Grant: Operating Grant

Our group has been at the forefront of discovering and characterizing a family of enzymes known as the proprotein convertases and in unraveling their role in normal biology and in human disease. In this application we propose to continue this line of research with a particular focus on the role of the convertase PCSK9. Recently, we functionally and genetically linked PCSK9 to the development of cardiovascular diseases in humans, including dyslipidemias and fat metabolism, and showed that PCSK9 triggers the degradation of receptors that regulate cholesterol levels. The absence of functional PCSK9 lowers the levels of circulating low density lipoprotein (LDL)-cholesterol by 80%. The proposed research will define the mechanisms behind the molecular functions of PCSK9 in the test tube, cell lines, mouse knockout and transgenic models. The identification of Annexin A2 as a physiological PCSK9 inhibitor, will allow us to design inhibitory peptide mimics. We will identify the proteins targeted by PCSK9 in live cells and mice and use state-of-the-art technology to study the mechanisms underlying their functions, with the aim of developing new treatment strategies for PCSK9-dependent diseases. These include hypercholesterolemia, fatty liver (steatosis), fat distribution, atherosclerosis and hepatitis.