Grant: Foundation Grant

My team discovered and characterized a family of 9 enzymes, known as the proprotein convertases (PCs), key molecular scissors involved in producing the final forms of active proteins. Abnormal (higher/lower) activities of these enzymes can result in severe biological disorders, and hence PCs are prime targets for therapy in a number of human diseases. We are world leaders in understanding the role of PCs in pathologies, including cardiovascular diseases resulting from high levels of the bad cholesterol (low density lipoprotein, LDL), cancer, viral infections, brain dysfunctions such as in Alzheimer's disease and those resulting in increased anxiety and depression. Our research program will focus on the biology of two of the PCs that we discovered, namely PCSK9 and PC7. 1-PCSK9 regulates the levels of LDL in the blood. Hence, too much of this enzyme results in high levels of cholesterol that are associated with coronary heart disease, heart attacks and stroke. Resulting in large part from our pioneering work on this protein, new injectable treatments using antibodies to block PCSK9 have been developed and shown in early clinical tests to lower LDL by as much as 60% in high-risk patients. However, this approach has some limitations and our own research suggests that serious long-term effects could result from a general blockade of PCSK9. Our goal is to fully describe the molecular mechanisms through which PCSK9 acts and to use this knowledge to develop more effective and better-targeted drugs against PCSK9. 2-The engineered PC7 inactivation in mice results in much reduced anxiety, depression and emotional fear. In humans, lower PC7 levels are also associated with a more efficient iron metabolism, higher levels of the good cholesterol high density lipoprotein (HDL) and lower levels of the bad triglycerides. We will study the biology of PC7 in mice and humans and develop PC7 inhibitors that should find new therapeutic clinical applications for the above indications.