Omics approaches to identify regulators of vascular remodelling in pulmonary hypertension

Pulmonary hypertension (PH) is a highly morbid condition culminating in right heart failure and ultimately, premature death.

Vascular remodelling driven by dysfunctional endothelium leads to hyperproliferation and expansion of media and neointima, vessel stiffening and elevated resistance. Molecular drivers and thus treatment targets remain poorly understood. PH is divided clinically into aetiological subgroups.

I and others have defined metabolomic, proteomic and genomic associations with pulmonary arterial hypertension (PAH) development and prognosis (Group 1 PH). There is a knowledge gap in other, more common aetiologies of PH.

I propose RNAseq and DNA methylation analyses in this broader population to delineate molecular features specific or common to multiple PH subsets.

This will enable re-classifying these diseases according to molecular features, informing logical choice of therapy (‘precision medicine’) and re-purposing opportunities.

These data will be integrated through in silico-network analysis and wet-lab analyses, including endothelial cells from PH patient samples.

This approach, modelled on my work with the new PAH gene SOX17, will improve understanding of the pathological role of these molecular patterns and rescue using novel in silico-predicted therapeutic strategies.

This work will be enhanced by my strong national and international collaborator network, including the BHF-UK National PAH Cohort, US-PAH Biobank, US-PVDomics.