Spinal cord injury (SCl) is a devastating condition currently affecting approximately 200,000 people in the United States, with approximately 10,000 new cases diagnosed each year 4'5. Following injury to the spinal cord, endogenous progenitor cells are activated and participate in a partial restoration of the injury zone 6'7'8. The anatomical source of dividing progenitor cells following spinal cord lesion is now a major focus of study. Here we propose that new spinal cord gila are generated from separate astrocyte and oligodendrocyte producing aNPC lineages. We hypothesize that epidermal growth factor (EGF) specifically directs the formation of the oligodendrocyte lineage from activated progenitor cells following traumatic spinal cord injury. This hypothesis is based on the following observations. First, acute mitotic labeling in the adult spinal cord reveals only two significant populations of dividing cells: astrocyte and oligodendrocyte progenitor cells. Second, EGF infused intraventricularly selectively increases the proliferation of oligodendrocyte progenitor cells but not astrocyte progenitor cells. Thirdly, fate determination of EGF expanded progenitor cells shows an increase in new oligodendrocytes but no change in the number of new astrocytes. We propose to use a combination of molecular and histological tools to determine if EGF can selectively amplify glial progenitor cells in a model of SCI.
Aim I will determine the effect of EGF on proliferation of progenitor cells and net survival of differentiated gila in a model of spinal cord trauma.
Aim II will characterize the fate of a distinct population of glial progenitor cells that respond to EGF.
Aim III will characterize the formation of myelin by EGF expanded progenitor cells following injury. These studies will lead to a better understanding of the molecular controls that govern stem cell fate following injury and potentially reveal a novel mechanism for inducing cellular regeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS046724-01A1
Application #
6822670
Study Section
Special Emphasis Panel (ZRG1-CNNT (01))
Program Officer
Kleitman, Naomi
Project Start
2004-05-15
Project End
2009-04-30
Budget Start
2004-05-15
Budget End
2005-04-30
Support Year
1
Fiscal Year
2004
Total Cost
$326,710
Indirect Cost
Name
University of Washington
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Powers, Berit E; Lasiene, Jurate; Plemel, Jason R et al. (2012) Axonal thinning and extensive remyelination without chronic demyelination in spinal injured rats. J Neurosci 32:5120-5
Stoll, Elizabeth A; Cheung, Willy; Mikheev, Andrei M et al. (2011) Aging neural progenitor cells have decreased mitochondrial content and lower oxidative metabolism. J Biol Chem 286:38592-601
White, Bryan D; Nathe, Ryan J; Maris, Don O et al. (2010) Beta-catenin signaling increases in proliferating NG2+ progenitors and astrocytes during post-traumatic gliogenesis in the adult brain. Stem Cells 28:297-307
Lasiene, Jurate; Matsui, Aya; Sawa, Yuhito et al. (2009) Age-related myelin dynamics revealed by increased oligodendrogenesis and short internodes. Aging Cell 8:201-13
Sellers, Drew L; Maris, Don O; Horner, Philip J (2009) Postinjury niches induce temporal shifts in progenitor fates to direct lesion repair after spinal cord injury. J Neurosci 29:6722-33
Keene, C Dirk; Chang, Rubens; Stephen, Christina et al. (2009) Protection of hippocampal neurogenesis from toll-like receptor 4-dependent innate immune activation by ablation of prostaglandin E2 receptor subtype EP1 or EP2. Am J Pathol 174:2300-9
Mikheev, Andrei M; Stoll, Elizabeth A; Mikheeva, Svetlana A et al. (2009) A syngeneic glioma model to assess the impact of neural progenitor target cell age on tumor malignancy. Aging Cell 8:499-501
Lasiene, Jurate; Shupe, Larry; Perlmutter, Steve et al. (2008) No evidence for chronic demyelination in spared axons after spinal cord injury in a mouse. J Neurosci 28:3887-96

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