Grant: Doctoral: Vanier Canada Graduate Scholarships

Proteases, such as matrix metalloproteinases (MMPs), are proteins that cut other proteins to change their activity and thereby control normal processes in the body, typically in connective tissue. Such processes like normal cell growth, tissue growth and blood vessel formation can be modified by the actions of these proteases. In addition, disease processes, such as cancer, depend on the activities of these proteases in order to develop and progress. The Overall lab has revealed new roles of MMPs beyond just degrading proteins that hold cells in place (extracellular matrix). MMPs also cut proteins that are important in inflammation and cell signaling. The Overall lab has developed new techniques to identify proteins cut by extracellular proteases and where they are cut. Techniques like "Terminal Amino Isotopic Labeling of Substrates (TAILS)" have found several cut proteins involved in cell to cell signaling that are typically found only within cells and not outside in the extracellular matrix. These unexpected proteins include the tRNA synthetases, proteins that are essential for making proteins within cells where they join amino acids to their carrier tRNA molecules. This novel class of proteins with new functions outside of the cell distinct from the jobs they do inside are called "moonlighting" proteins and may represent new and exciting drug targets for therapy. The cleavage of the tRNA synthetases indicated by TAILS will first be confirmed by basic biochemical techniques. Next, the functions of the intact and protease cleaved of these tRNA synthetases will be investigated using cell cultures, biological assays and mouse models. Finding out which proteins have novel functions in normal and disease states and how these are affected by modification by proteases will help us understand new pathways and stages in disease. Moreover, it will identify novel drug targets and indicators (biomarkers) of disease in processes of inflammation and cancer.