Repair mechanisms are activated in response to injury in the adult spinal cord; these begin wound healing and reconstructing the cord tissue including the regrowth of severed axons. However, at about the 4th week after the injury, the natural inherent repair is aborted and decay processes take over yielding a permanent wound gap. The severed nerve fibers fail to cross the wound gap, leaving the cord beyond the site of injury permanently disconnected from the brain and the related muscles become and remain paralyzed. The long-term goal of our research is to identify the mechanisms by which the intrinsic repair is aborted. Identifying the ~who"""""""" and understanding the ~how~ will enable us to develop therapeutic clinical strategies for facilitating the intrinsic repair thereby preventing paralysis. Thus far, by using x-irradiation in an analytical setting as used to eradicate proliferating cells-it has been possible to identify one cell, the reactive astrocyte, that plays an important role in discontinuing the wound healing processes. Further, it was possible to demonstrate that the destructive outcome of injury can be averted and the natural inherent repair of structure and motor function can be attained provided that reactive glia at the damage site are destroyed by x-ray therapy targeted at the right time after transection injury in adult rat spinal cord. The objective of this proposal is to establish the methods to transform a strategy which is effective in the experimental setting into a strategy effective in a clinical setting in facilitating structural and functional repair in injured spinal cord. The parameters of radiation therapy protocols that are clinically safe for the human spinal cord are very well defined and in routine use to eradicate tumor cells. These clinical radiation parameters will be used by themselves and in conjunction with the clinical procedures currently used in human spinal cord injury, such as drugs to prevent secondary damage and protect the spared fibers tracts. The efficacy of these in facilitating intrinsic repair will be examined in transection and contusion injuries in the rat spinal cord. Studies in each of the specific aims are focused on identifying the parameters (e.g., window of opportunity for the therapy) and defining the conditions (e.g., dose protocol) at which repair is facilitated. Analysis of repair is conducted using magnetic resonance imaging of the lesion site at the cord, quantitative histologic and electrophysiologic methods and behavioral methods.
| Ichiyama, Ronaldo; Potuzak, Melissa; Balak, Marissa et al. (2009) Enhanced motor function by training in spinal cord contused rats following radiation therapy. PLoS One 4:e6862 |
| Kalderon, Nurit; Muruganandham, Manickam; Koutcher, Jason A et al. (2007) Therapeutic strategy for acute spinal cord contusion injury: cell elimination combined with microsurgical intervention. PLoS One 2:e565 |
| Kalderon, Nurit (2005) Cell elimination as a strategy for repair in acute spinal cord injury. Curr Pharm Des 11:1237-45 |
