The potential role of extracellular proteases, namely the plasminogen activator/ plasminogen (PA/plgn) system in synaptic remodeling in the injured spinal cord of rodents will be the focus of these studies. The PA/plgn system has been suggested to play a role both in axonal outgrowth and synaptic plasticity. Most importantly studies will be performed to further clarify in mice the interesting crossed phrenic nerve phenomenon, an example of synaptic remodeling following spinal cord injury;whereby synaptic contacts on injury-silenced phrenic motor neurons are activated;thereby, restoring phrenic motor neuron activity and promoting recovery of diaphragm function. Having previously shown that induction of PA/plgn system genes is important for generating the crossed phrenic phenomenon in mice, our studies in wildtype and knockout mice deficient in these PA/plgn genes will explore the mechanism(s) by which the induction of the PA system acts to promote the synaptic changes that permit a restoration of lung function. An understanding of specific molecular pathway signaling involved in the ability of PA to initiate this synaptic plasticity may indicate pharmacological approaches to accomplish the same effect. Activation of these synaptic contacts is probably not unique to the phrenic motor nucleus and may occur at additional sites within the spinal cord leading to partial restoration of other physiological functions. The mechanistic knowledge gained from this project may lead to translational studies as a potential therapy to promote synaptic formation, re-activation and recovery of function following human spinal cord injury. ?2R01 NS044129-06A2 Seeds, Nicholas
The studies proposed in this application will further explore the role of the PA/plgn system in the injured spinal cord, not only in promoting synaptic remodeling and recovery of function but in facilitating axonal regeneration. Understanding the molecular mechanisms responsible for recovery of function after SCI in model systems may lead to new approaches to treatment and therapy. In the treatment of SCI, even a modest recovery of synaptic activity and diaphragm function may make a big improvement in the patient's quality of life.
