Our research goals at the University of Texas Medical Branch are to use neurotrophin factors for the purpose of reducing cell death and dysfunction in paradigms relevant to trauma, ischemia, and aging in CNS. Neurotrophin factors have been shown to spare neurons from delayed cell death after injury.
The neurotrophins include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3). While their mechanisms of action are diverse and overlapping, they differentially enhance cellular defenses by increasing antioxidant activity and pyridine nucleotide metabolism, critical to neuronal resistance to and recuperation from injury.
For example, while some physiological elements responsible for cerebral ischemia have been described, less is known about underlying mechanistic causes of cell death and dysfunction at a cellular and molecular level. Recently, we have applied non-invasive multimodal magnetic resonance imaging (MRI) and 31P-nuclear magnetic resonance (NMR) to a rat ischemia model that uses middle cerebral artery (MCA) occlusion to produce a core of irreversible cell death, surrounded by a region of ischemic penumbra, where cell death occurs after 24 hr. Ischemia disrupts availability of neurotrophic factors to neurons, shifts local oxidant-antioxidant balance, and impairs cellular energy homeostasis, and so increases reactive oxygen species, an important cause of damage.
Neurotrophins rescue neurons from apoptosis due to intrinsic (programmed cell death in development) and intrinsic (trauma- and ischemia-mediated death) processes. Our hypothesis is that neuronal apoptosis due to oxidative stress shares transcription factor elements with intrinsic death due to neurotrophin (NT) deprivation due to perturbations in transcription factor activation. It is our long term goal to develop integrated approaches for the regulated and augmented expression of neurotrophins that will elicit robust and prompt patient recovery and return to function.
Sampath, D. Jackson, G.R., Werrbach-Perez, K. and Perez-Polo, J.R. Effects of NGF on Glutathione peroxidase and catalase in PC12 cells. J. Neurochemistry, 62:2476-2479, 1994.
Roner, S., Perez-Polo, J.R., Wiley, R.G., Schliebs, R. And Bigl, V. Differential expression of immediate early genes in distinct layers of rat cerebral cortex after selective immunolesion of the forebrain cholinergic system. J. Neurosci. Res., 38:282-293, 1994.
Yang, K., Faustinella, F., Xue, J.J., Whitson, J., Kampfl, A., Mu, S., Taglialatela, G.,Perez-Polo, J.R., Clifton, G. And Hayes, R.L. Optimizing liposome-mediated gene transfer in primary rat septo-hippocampal cell culture. Neurosci. Lett., 182:287-290, 1994.
Roner, S., Schliebs, R., Perez-Polo, J.R., Wiley, R.G. and Bigl, V. Differential changes in cholinergic markers from selected brain regions after specific immunolesion of rat cholinergic basal forebrain system. J. Neurosci. Res., 40:31-43, 1995.
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