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
: Each year an estimated 10,000 individuals, mostly young adults, suffer spinal cord injuries due to accidents or violence, leading to loss of motor function and varying degrees of paralysis. Many of these are traumatic injuries to the cervical spinal cord that interrupt descending bulbospinal respiratory pathways from the medulla often rostral to the level of the phrenic motor nucleus. Such injuries cause respiratory muscle paralysis and in human cases require mechanical ventilator support. In animal models and some human cases there is often some degree of respiratory recovery. Therefore, a greater understanding of the cellular mechanisms leading to respiratory pathway recovery and plasticity in the injured spinal cord may lead to new therapies for treating these spinal cord injuries. The studies proposed in this application will further explore the role of the PA/plgn system in the injured spinal cord in promoting synaptic remodeling and recovery of function. Understanding the molecular mechanisms responsible for recovery of function after SCI in model systems may lead to new approaches to treatment and therapy. Characterizing the induction of PA by motor neurons following SCI and its action on cellular signaling pathways promoting synaptic remodeling events will provide insight into potential translational pharmacological approaches to trigger remodeling of inactive synapses leading to recovery of spinal cord functions. 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. ? Jobs created and retained through awarding this grant: Both Dr. Kenneth Minor (postdoctoral fellow), an expert biochemist and surgeon who has worked on these studies for several years and Ms. Susan Haffke (Sr. PRA) an expert histologist/electron microscopist/biochemist technician, who has worked on the PA projects for a number of years, had to be let go last year due to a lack of funding. They have indicated a strong interest in returning to the project if new funds are forthcoming. A new technician (PRA) will be hired to oversee the mouse colony, due genotyping, plasmid and tissue preparation;as well as assist Drs. Minor and Seeds with the neural surgeries and molecular biological studies.
