Thomas O'Halloran


PhD, Columbia

Interdisciplinary Biological Sciences Program
Department of Molecular Biosciences
Chemistry

Office Phone: 847.491.5060
Fax: 847.491.7713
Email
The O'Halloran Group

Research

My group adopts a highly interdisciplinary approach to elucidate the structure, function and chemistry of novel inorganic regulatory pathways. We are also striving to develop physiological models of cancer progression and developing nanoparticulate drugs for treatment of cancer. In the former area, we have developed a wide array of methods for understanding how changes in subcellular distributions of metals regulate cell cycle, growth and proliferation pathways. In the course of these studies we have discovered the structures, biochemistry and physiology of new transition metal receptors for zinc, copper and iron and described how they regulate these intracellular metal fluxes. These results are directly relevant to the uptake and/or resistance processes that alter the activity and efficacy of well-established anticancer drugs, such as cisplatin.

We have discovered a number of examples of metalloregulatory proteins--factors that govern metal responsive gene expression.  Through structure, function, genetic and thermodynamic studies we have established the molecular basis of allosteric control and metal ion selectivity. Our discovery and characterization of these biological metal ion receptors revealed that the pool of free zinc or copper ions in the cellular cytoplasm under resting conditions is vanishingly small.  This controversial conclusion challenges long-held views.
Using new zinc specific fluorescent probes and synchrotron x-ray fluorescence microscopy, we discovered that zinc fluxes in the mammalian egg regulate both the exit from the meiotic cell cycle and the resumption of mitosis upon fertilization. Using fluorescence confocal microscopy we also discovered a system of cortical vesicles that play a role in the earliest stages of embryo development. We are now investigating parallel regulatory fluxes in subcellular zinc distribution in the male gamete.

Finally, an important goal in the group is to develop a molecular level understanding of how nanoscale therapeutics target and then release their cargo within tumor cells, with the overarching goal of increasing the therapeutic index of some of the most potent anticancer drugs. Our strategy revolves around the development of targeted nanoscale lipid drug delivery systems that are highly reproducible and readily scaled up. We have repeated demonstrated targeted delivery of multi-functional metal-based therapeutic agents for treatment of hematological cancer and solid tumors: these agents are moving towards clinical applications. Our formulations have been shown to protect the drug from early release, decrease off target toxicity in vulnerable organs, and are easily modified with targeting ligands thorough bioconjugation chemistry.

 

Selected Publications

Alvarez HM, Xue Y, Robinson CD, Canalizo-Hernandez MA, Marvin RG, Mondragon A, Penner-Hahn JE, O’Halloran TV. Tetrathiomolybdate Inhibits Copper Trafficking Proteins Through Metal Cluster Formation. Science. 2010 Jan 15;327(5963):331-4. PMCID: PMC2265432

Ahn, R.W., Chen, F., Chen, H., Stern, S.T., Clogston, J.D., Patri, A.K., Raja, M.R., Cryns, V.L., O’Halloran, T.V. “A Novel Nanoparticulate Formulation of Arsenic Trioxide with Enhanced Therapeutic Efficacy in a Murine Model of Breast Cancer” Clinical Cancer Research 2010 Jul 15;16(14):3607-17. PMCID: PMC2943376

Gilston BA, Wang S, Marcus MD, Canalizo-Hernández MA, Swindell EP, Xue Y, Mondragón A, O'Halloran TV. Structural and mechanistic basis of zinc regulation across the E. coli Zur regulon. PLoS Biology. 2014 Nov 4;12(11):e1001987. doi:10.1371/journal.pbio.1001987. eCollection 2014. PMID: 25369000 PMCID: PMC4219657

Que EL, Bleher R, Duncan FE, Kong BY, Gleber SC, Vogt S, Chen S, Garwin SA, Bayer AR, Dravid V, Woodruff TK, O’Halloran TV. Quantitative mapping of zinc fluxes in the mammalian egg reveals the origin of fertilization-induced zinc sparks. Nature Chemistry(2015) Feb;7(2):130-9. doi: 10.1038/nchem.2133. Epub 2014 Dec 15. PMCID: PMC4315321

Philips SJ, Canalizo-Hernandez M, Yildirim I, Schatz GC, Mondragón A, O'Halloran TV. Allosteric transcriptional regulation via changes in the overall topology of the core promoter. Science. 2015 Aug 21;349(6250):877-81. doi: 10.1126/science.aaa9809. PMID: 26293965 NIHMSID: 726073

 

Links

View all publications by publications by Thomas V. O'Halloran listed in the National Library of Medicine (PubMed).

Recent Photos

October 27, 2015