Grant: Operating Grant

We are at the forefront of the discovery and characterization of the proprotein convertases (PCs), a family of mammalian proteases involved in the activation of a wide variety of precursors, a crucial regulatory process in both normal & disease states. In the past 5 years, we concentrated on the constitutively secreted convertases PC5, furin, PACE4, and PC7. Our results unraveled many new physiological and pathological functions of these proteases in cells, mice and humans. Thus, PC5 was shown to be critical for body axis patterning during development in mouse, as also evidenced in human congenital diseases, and regulates blood vessel stiffening with age. Furin and/or PACE4 play major roles in lipid metabolism, cancer and cancer metastasis, as well as in heart development and blood vessels survival. PC7 regulates specific cell surface protein activity, and in mice modulates anxiety and depression. The main aims of the present proposal are centered on the extension of our knowledge of the functional implications of PC5, furin and PC7 in multiple biological pathways, with a strong emphasis on their in vivo roles using genetically modified mice. The expected outcomes of this research would be the identification of the tissue-specific functions of these convertases and the development and validation of realistic approaches to regulate their functions in disease states.