Grant: Operating Grant

Calpains are enzymes in every cell of our body that are regulated by calcium ions to cut other proteins in a selective and highly controlled way. This is a normal and essential process required for cell functions like motility, cell division, and developmental changes. However, in certain diseases such as stroke, heart attack, blunt trauma, cataract and neurodegenerative diseases like Alzheimer's and Huntington's, calcium levels rise inside the cell. This triggers the calpains to become over-active and unregulated. They then cause extensive tissue damage to the affected areas. We have several objectives in this application. The first is to develop better inhibitors of calpain that are more effective than present ones and that do not affect other enzymes in the cell. For inhibitor development we have two approaches. One is to use modeling and simulations to design better inhibitors based on the structures we have recently solved by X-ray crystallography, including that of calpain bound to its natural inhibitor, calpastatin. The other is to use a high-throughput screening assay to look through tens of thousands of compounds for better inhibitors At the same time we are studying the metabolism and turn-over of the main calpains to see how they are normally controlled and what other opportunities there are to stop them from becoming too active. We are also extending this investigation to include tissue-specific forms of calpain to see how these minor calpains of uncertain function might be affected by inhibitors we design.