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Calcium ions are used as messenger molecules that regulate many important intracellular processes. We need to learn how calcium’s ‘messages’ are interpreted by cells in order to understand how cells move, divide, grow, become cancerous, or die. A variety of calcium binding proteins function to respond to calcium’s ‘message’ and my work is focussed on one family of these proteins; the proteolytic enzymes called calpains. The CALPAIN website has a picture of the enzyme structure and information about the various isoforms. Calpains are ubiquitously present in eukaryotic cells including nematodes, fruit flies and humans. These enzymes must do something very important as their absence is lethal during the development of mouse embryos. This was shown by targeted deletionof the capn4 or capn 2 gene.
The family of calpains may be as large as 15 –20 enzymes although only 3 or 4 have been studied in any detail. Genetic studies have linked several novel calpains to specific disease processes. For example malfunction of calpain-3 is the cause of an inherited disease, Limb-Girdle muscular dystrophy (type IIA) . Loss of calpain-9 is linked to oncogenesis and variations in calpain-10 were identified as a risk factor for type 2 diabetes.
Calpains are also therapeutic targets for drug development due to evidence linking them to neurodegenerative diseases and in some pathways related to cancer. Over the past 25 years my laboratory has made significant contributions to our understanding of the biochemistry of calpain-1 and calpain –2 and the protein calpastatin that specifically inhibits these enzymes. Ongoing studies continue to investigate how calpains’ protein structure relates to their catalytic function and regulation.
We are also interested in exploiting the biochemistry of these proteins to learn why these enzymes are important physiologically. We continue to work towards identifying how calpains are regulated in vivo and what proteins they cleave. We have recently initiated experiments to look at calpain expression and function using zebrafish, studies made possible by the construction of a zebrafish ‘farm’ in Hitchner Hall. Zebrafish will provide the opportunity to investigate isoform specific calpain expression and function in a living vertebrate organism. These studies are expected to provide important information about the physiological roles of this family of enzymes.