Mary Bartlett Bunge, Ph.D., The goals of the Bunge laboratory over the past 15 years have been to study the efficacy of a Schwann cell (SC) bridge spanning the spinal cord injury site and to develop combination strategies to further improve the repair response. CNS axons regenerate onto a SC bridge but do not exit the bridge to grow back into the spinal cord. Also, the SC bridge by itself does not lead to axonal regeneration from brainstem neurons that are distant from the thoracic SC implant. A number of combination strategies have been investigated: SC implantation with methylprednisolone, neurotrophins or olfactory ensheathing glia, all of which led to improved outcomes over SC implants alone. A combination strategy tried more recently is SC transplantation and elevation of cyclic AMP. This combination led to the most significant improvements seen so far by the Bunge team. This strategy, therefore, is worthy of further exploration. Thus, in Project 1 the elevation of cyclic AMP will be combined with the addition of neurotrophin to the SC implant to improve axonal regeneration and walking after acute and chronic contusion injury. Ongoing experiments in the Bunge laboratory have shown that the addition of neurotrophin to SC implants leads to a far greater ingrowth of axons. Neurotrophin will be increased in SC implants by transducing the SCs to secrete a bifunctional neurotrophin molecule with BDNF and NT-3 activity. We also prepare SCs transduced to secrete only NT-3, and these will be sent to Dr. Mendell for implantation in a collaborative experiment. Another way to provide neurotrophins in our spinal cord injury models, which would be minimally invasive, is by transducing nearby motor neurons to secrete neurotrophin following injection of viral vectors into the appropriate muscles. This will be done in collaboration with Drs. Gage and Parada and the Viral Vector Core. Whereas most of our interventions have been in the area of the injury, it is undoubtedly important to provide stimulation of the parent neuronal somata of those axons that have been damaged. Therefore, another project, in collaboration with Dr. Parada, will involve the introduction of MEK and ERK genes into reticular neurons to improve the regenerative response. The regenerated fibers in SC implants may not leave the implant in part because of inhibitory molecules present at the interface between the implant and the spinal cord. We are interested, therefore, in modifying the integrins of the surfaces of axons to enable them to overcome inhibition in a tenascin-containing environment; this will be investigated in collaboration with Drs. Fawcett and ffrench-Constant. Another combination, valproic acid and cAMP elevation/SC implants, will be studied in collaboration with the Gage laboratory. Finally, rehabilitation will undoubtedly be an important component of therapy, no matter what the neuroprotection or regeneration strategy used to help people following spinal cord injury. Therefore, the Consortium could provide an outstanding opportunity for the Bunge laboratory to combine the elevated cyclic AMP/SC transplantation therapy with rehabilitation. If an improvement is seen with rehabilitation, then the Electrophysiological Core and Dr. Mendell would be brought in for additional assessment to better understand what may be responsible for the observed improvement. The opportunities that have opened up through the Reeve Foundation International Research Consortium on Spinal Cord Research will enable the Bunge team to advance in exploring ways in which axonal regeneration may be optimized, leading to substantially improved functional recovery. |