TARGETING DNA METHYLATION AS A NOVEL APPROACH TO RESTORE ENDOTHELIAL COLONY-FORMING CELL ANGIOGENIC DYSFUNCTION IN ISCHAEMIC DISEASE

The overall aim of this project is to investigate whether epigenetic regulation, specifically DNA methylation, plays a critical role in promoting endothelial colony-forming cell (ECFC) dysfunction, which may be targeted to promote therapeutic angiogenesis for improved management of cardiovascular disease (CVD). 

Impaired angiogenesis is critical in driving ischaemic CVD, with stresses such as hyperglycaemia and hypoxia promoting endothelial dysfunction. Whilst DNA methylation regulates endothelial homeostasis and stress-induced dysfunction, its role in determining the angiogenic response of progenitor ECFCs is not defined. This is critical given their capacity for vascular repair, reported dysfunction in CVD, and therapeutic potential. As stress-induced DNA methylation alterations are linked with angiogenesis, we hypothesise that this key epigenetic modification is central role in driving ECFC dysfunction in CVD and can be targeted to promote therapeutic angiogenesis. We aim to (1) define the specific role of DNA methylation in regulating in vitro ECFC angiogenic function through extensive methylome/transcriptome profiling; (2) investigate whether adverse DNA methylation changes can be reversed by methylome editing to restore angiogenic capacity in vitro and in vivo. Successful delivery will identify important ECFC DNA methylation changes linked with angiogenic dysfunction whilst providing proof-of-concept for in vitro and in vivo modulation, which is critical to support emerging allogeneic or endogenous therapeutic strategies for ischaemic CVD. 

Start Date: October 2022