Grant: Project Grant

According to the World Health Organization, 30% of all deaths are attributable to cardiovascular diseases, which includes heart failure, and represent the second cause of mortality in Canada with more than 100,000 Canadian adults dying from such complications yearly (e.g. around 12 every hour). Despite advances in preventing and managing heart diseases, medication therapies have not substantially decreased the morbidity and mortality rates over the years, suggesting the need for better drugs. Our research focuses on a specific membrane receptor, namely the AT1R that binds the vasoactive hormone Angiotensin II (ANGII) and is involved in regulating vascular and cardiac functions, and which contributes to pathophysiological responses such as cardiac fibrosis and hypertrophy. Our research has unveiled unique properties of a new class of molecules derived from ANGII that act in an unconventional way on AT1R to selectively affect responses in cells (biased ligands). We propose to investigate how structurally and mechanistically AT1R and ANGII ligands differently engage the receptor in distinct signaling responses, potentially leading to cardio-protective properties. We propose investigating the effects of these new ligands on different cell models relevant to cardiac functions, which will allow us to link the ligands' signaling properties to their patho- and physiological responses. Our project will have a significant impact on understanding functional selectivity for AT1R and for other hormone receptors, and should facilitate the development of class of drugs with optimal pharmacological and therapeutic profiles, including for cardiovascular therapies.