Loss of white matter at the site of traumatic spinal cord injury (SCI) interrupts critical ascending and descending tracts and thus precludes normal function in the spinal cord distal to the site of injury. In the last project period we identified a previously unrecognized process involved in the loss of functional white matter: the AMPA receptor-mediated loss of oligodendrocytes. Approximately twice as much white matter is spared in a standardized contusion SCI model when glial loss is inhibited with the AMPA receptor antagonist, NBQX. Our data support a new understanding of the critical role oligodendrocytes play in trophic support of axons. We have examined the effect of SCI on endogenous glial precursor cell (GPC) populations in vivo, developed an in vitro model to study these cells and identified glial growth factor 2 (GGF2) as an important mitogen for GPC cells in vitro and in vivo. In the new project period we propose to investigate the hypothesis that the endogenous GPCs can be experimentally manipulated to improve recovery of function after incomplete SCI. We have three specific aims. (I) Test the effect of increasing endogenous GPC proliferation on functional recovery in a clinically relevant in vivo model of SCI in the rat.We will compare functional recovery and chronic histopathology in rats that receive GGF2 beginning at different times after SCI, and with or without FGF2 that may produce increased proliferation, or acute TTX treatment that we have shown preserves axons per se. (II). Evaluate the mechanism(s) through which increasing endogenous GPCs with GGF2 improves functional recovery after SCI in the rat,including effects on cell proliferation, survival and differentiation as well as chronic white matter pathology and preservation of axons. (Ill)Develop and use a model of SCI in mice expressing enhanced green fluorescent protein (EGFP) under the control of the CNP promoter that is expressed in glial progenitors to critically evaluate the temporal-spatial effect of SCI on GPC electrophysiological and immunocytochemical phenotypes in situ in tissue slices and the effect of treatment with GGF2 on these properties. We will gain new information about whether endogenous GPCs can be manipulated after SCI to enhance functional recovery. As SCI and brain injury create devastatingand permanent functional deficits for large numbers of Americans, and such injury is especially prevalent in young people and leads to life-long disabilities, therapies to enhance recovery will benefit public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035647-12
Application #
7741205
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Owens, David F
Project Start
1997-04-01
Project End
2012-12-31
Budget Start
2010-01-01
Budget End
2012-12-31
Support Year
12
Fiscal Year
2010
Total Cost
$341,218
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

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