The studies proposed in this grant application focus on identifying and characterizing the molecular signaling events involved in apoptotic cell death following traumatic spinal cord injury (SCI). Despite the recent evidence of widespread apoptosis in neurons and glia after SCI, the molecular components of the apoptotic pathway remain largely unknown. The proposed experiments will provide evidence of components in the apoptotic machinery responsible for initiating and executing this cell death process. In addition, experiments are proposed to demonstrate that blocking steps involved in the apoptotic cell death pathway provides neuroprotection and promotes functional recovery in acute SCI. We hypothesize that calcineurin-mediated BAD dephosphorylation is one of the initial upstream events in the apoptotic cascade and is linked to caspase-3 activation. Glutamate-induced Ca2+ influx leads to calcineurin activation and high levels of glutamate are released soon after SCI. Therefore, we will examine whether intrathecal injections of selective glutamate receptor agonists into uninjured spinal cord lead to calcineurin- mediated BAD dephosphorylation. In addition, we will demonstrate that injections of glutamate receptor antagonists reduce activation of the caspase-3 apoptotic cascade. Finally, the contribution of apoptosis to the functional deficits observed following SCI is not clear at this time. Therefore, we will treat injured animals with inhibitors targeting calcineurin and caspase-3 and use morphological, histological, and behavioral criteria to measure indices of apoptotic cell death and functional recovery. The outcome of these studies will have clear clinical implications for minimizing secondary neuronal and glial cell death and promoting recovery of function following SCI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS040015-04S1
Application #
6763914
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Kleitman, Naomi
Project Start
2000-02-07
Project End
2005-01-31
Budget Start
2003-07-01
Budget End
2005-01-31
Support Year
4
Fiscal Year
2003
Total Cost
$63,864
Indirect Cost
Name
University of Kentucky
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
McEwen, Melanie L; Springer, Joe E (2006) Quantification of locomotor recovery following spinal cord contusion in adult rats. J Neurotrauma 23:1632-53
McEwen, Melanie L; Springer, Joe E (2005) A mapping study of caspase-3 activation following acute spinal cord contusion in rats. J Histochem Cytochem 53:809-19
Jin, Ying; McEwen, Melanie L; Nottingham, Stephanie A et al. (2004) The mitochondrial uncoupling agent 2,4-dinitrophenol improves mitochondrial function, attenuates oxidative damage, and increases white matter sparing in the contused spinal cord. J Neurotrauma 21:1396-404
Candelario-Jalil, Eduardo; Gonzalez-Falcon, Armando; Garcia-Cabrera, Michel et al. (2003) Assessment of the relative contribution of COX-1 and COX-2 isoforms to ischemia-induced oxidative damage and neurodegeneration following transient global cerebral ischemia. J Neurochem 86:545-55
Nottingham, Stephanie A; Springer, Joe E (2003) Temporal and spatial distribution of activated caspase-3 after subdural kainic acid infusions in rat spinal cord. J Comp Neurol 464:463-71
Nottingham, Stephanie; Knapp, Pamela; Springer, Joe (2002) FK506 treatment inhibits caspase-3 activation and promotes oligodendroglial survival following traumatic spinal cord injury. Exp Neurol 177:242-51
Springer, Joe E (2002) Apoptotic cell death following traumatic injury to the central nervous system. J Biochem Mol Biol 35:94-105
Mu, Xiaojun; Azbill, Robert D; Springer, Joe E (2002) NBQX treatment improves mitochondrial function and reduces oxidative events after spinal cord injury. J Neurotrauma 19:917-27
Springer, J E; Nottingham, S A; McEwen, M L et al. (2001) Caspase-3 apoptotic signaling following injury to the central nervous system. Clin Chem Lab Med 39:299-307
Springer, J E; Azbill, R D; Nottingham, S A et al. (2000) Calcineurin-mediated BAD dephosphorylation activates the caspase-3 apoptotic cascade in traumatic spinal cord injury. J Neurosci 20:7246-51

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