Regents of the University of Colorado, UCDHSC
Kenneth Minor, Ph.D.
Postdoctoral Student

Proteases and Spinal Cord Regeneration

Spinal cord injury results in devastating clinical consequences including paralysis and death. The main reason that the spinal cord fails to repair itself following trauma seems to be the presence of growth barriers that are present in the injury site. Although immediately following injury, injured nerve fibers in the spinal cord may attempt to grow and repair, but this event is short-lived as the injury site becomes more hostile and non-permissive until eventually all hope of regeneration has passed. The following proposal investigates the potential that enzymatic proteases may offer a potential therapeutic strategy in combating the non-permissive environment of the injured spinal cord and promoting regeneration and repair. This proposal focuses on a protease known as tissue-type plasminogen activator (tPA) that has been shown to promote repair in peripheral nerves following injury by facilitating outgrowth of damaged nerve fibers to the point where neural/muscular function was restored. Since regeneration in the injured spinal cord doesn’t normally occur, we plan on investigating the role of tPA in a spinal cord regeneration model known as the conditioning lesion paradigm, in which damage to a peripheral nerve can promote the ability of that nerve to carry out regeneration of its axons that reside in the spinal cord. The molecular mechanisms that facilitate the conditioning lesion paradigm are largely unknown and represents an important step in defining agents that can promote regeneration following spinal cord injury. We hypothesize that peripheral injury promotes spinal cord regeneration by causing injured nerves to upregulate and transport tPA along their central axons and into the spinal cord. This results in an accumulation of tPA in these axons that correlates with the ability of those axons to overcome inhibitory barriers and regenerate following spinal injury. To test this hypothesis, the following aims are set forth: (1) To correlate the transport and localization of tPA in the spinal cord with conditioning-injury induced regeneration and evaluate the importance of this localization event using gene knock-out models, and (2) To test the potential therapeutic value of using exogenous tPA in the promotion of spinal cord regeneration. These studies will provide insight into the potential therapeutic value of using proteases, here tPA, in the treatment of spinal cord injury. These studies will further our discovery of possible factors that may be used for treatments, with the ultimate goal of developing multi-faceted, combinatorial therapies that will promote spinal cord regeneration and finally bring about a cure for paralysis.