Danyelle Townsend, Ph.D.
| Title: | Assistant Professor |
| Education George Mason University, Fairfax, VA, B.S., Biology and Mathematics, 1993 George Mason University, Fairfax, VA, M.S., Molecular Genetics, 1995 University of Virginia Medical School, Ph.D., Cell Biology, 2001 | ||
| Description of Program My research interests are on the preclinical development and pharmacokinetic / dynamic analysis of anti-cancer agents for the treatment of solid tumors. I am currently investigating anti-cancer agents that trigger oxidative or nitrosative stress and thereby modulate redox balance and glutathione metabolism. In principle, drug response is dependent upon signaling events triggered by a redox sensitive post-translational modification on cysteine residues, S-glutathionylation. A GST activated prodrug PABA/NO induces S-glutathionylation of numerous proteins, concurrent with alterations in kinase signaling. Protein disulfide isomerase (PDI) was among those proteins modified. By extrapolation, the mechanism of action of PABA/NO may be linked with induction of endoplasmic reticulum (ER) stress. The ER is the first compartment of processing for secretory and transmembrane proteins that undergo a series of post-translational modifications, notably glycosylation and disulfide bond formation. The ER stress response is a cascade of transcriptional and translational events that sense the folding capacity and attempt to counter balance ER stress by three mechanisms: 1) increase the expression of ER resident chaperones, 2) decrease the flux of nascent polypeptide imported, and 3) elimination of terminally misfolded proteins via translocation to the cytosol for proteosomal degradation. When the ER stress response is unable to modulate the ER environment to handle the protein folding capacity, apoptotic pathways are activated. Unsurprisingly, an accumulation of misfolded proteins is found in a number of human pathologies, including cancer. As such, my goal is to understand the precursor and/or proximal events leading to the ER stress response, notably through investigating the stress-induced impact on proteins directly involved in the protein folding process. Thus, there would seem to be merit in considering whether S-glutathionylation is cause: effect related to these drug induced changes. Selected Publications Findlay, V.J., Townsend, D.M. and Tew, K.D. Glutathione and Glutathione S-Transferases as Targets for Anticancer Drug Development. In Toxicology of Glutathione S-Transferases. Ed. Awasthi, Y. Taylor and Francis Books, Inc., Boca Raton, FL., 2005. Townsend, D.M., Findlay, V.J., Fazilev, F., Ogle, M., Fraser, J.,Saavedra, J.E., Keefer, L.K. and Tew, K.D. Nitrosative stress from a Glutathione S-transferase p activated pro-drug causes kinase activation concurrent with S-glutathionylation of proteins. 2005. Molecular Pharmacology. 69 (2): 501-508. Findlay, V.J., Townsend, D.M., Morris, T.E., Fraser, J.P., He, L., Keefer, L.K., and Tew, K.D. A novel role for sulfiredoxin in the removal of glutathionylation. 2006. Cancer Research, Jul 1(66): 13: 6800-6806. McIlwain, C.C., Townsend, D.M. and Tew, K.D. Glutathione S-Transferase Polymorphisms: Cancer Incidenceand Therapy. 2006. Oncogene. (11): 1639-1648.Saavedra, J.E., Srinivasan, A., Buzard, G., Davies, K.M., Waterhouse, D.J., Wilde, T.C., Citro, M., Cuellar, M., Deschamps, J.R., Parrish, D., Shami, P.J., Findlay, V.J., Townsend, D.M., Tew, K.D., Singh, S., Xinhua, J. and Keefer, L.K. PABA/NO as an anticancer lead: Analog synethesis, structure revision, solution chemistry, reactivity toward glutathione and in vitro activity. 2006. J. Med. Chem., Feb9; 49(3) 1157-1164. | ||
Contact Information
Department of Pharmaceutical Sciences
280 Calhoun Street
Charleston SC 29425
Sandy Spence 843-792-3117