Grant: Project Grant

Sepsis is epidemic, with almost 18 million cases a year estimated across the world, and a top ten cause of death across the world over 120,000 deaths each year only in the USA. Acute cardio-vascular and renal dysfunctions are prevalent during sepsis, with the worst mortality rate ever during septic shock, provoking a similar number of deaths to that reported collectively from acute myocardial infarction, lung or breast cancers. Existing medication to hemodynamic treatment in septic shock are insufficient. Apelins have demonstrated a strong effectiveness in improving hemodynamics and outcomes at a preclinical stage of septic shock. ELABELA (ELA) has recently revealed superiority over apelins on cardio-renal preservation in this context. -A 1st Aim will elucidate the structure-signaling relationship of optimized ELA analogues (ELA-A); -A 2nd Aim will demonstrate protective impacts of ELA-A in acute cardio-vascular and renal dysfunctions by using an experimental model of cecal ligation puncture which closely mimics septic shock at bedside, . This group of investigators is the only one in Canada and among few in the world, to possess complementary expertises on apelins (and ELABELA, a second endogenous lligand of the apelin receptor), including O. Lesur (MD PhD, intensive care & experimental models); E. Marsault (PhD, medicinal chemistry); M. Auger-Messier (PhD, cardiac pathophysiology & pharmacology); P. Sarret (PhD, G protein-coupled receptor pharmacology & physiology); R. Dumaine (PhD, cardiac electrophysiology). The outcomes of the proposed research will be a validation of the potential of ELABELA and analogues as new avenues for the treatment of septic shock, preparing the ground toward a clinical translation into patients at bedside.