The ultimate goal is to promote neuronal regeneration by preventing these changes in astrocytes, adding permissive molecules to astrocytes, or causing neurons to ignore the inhibitory cues. We are evaluating the mechanisms by which astrocytes provide directional cues for neurons. We have focussed on the behavior of a growing neurite as it encouters a boundary. Guidance is provided by molecules that impart directional, as opposed to growth-modifying, cues to neurites. These molecules reside within the extracellular matrix, where growing neurons will encounter them.
Some molecules are permissive for growth and guidance, while other molecules are inhibitory.
We believe that repair of the injured nervous system will be increased by harnessing the permissive cues, and blocking the inhibitory ones. One major area is to understand the signals that are initiated within a neuron after encountering these cues, and then how to modify them to persuade the neuron to grow. We have identified integrin receptors, as well as protein kinase C and the Rho family of GTPases as being important in signaling neuronal guidance cues from the extracellular matrix to the cytoskeleton. Experiments are in progress to alter these pathways to increase neuronal growth, and to identify other signal transduction mechanisms utilized by neurons to sense the cues provided by astrocytes, with the object of overcoming the inhibitory cues found in a glial scar after injury. We have recently cloned this enzyme, and experiments are in progress to determine how the level and activity of these molecules are regulated in the astrocyte, as well as in the brain after injury.