Gpr146 a novel target against lipid-related cardiovascular diseases – GENESIS

Despite major progress in the treatment against atherosclerotic cardiovascular disease (ASCVD), new therapeutic alternatives are needed for patients at very high ASCVD risk and/or with side effects upon available therapies. Recently, the inhibition of the G protein-coupled receptor 146 (GPR146), a family of proteins widely used in pharmaceutical targeting, was shown to be protective against hypercholesterolemia and atherosclerosis in mice. The present project aims at : i) Evaluating the druggability-potential of GPR146-inhibition in human. We will systematically look for genetic variations in GPR146 in population cohorts and familial cases of hyper- and hypocholesterolemia and assess their cardiometabolic consequences. ii) Identifying the phenotypic consequences of Gpr146 inhibition in several mouse models with cardiometabolic disorders (dyslipidemia, diabetes, NASH). iii) Refining the GPR146-natural ligand(s) and intracellular signaling pathways in hepatocytes-like cells.