Proteases are naturally expressed in all organisms and constitute 1-2% of the human genome; they play key roles in the regulation of several normal and pathological processes such as apoptosis, protein degradation, extracellular matrix turnover, antigen presentation and inflammation. Proteases are found to be misregulated in several pathologies such as cancer, atherosclerosis, arthritis and autoimmune diseases. All proteases are synthesized in the cell as inactive enzymes (zymogens). Their activation is tightly regulated post-translationally, consequently they are difficult to study since their abundance often does not correlate with their activity. My laboratory is interdisciplinary combining chemistry, biochemistry and pharmacology; our interests are in 1) design and synthesis of novel activity based probes (ABPs) that specifically target various cystein proteases. 2) Using these probes to investigate cystein protease function in various normal and pathological human processes and 3) applying fluorescently labeled ABPs for non-invasive imaging and tandem targeted therapy of various pathologies in vivo such as cancer and atherosclerosis. Most research projects in the lab combine chemical synthesis, cell biology, biochemistry, microscopy and in vivo imaging.
We are currently using synthetic chemistry methods for generating new probes that will be used for simultaneous non-invasive imaging and real time treatment of pathologies. These probes will be applied to mice models of cancer and atherosclerosis. In addition, we are designing novel fluorescent reagents that will target caspase activity in live cells and will allow for real time imaging of caspase activity during apoptosis. These probes will be further used to study chemotherapy resistance to cancer therapy. All in all we are convinced that our research will open new horizons in the fields of disease diagnostics combined with real time therapy.
This scheme demonstrates the docking of a novel fluorescent probes to its target cathepsin L; this unique probe generates a fluorescent signal only after interaction with the active cysteine cathepsin. This probe was then applied to real time imaging of cathepsin L in live cells. After chemical modification the probe was applied for non-invasive fluorescent imaging of cancer in mice.
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Edgington LE*, Berger AB*, Blum G*, Albrow VE, Paulick MG, Lineberry N, Bogyo M. Noninvasive optical imaging of apoptosis by caspase-targeted activity-based probes.Nat Med. 2009 Aug;15(8):967-73.
Blum G, Weimer RM, Edgington LE, Adams W, Bogyo M. Comparative assessment of substrates and activity based probes as tools for non-invasive optical imaging of cysteine protease activity. PLoS One. 2009 Jul 28;4(7):e6374.
Blum G, von Degenfeld G, Merchant MJ, Blau HM, Bogyo M. Noninvasive optical imaging of cysteine protease activity using fluorescently quenched activity-based probes. Nat Chem Biol. 2007 Oct;3(10):668-77.
Blum G, Mullins SR, Keren K, Fonovic M, Jedeszko C, Rice MJ, Sloane BF, Bogyo M. Dynamic imaging of protease activity with fluorescently quenched activity-based probes.Nat Chem Biol. 2005 Sep;1(4):203-9