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304G Carolyn Lynch Laboratory |
My laboratory focuses on developing and exploiting new technologies at the interface between biology and chemistry to study protease function. We use a variety of techniques including the synthesis of small molecule inhibitors, quantitative proteomics, genomics, recombinant protein expression, and molecular genetics in order to better understand proteolytic systems. Although these tools are useful to study any biological system, much of our biological efforts are aimed at understanding proteases in the parasite P. falciparum, the causative agent of malaria. The completed genomes of many pathogens including P. falciparum are a rich resource in the search for novel therapies and allow the possibility of more systematic approaches to therapeutic discovery and design. In particular, I believe chemical strategies for global proteome analysis will become increasingly more important to enable functional characterization and profiling of enzyme activity. Therefore we develop universal chemical-based proteomics tools to functionally analyze the role of proteases in a variety of biological systems. We can use these chemical tools for enzyme discovery, for screening of small molecule and for investigating biological pathways. In summary, my laboratory will focus on the following areas of research: (1) Malaria protease function: Functional characterization of malarial proteases using chemical, biochemical and genetic tools (2) Activity-based probes: Development of new small molecule and macromolecular probes for proteases for genome-wide protease discovery and characterization (3) Protease substrate discovery: Development of novel and adaptation of established proteomics techniques to uncover proteases substrates and proteolytic pathways (4) Protease biochemistry: Recombinant expression and characterization of protease specificity and inhibitor assay development Selected Publications: Joyce J, A. Baruch, K. Chehade, N. Meyer-Morse, E. Giraudo, F. Tsai, D.C. Greenbaum, J. Hager, M. Bogyo, D. Hanahan (2004) Cathepsin cysteine proteases are effectors of invasive tumor growth and angiogenesis during multistage tumorigenesis. Cancer Cell 5:443-453. Yasothornsrikul, S, D.C. Greenbaum, K. Medzihradszky, T. Toneff, R. Bundey, R. Miller, B. Schilling, I. Petermann, J. Dehnert, A. Logvinova, P. Goldsmith, J. Neveu, W. Lane, B. Gibson, T. Reinheckel, C. Peters, M. Bogyo, V. Hook (2003) Cathepsin L in secretory vesicles functions as a prohormone-processing enzyme for production of the enkephalin peptide neurotransmitter. PNAS 100:9590-9595 Greenbaum DC, A. Baruch, M. Grainger, Z. Bozdech, K. Medzihradszky, J. Engel, A. Holder, J. DeRisi, M. Bogyo (2002) A role for the protease falcipain 1 in host cell invasion by the human malaria parasite. Science 298:2002-2006. Greenbaum DC, W. Arnold, F. Lu, L. Hayrapetian, D. Bromme, I. Kuntz I, M. Bogyo (2002) Small molecule affinity fingerprinting: a tool for enzyme family subclassification, target identification, and inhibitor design. Chem. Biol. 9:1085-1094. Greenbaum DC, K.F. Medzihradszky, A. Burlingame, M. Bogyo (2002) Epoxide electrophiles as activity-dependent cysteine protease profiling and discovery tools. Chem. Biol. 7:569-581.
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