The normal spinal cord is a complex community of interacting and interdependent cells. With traumatic spinal cord injury (SCI) this cellular organization is profoundly disturbed and secondary injury mechanisms are triggered that act to exacerbate the loss of cells and functional capacity. Substantial progress has been made in identifying secondary injury mechanisms that contribute to loss of white matter after SCI. Specifically, data has been generated to suggest that tetrodotoxin (TTX)-sensitive Na+ channels play an important role in secondary injury and acute loss of white matter axons. However, the PI also has data implicating ionotropic AMPA and/or kainate receptors in mediating oligodendrocyte cell death and consequently abnormal myelination of surviving axons after incomplete SCI. In the new project period these hypotheses will be tested using a standardized rat model of clinically-relevant contusive SCI. Using electron microscopy and quantitative morphological analysis, they will determine whether: a) acute treatment with TTX will permanently preserve axons 'at risk' after SCI and b) Na channel blockers other than TTX are effective in reducing axonal loss. With immunocytochemistry and in situ hybridization they will determine how treatment with Na channel blockers affects glial loss, the proliferation of glial precursor cells, and myelin gene expression in the injured spinal cord. They will use selective antagonists of specific glutamate receptors to determine their effect on: a) survival of white matter oligodendrocytes acutely over the first 24 h after injury; and b) the myelination of spared axons chronically after SCI. Based on these results they will investigate a third hypothesis: the combination of an acute Na channel blocker and an acute AMPA and/or kainate receptor antagonist will produce an additive effect in reducing chronic white matter pathology and functional deficits after SCI. It is their goal to provide insights to ways of enhancing tissue sparing and functional recovery after SCI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035647-07
Application #
6639510
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Kleitman, Naomi
Project Start
1997-04-01
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
7
Fiscal Year
2003
Total Cost
$273,000
Indirect Cost
Name
Georgetown University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Lee, Hyun Joon; Wu, Junfang; Chung, Jumi et al. (2013) SOX2 expression is upregulated in adult spinal cord after contusion injury in both oligodendrocyte lineage and ependymal cells. J Neurosci Res 91:196-210
Whittaker, Matthew T; Zai, Laila J; Lee, Hyun Joon et al. (2012) GGF2 (Nrg1-ýý3) treatment enhances NG2+ cell response and improves functional recovery after spinal cord injury. Glia 60:281-94
Wu, Junfang; Leung, Philberta Y; Sharp, April et al. (2011) Increased expression of the close homolog of the adhesion molecule L1 in different cell types over time after rat spinal cord contusion. J Neurosci Res 89:628-38
Wu, Junfang; Wrathall, Jean R; Schachner, Melitta (2010) Phosphatidylinositol 3-kinase/protein kinase Cdelta activation induces close homolog of adhesion molecule L1 (CHL1) expression in cultured astrocytes. Glia 58:315-28
Wu, Junfang; Yoo, Soonmoon; Wilcock, Donna et al. (2010) Interaction of NG2(+) glial progenitors and microglia/macrophages from the injured spinal cord. Glia 58:410-22
Lytle, Judith M; Chittajallu, Ramesh; Wrathall, Jean R et al. (2009) NG2 cell response in the CNP-EGFP mouse after contusive spinal cord injury. Glia 57:270-85
Wrathall, Jean R; Lytle, Judith M (2008) Stem cells in spinal cord injury. Dis Markers 24:239-50
Leung, Philberta Y; Johnson, Christopher S; Wrathall, Jean R (2007) Comparison of the effects of complete and incomplete spinal cord injury on lower urinary tract function as evaluated in unanesthetized rats. Exp Neurol 208:80-91
Lee, Jae K; Johnson, Christopher S; Wrathall, Jean R (2007) Up-regulation of 5-HT2 receptors is involved in the increased H-reflex amplitude after contusive spinal cord injury. Exp Neurol 203:502-11
Yoo, Soonmoon; Wrathall, Jean R (2007) Mixed primary culture and clonal analysis provide evidence that NG2 proteoglycan-expressing cells after spinal cord injury are glial progenitors. Dev Neurobiol 67:860-74

Showing the most recent 10 out of 32 publications