Biochemistry and Molecular Biology

University of Texas Medical Branch


Faculty

J. Regino Perez-Polo, Ph.D., Chair & Professor

Our long-term goals are to understand the mechanisms of neuronal cell death and deficits associated with both acute and chronic trauma to the central nervous system at a molecular and cellular level. We have developed an array of interventions ranging from modified Bax (red) localizes both perinuclearly and intranuclearly 1h after perinatal hypoxic-ischemic insult. Bax expression has little colocaliztion with the resident ER protein, protein disulfide isomerase (green).liposomal gene transfer, endogenous receptor antagonists and gene specific “decoy” inhibition of transcription factor binding to promoter sites as intervention approaches to therapy at the transcriptional level. We are also focusing on the role of intracellular trafficking in stress response mechanisms. Our hypothesis is that oxidative stress in the nervous system, caused by chronic or acute trauma, triggers inflammatory responses that result in the uncoupling of gene networks responsible for cell viability and function that result in the altered phenotypes associated with neural deficits present after injury. In addition, we hypothesize that trauma-induced phosphorylation events affect organelle occupancy by proteins regulating cell death. For example, inflammatory cascades activated by trauma have genotoxic and energetic consequences that activate stress response genes via the NF-B transcription factor. Transcription factors bind to cognate DNA sequences that regulate stress response gene expression essential to survival and function. We

Figure. Demonstration of intranuclear
and perinuclear BAX in CNS neurons.
Chromosome, mitochondria/ER markers.
believe that transcription factor binding to cognate

DNA sequences is finely tuned by the specificity of the sequence, position within a promoter and protein-protein interactions with other sites on a promoter. Our ongoing studies focus on: the Bcl-protein family of genes, COX-2, iNOS, and the IL-1 cytokine. We rely on in vitro and working animal models for perinatal ischemia, spinal cord injury, and head injury in rats and mice. In vitro models used are the PC12 line and primary cultures derived from fetal and neonatal brain. We use in vivo MRI techniques to assess damage and vascular changes in brain and spinal cord in addition to confocal immunocytochemistry to assess organelle function in response to oxidative stress. In vitro reporter constructs and transgenic models suitable to unraveling the role of the NF-kB transcription factor in transcriptional regulation of select genes are also used. In addition, we are applying genomic, proteomic and bioinformatics approaches to analyses of time course studies of post-traumatic injury response. Our animal studies look at outcomes to trauma and therapeutic molecular interventions in terms of locomotor functional recovery, cognitive and sensory outcomes. Studies are presently supported in part by NICHD, DOD, Israel/US Bilateral Agreement, Shriners and the Mission Connect Consortium. Collaborative efforts include the Baylor College of Medicine, University of Texas Houston Medical School, University of Leipzig, Germany, University of Montpellier, France, and Ben-Gurion University, Israel. We presently have two graduate students and two research associates and a visiting scientist in the group.

Publications:

Cittelly DM, Nesic-Taylor O, Perez-Polo JR, Phosphorylation of Bcl-xL after spinal cord injury. J. Neuroscience Res., 85(9):1894-1911, 2007.

Rafati DS, Geissler K, Johnson K, Unabia G, Hulsebosch C, Nesic-Taylor O, Perez-Polo JR. Nuclear factor-kappaB decoy amelioration of spinal cord injury-induced inflammation and behavior outcomes. J. Neuroscience Res., 86:(3):566-580, 2007.

Bockhorst KY, Narayana PA, Liu R, Ahobila-Vijjula P, Ramu J, Kamel M, Wosik J, Bockhorst T,Hahn K, Hassan KM, Perez-Polo JR. Early postnatal development of rat brain: In vivo diffusion tensor imaging. J. Neurosci., Res., 2008, Jan 11: PMCID: 18189320

Cittelly, DM, Nesic-Taylor, O., Perez-Polo JR, Detrimental effects of anti-apoptotic treatments in spinal cord injury. Experimental Neurology 210:295-307, 2008 doi:10.1016/j.expneurol.2007.03.001.

Gill, Martin, K.H. Bockhorst, P.A. Narayana, J.R. Perez-Polo. Bax shuttling after neonatal hypoxia-ischemia: hyperoxia effects. J. Neuroscience Res., DOI:10.1002/jnr.21795