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.
