Defining and exploiting the endothelial cell heterogeneity in pulmonary vasculature of patients with pulmonary arterial hypertension (PAH)

Pulmonary arterial hypertension (PAH) is a rare but severe remodelling of the distal lung vasculature. The endothelium is crucial in the early responses to PAH and the subsequent remodelling of blood vessels. Here, we strive to understand the transcriptomic heterogeneity of endothelial cells in lung explant samples from human PAH patients using single nucleus RNA-Sequencing technology (snRNA-seq). The findings of the snRNA-seq in human lungs would be compared with the existing mouse dataset to advance the understanding of cellular and molecular responses in PAH. The identification and validation of novel candidates from the study would help in better understanding of the disease progression and might potentially be used for therapeutic intervention to ameliorate the impact of pathological remodelling. Proposed Aims: 1. To explore the molecular and cellular heterogeneity of human lung vasculature using frozen samples of human lung of PAH patients and controls using 10X single nucleus RNA-Sequencing (snRNA-Seq) and associated bioinformatics. 2. To compare the snRNA-Seq results with existing scRNA-Seq data of PAH mouse and human IPAH. 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.