Studies will focus on the potential role of extracellular proteases, namely the plasminogen activator/plasminogen (PA/pign) system in synaptic remodeling and axonal regeneration in the injured spinal cord of rodents. The PA/plgn system has been suggested to play a role both in axonal outgrowth and synaptic plasticity. The PA genes are induced following peripheral nerve injury and are required for timely PNS regeneration. Studies will be directed at assessing the role of these PA/plgn genes in the ability of dorsal root ganglia sensory axons to regenerate their CNS collaterals in the dorsal column of the spinal cord. Most importantly studies will be performed to assess whether the interesting crossed phrenic nerve response, an example of synaptic remodeling following spinal cord injury, requires the induction of the PA/pign system to promote these synaptic changes that permit a restoration of lung function. Mice deficient in various PA/plgn genes will be compared for their plasticity and regenerative abilities to demonstrate any requirement for these protease activities. Furthermore, expression of the PA/pign system [tissue plasminogen activator (tPA), urokinase plasminogen activator(uPA), plasminogen, plasminogen activator inhibitor-i (PAIl), and protease nexin(PN)] in the lesioned or injured spinal cord will be studied by in situ hybridization with 35S-CRNA probes and antibodies to these PA system proteins, to determine whether this gene system is also induced in the CNS and whether it plays a role in axonal regeneration and synaptic plasticity. An understanding of this protease system in the injured spinal cord may allow us to effectively enhance axonal regeneration by supplying either PA/plgn or their inhibitors to the site of injury. Similarly, PA/pign expression may be important for synaptic remodeling at sites below a spinal cord lesion, such that induction of the PA/pign genes may lead to partial restoration of function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS044129-01
Application #
6506070
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Kleitman, Naomi
Project Start
2002-06-15
Project End
2007-04-30
Budget Start
2002-06-15
Budget End
2003-04-30
Support Year
1
Fiscal Year
2002
Total Cost
$304,530
Indirect Cost
Name
University of Colorado Denver
Department
Biochemistry
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Subhadra, Bobban; Schaller, Kristin; Seeds, Nicholas W (2013) Neuroserpin up-regulation in the Alzheimer's disease brain is associated with elevated thyroid hormone receptor-?1 and HuD expression. Neurochem Int 63:476-81
Seeds, Nicholas; Mikesell, Steve; Vest, Rebekah et al. (2011) Plasminogen activator promotes recovery following spinal cord injury. Cell Mol Neurobiol 31:961-7
Seeds, Nicholas W; Akison, Lisa; Minor, Kenneth (2009) Role of plasminogen activator in spinal cord remodeling after spinal cord injury. Respir Physiol Neurobiol 169:141-9
Minor, Kenneth H; Akison, Lisa K; Goshgarian, Harry G et al. (2006) Spinal cord injury-induced plasticity in the mouse--the crossed phrenic phenomenon. Exp Neurol 200:486-95
Siconolfi, Lisa B; Seeds, Nicholas W (2003) Mice lacking tissue plasminogen activator and urokinase plasminogen activator genes show attenuated matrix metalloproteases activity after sciatic nerve crush. J Neurosci Res 74:430-4
Seeds, Nicholas W; Basham, Mark E; Ferguson, Jayne E (2003) Absence of tissue plasminogen activator gene or activity impairs mouse cerebellar motor learning. J Neurosci 23:7368-75