studies build up on the experience of endothelial scRNAseq, metabolism, hypoxia and pulmonary vascular disease in the two laboratories. The project also benefits from a long-term collaboration with Nick Morrell, Cambridge, UK. The candidate will be based on Edinburgh but be expected to spend extended periods of time for research in Leuven.