Calpain and calcium-mediated proteolytic regulation of cell signalling networks

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Systems-wide investigation of cell signals adds to our understanding of complex biological processes. My unbiased approach of using global analysis guides my research into deciphering key mechanisms of biology. Proteolysis is a key and irreversible modification but remains understudied at a systems-wide level. It is an essential area of study since the cutting of proteins drastically modifies their functions, yet only ~50% of proteases (enzymes that can cut other proteins) have known substrates. My core expertise in systems biology positions me to pioneer transformative proteomics technologies and will elevate Canada's biochemical knowledge of cell signaling and protease biology during Calcium (Ca2+) activation.******Vision and long-term objectives***My research program focuses on developing system-wide mass spectrometry approaches to understand the contribution of proteolytic regulation to cell signaling. I will contribute to the field in the following areas:***1- Ameliorate proteomics enrichment methods of proteolysis***2- Refine bioinformatics analysis of cell signaling ***3- System-wide identification of protease substrates******The results of a protease's activity are defined by what it cuts and to better understand these changes, the substrates of a protease need to be identified and validated. Ca2+ is an essential signaling molecule and among the key downstream effectors of Ca2+ signaling are a family of proteins called calpains that are directly activated by changes in Ca2+ levels. Calpains are key proteases and major effectors of signal transduction, migration and cell death through targeted processing yet little is known about what proteins they cut. This proposal will identify the substrates of calpains and how Ca2+ impact cell physiology. ******My specific objectives for this NSERC discovery grant are:***1- Identify calpains' substrates usingunbiased quantitative proteomics.***2- Integrate the role of Ca2+ with calpain proteolysis using bioinformatics.***3- Validate the proteins cut by calpains to better understand their physiological roles.******Innovative and anticipated outcomes***Systems biology creates the potential for entirely new avenues of exploration and promotes constant innovation over iterative cycles. Proteolysis and Ca2+ signaling are fundamental processes in biology yet little is known about their inter-dependency. My research program is focused on using cutting edge proteomics and bioinformatic technologies to investigate the regulated signaling cellular networks during Ca2+ activation and tackle these crucial knowledge gaps. This proposal is designed to characterize what proteins are cut during Ca2+ activation and to complement our current knowledge of signal transduction in immune cells.**