The underlying mechanism of delayed cell death in the spinal cord after injury is poorly understood. Secondary injury has been proposed to cause progressive cell death and tissue loss after the initial physical insult. Post-traumatic inflammatory reaction may play an important role in the secondary injury. Cardinal features of an acute inflammatory response have been demonstrated in the injured cord for at least several days after the traumatic insult. Inflammatory processes in the CNS have a predilection for the white matter. White matter lesions, including demyelination, are the major cause of disability after SCI. Cytokines are inflammatory mediators expressed by inflammatory cells. Cytokines, particularly tumor necrosis factor-alpha (TNF), have been shown to cause apoptosis in oligodendrocytes (ODCs) in vitro and demyelination in vivo. We will explore a possible pathogenic role of TNF-alpha in ODC apoptosis in the context of a post-traumatic inflammatory reaction. A simplified scheme is shown below: This project will focus mainly on the role of TNF-alpha in ODC apoptosis after SCI. In vivo studies, using rat and transgenic mouse SCI models, and in vitro studies, using ODC cultures, will be conducted to test the hypothesis that TNF-alpha expression contributes, at least partially, to ODC apoptosis after SCI. We will also test the hypothesis that apoptotic ODC cell death and subsequent demyelination is reduced and functional outcome is improved by interventions that effectively inhibit TNF-alpha expression or block its actions. This project will also serve as a platform for developing new therapeutic regimens, including combination strategies directed at different steps in the post-traumatic inflammatory cascade. The ultimate goal of this project is to enhance functional recovery after SCI through a reduction in ODC death.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037230-05
Application #
6393900
Study Section
Neurology A Study Section (NEUA)
Program Officer
Kleitman, Naomi
Project Start
1997-09-17
Project End
2003-05-31
Budget Start
2001-06-01
Budget End
2003-05-31
Support Year
5
Fiscal Year
2001
Total Cost
$308,546
Indirect Cost
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Lee, Jiunn-Tay; Xu, Jan; Lee, Jin-Moo et al. (2004) Amyloid-beta peptide induces oligodendrocyte death by activating the neutral sphingomyelinase-ceramide pathway. J Cell Biol 164:123-31
Yan, Ping; Liu, Naikui; Kim, Gyeong-Moon et al. (2003) Expression of the type 1 and type 2 receptors for tumor necrosis factor after traumatic spinal cord injury in adult rats. Exp Neurol 183:286-97
Yin, K J; Lee, J-M; Chen, S D et al. (2002) Amyloid-beta induces Smac release via AP-1/Bim activation in cerebral endothelial cells. J Neurosci 22:9764-70
Kim, Eun-Sang; Kim, Gyeong-Moon; Lu, Xiaobin et al. (2002) Neural circuitry of the adult rat central nervous system after spinal cord injury: a study using fast blue and the Bartha strain of pseudorabies virus. J Neurotrauma 19:787-800
Yin, J H; Yang, D I; Chou, H et al. (2001) Inducible nitric oxide synthase neutralizes carbamoylating potential of 1,3-bis(2-chloroethyl)-1-nitrosourea in c6 glioma cells. J Pharmacol Exp Ther 297:308-15
Xu, J; Kim, G M; Chen, S et al. (2001) iNOS and nitrotyrosine expression after spinal cord injury. J Neurotrauma 18:523-32
Yan, P; Li, Q; Kim, G M et al. (2001) Cellular localization of tumor necrosis factor-alpha following acute spinal cord injury in adult rats. J Neurotrauma 18:563-8
Xu, J; Kim, G M; Ahmed, S H et al. (2001) Glucocorticoid receptor-mediated suppression of activator protein-1 activation and matrix metalloproteinase expression after spinal cord injury. J Neurosci 21:92-7
Kim, G M; Xu, J; Xu, J et al. (2001) Tumor necrosis factor receptor deletion reduces nuclear factor-kappaB activation, cellular inhibitor of apoptosis protein 2 expression, and functional recovery after traumatic spinal cord injury. J Neurosci 21:6617-25

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