The development of novel Epac1-selective agonists

Cardiovascular diseases (CVDs) are currently the leading cause of mortality, amounting to 31% of all deaths worldwide. The pro-inflammatory cytokine IL-6 plays an important role in the development of atherosclerosis, the underlying cause for many CVDs. Suppressor of cytokine signalling 3 (SOCS3) inhibits development of CVDs by blocking IL-6 trans-signalling in vascular endothelial cells (VECs). Activation of exchange protein activated by cAMP 1 (Epac1), an effector protein in the ubiquitous cAMP signalling pathway, induces SOCS3 expression in VECs. However, the exact mechanisms that underpin this interaction are still unknown. Furthermore, the currently available compounds for researching Epac proteins are far from optimal. Therefore, there exists a need for new adequate molecular tools to study Epac activity. The aim of my research project is the development of such tools, based on the recently identified novel Epac1-selective partial agonist, I942. Establishing a series of protein-based and cell-based assays will allow us to screen derivatives of I942 for suitable compounds, which subsequently can be used to study Epac1 function, in particular the mechanism underlying Epac1-mediated SOCS3 induction. Eventually, this will lead to more insight in the molecular pathways that play a role in the pathogenesis of atherosclerosis and to new therapeutic targets in the treatment of CVDs.