Project 452074

The development of cardiovascular diseases such as hypertension, atherosclerosis and heart failure has often been associated with impaired function of cell surface proteins named receptors. These are the targets of more than 50% of all drugs sold today. Blocking the activation of the receptor often results in important sides effects. Therefore, the identification of new intracellular pharmacological targets will allow us to design more effective and specific drugs to treat cardiovascular diseases. Our research team has engaged in the study of an intracellular protein that is activated by hormone stimulation. We have shown that this protein named ARF is a central regulator of several cellular responses misregulated in cardiovascular diseases. Our findings indicate that this protein could be a promising new drug target. We propose here to further study its function in cells of the vasculature in order to further demonstrate its key role in responses altered in pathology. In this project, our main goal is to study the function of ARF in vascular smooth muscle cells. These constitute the main body of cells in arteries and are responsible for the contractile response. Our main hypothesis is that the intracellular protein ARF6 drives changes in cell response rendering them pathological. The first objective of our research project is to elucidate the molecular mechanisms by which the isoform ARF6 regulates atherosclerosis development when animal models are subjected to increased stimulation by Angiotensin II, a potent vasoactive and mitogenic hormone of the cardiovascular system.The second aim is to define the molecular details of ARF6 action. Last, we propose to engineer new animal models to study the role of other ARF isoforms in vivo also in the context of atherosclerosis. We will be able to study these animals and understand the role ARF plays to drive disease progression.