Project Description :
The Franz Lab seeks to understand the roles of metals in biological systems. The projects discussed here investigate how chelators (molecules that bind metals) can be used to disrupt copper homeostasis and cause cytotoxicity in bacteria and cancer cells. We utilize a prodrug strategy to release a chelator specifically at the disease site, thus reducing undesired off-target effects. Our goal is to understand the mechanisms by which these "prochelators" and their associated free chelators inhibit cell growth or cause cell death.
The first project focuses on a prochelator that targets drug-resistant bacteria by exploiting the presence of the enzyme β-lactamase. When β-lactamase cleaves our prochelator, a chelating moiety is released that inhibits cell growth. The mechanism behind this growth inhibition is not clear, so future work will attempt to elucidate how this effect is achieved.
The second project utilizes a second prochelator that targets cancer cells. The enzyme γ-glutamyltransferase is overexpressed by cancer cells, so it was chosen as the trigger for our prochelator. The prochelator has been shown to cause cell death, although the underlying mechanism is unknown.
These projects involve:
-susceptibility testing on bacteria and mammalian cells (broth microdilution assays and spot assays on agar plates)
-analysis of intracellular metal content (ICP-MS)
-analysis of intracellular elemental colocalization (X-ray fluorescence imaging)
-synthesis, purification, and characterization of the prochelator compounds (setting up reactions, using columns to purify the desired product, analysis by LC-MS and NMR to confirm the structure of the product)
It is very likely that as our understanding grows, the projects will evolve and move in new directions. For example, we expect to use competitive binding assays to understand the metal binding capabilities of our chelators and prochelators, investigate the production of reactive oxygen species in vitro, and expand our work to new cell lines.
The selected student will work with me (Jacqueline Zaengle-Barone, graduate student in the Franz Lab). If you are interested in summer research, please email me directly at email@example.com. Thank you for your interest, and I look forward to hearing from you.