Dr. Zachara and her team are engaged in understanding which proteins are modified dynamically by O-GlcNAc in response to stress, and how this alters protein function in such a way that elevating O-GlcNAc before, or immediately after, cellular injury is protective in both in vitro and in vivo models.
In response to multiple forms of cellular stress, levels of the O-linked β-N-acetylglucosamine (O-GlcNAc) protein modification are elevated rapidly and dynamically on myriad nuclear, mitocohdrial and cytoplasmic proteins. Several studies demonstrate that elevation of O-GlcNAc prior to heat stress, oxidative stress, hypoxia, trauma hemorrhage and ischemia reperfusion injury is protective, suggesting that increased O-GlcNAc in response to stress is a survival response of cells injury. However, the mechanisms by which O-GlcNAc regulates protein function leading to cell survival have not been defined.
Dr. Zachara's long-term goal is to determine how stress-induced changes in the O-GlcNAc protein modification lead to increased cell/tissue survival in response to injury, in order to develop novel strategies for the treatment of numerous diseases, including ischemia reperfusion injury.
Lab Website: Zachara Lab
Zachara N. E., O'Donnell N., Mercer J. J., Marth J. D., and Hart G. W. (2004) Dynamic O-GlcNAc modification of nucleocytoplasmic proteins in response to stress. A survival response of mammalian cells. J. Biol. Chem., 279, 30133-30142.
Jones S. P., Zachara N. E., Teshima Y., Hart G. W., and Marban E. (2008) Endogenously-recruitable cardioprotection by N-acetylglucosamine linkage to cellular proteins. Circulation, 117, 1172-1182.
Kazemi Z., Chang H., Haserodt S. K., McKen C., Zachara N.E. (2010) O-GlcNAc Regulates Stress-Induced Heat Shock Protein Expression in a GSK-3? Dependent Manner. J. Biol. Chem., 285, 39096-39107.
Jensen R.V., Zachara N.E., Nielsen P.H., Kimose H.H., Kristiansen S.B., and Botker H.E. (2013) Impact of O-GlcNAc on cardioprotection by remote ischemic preconditioning in non-diabetic and diabetic patients. Cardiovascular Research, 97(2): 369-378.
Zhong J., Martinez M., Sengupta S., Lee A., Wu X., Chaerkady R., O'Meally R., Cole R. N., Pandey A., Zachara N. E. (2015) Quantitative Phosphoproteomics Reveals Crosstalk Between Phosphorylation and O-GlcNAc in the DNA Damage Response Pathway. Proteomics, 15(2-3): 591-607.