Necrotic neuron death in the hippocampus, as occurs following hypoxia- ischemia, seizure, or hypoglycemia, appears to involve an excess of synaptic glutamate accumulation, of free cytosolic calcium, and pathologic overactivation of calcium-dependent degenerative events, such as oxygen radical formation. Furthermore, the de generative features of this cascade are worsened by the energy depletion that accompanies these neurological insults. Based on this knowledge, we will design a gene transfer strategy to protect hippocampal neurons from these insults; this will involve the transfer and overexpression of genes to enhance glucose uptake, calcium binding, or oxygen radical scavenging. We will use herpes simplex virus vectors to carry out such gene transfers with vectors carrying the gene for a) the rat brain glucose transporter, b) for calbindin DD-28K, or c) for bcl-2). We have already constructed these vectors and our pilot data indicate neuroprotective potential of each.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS032848-04
Application #
2750883
Study Section
Neurology C Study Section (NEUC)
Program Officer
Jacobs, Tom P
Project Start
1995-09-30
Project End
1999-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Dumas, Theodore C; Gillette, Todd; Ferguson, Deveroux et al. (2010) Anti-glucocorticoid gene therapy reverses the impairing effects of elevated corticosterone on spatial memory, hippocampal neuronal excitability, and synaptic plasticity. J Neurosci 30:1712-20
Zhao, Heng; Yenari, Midori A; Sapolsky, Robert M et al. (2004) Mild postischemic hypothermia prolongs the time window for gene therapy by inhibiting cytochrome C release. Stroke 35:572-7
Dumas, T C; Powers, E C; Tarapore, P E et al. (2004) Overexpression of calbindin D(28k) in dentate gyrus granule cells alters mossy fiber presynaptic function and impairs hippocampal-dependent memory. Hippocampus 14:701-9
Roy, Madhuri; Sapolsky, Robert M (2003) The neuroprotective effects of virally-derived caspase inhibitors p35 and crmA following a necrotic insult. Neurobiol Dis 14:1-9
Roy, Madhuri; Sapolsky, Robert M (2003) The exacerbation of hippocampal excitotoxicity by glucocorticoids is not mediated by apoptosis. Neuroendocrinology 77:24-31
Roy, M; Hom, J J; Sapolsky, R M (2002) HSV-mediated delivery of virally derived anti-apoptotic genes protects the rat hippocampus from damage following excitotoxicity, but not metabolic disruption. Gene Ther 9:214-9
Yenari, M A; Minami, M; Sun, G H et al. (2001) Calbindin d28k overexpression protects striatal neurons from transient focal cerebral ischemia. Stroke 32:1028-35
Phillips, R G; Monje, M L; Giuli, L C et al. (2001) Gene therapy effectiveness differs for neuronal survival and behavioral performance. Gene Ther 8:579-85
Roy, M; Hom, J; Sapolsky, R M (2001) Neuroprotection with herpes simplex vectors expressing virally derived anti-apoptotic agents. Brain Res 901:12-22
Gupta, A; Ho, D Y; Brooke, S et al. (2001) Neuroprotective effects of an adenoviral vector expressing the glucose transporter: a detailed description of the mediating cellular events. Brain Res 908:49-57

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