Defining and exploiting the reversibility of EndMT in atherosclerosis

Endothelial-to-mesenchymal transition (EndMT) has emerged as an important mechanism contributing to endothelial cell (EC) activation and associated tissue dysfunction in defined pathologies, such as vein grafting and atherosclerosis.

EndMT is a complex process characterised by the gradual loss of endothelial-specific markers and the expression of mesenchymal markers, thus leading to an aberrant fibroblast-like phenotype.

However, the molecular drivers that define EndMT, especially during intermediate stages, remain relatively poorly understood and exploited.

Recent studies also suggest that EndMT can function as a dynamic, reversible process affording the opportunity to exploit for potential reversal therapeutically.

I aim to define the molecular signatures acquired by ECs during this transition period to unravel the dynamics of commitment and reversibility, thus exploring EC capacity to restore or retain their functionality (cell resilience) in this context.

I will, for the first time, map the intermediate stages of EndMT in vivo and in vitro by adopting a multi-omics approach, using innovative lineage-tracing strategies, and genetic manipulation to define and exploit process reversal.

I will use atherosclerosis as the disease model to determine the therapeutic potential of harnessing and enhancing EndMT reversibility in human pathologies.