Molecular basis of endoglin function in cardiovascular diseases

The aim of my fellowship is to investigate molecular mechanisms of endoglin (ENG) function using structural and biochemical approaches and to validate the findings in human and murine primary cells and animal models. ENG is a transmembrane receptor highly expressed on vascular endothelial cells.

It interacts with bone morphogenetic protein 9 (BMP9) and BMP10 extracellularly and transforming growth factor-beta (TGFbeta) receptors intracellularly.

Aberrant ENG function has been implicated in numerous cardiovascular diseases (CVD), including preeclampsia and hereditary haemorrhagic telangiectasia.

Therapies targeting the ENG pathway are under development for treating CVD or for anti-angiogenesis therapies in cancers.

However, the mechanisms by which ENG functions at a molecular level under normal physiology and in CVD are not resolved.

This proposal will address these questions by investigating how ENG functions through its interactions with different TGFbeta family ligands and receptors, and how differential protein-protein interactions result in different downstream target genes and functional consequences in cells and in a murine preeclampsia model.

The outcome will provide essential molecular details on the structure-function relationship of ENG, facilitating the design of molecules that correct aberrant ENG function in CVD.