USU Neuroscience

asymes@usuhs.mil
 
Ph.D., University College of London, 1990
 
The role of cytokines in the injury response in the adult nervous system
 
Cytokines, traditionally thought to be messengers within the immune system, are now known to have a much broader range of functions throughout the body. In the nervous system cytokines influence neuronal and glial responses to injury, modulating many different facets of the injury response. After traumatic injury to the central nervous system viable axotomized neurons fail to regenerate. This regenerative failure is due, in part, to the inhibitory environment of scar tissue that forms after injury and acts as a molecular and physical barrier to axon regeneration. Determining the molecular pathways that lead to formation of the glial scar after traumatic injury to the CNS is, therefore, a critical step in our search for pharmacological interventions aimed at restoring neuronal function.
 
Traumatic injury to the CNS immediately results in a cytokine cascade that results in amongst other things infiltration of leucocytes and activation of glial cells. The cytokine TGF- is a central mediator in the glial response to injury: its inhibition leads to reduced scar formation, and its overexpression results in additional scarring. TGF- promotes deposition of the chondroitin sulfate proteoglycans, extracellular matrix proteins that are inhibitory to axon regrowth. Little is known of the mechanisms through which TGF- signals within the CNS after injury. TGF- regulates gene transcription in part through the actions of the transcription factors Smad2 and Smad3. We have therefore studied the effects of traumatic brain injury (TBI) and spinal cord injury (SCI) in Smad3 null mice. We have shown that Smad3 null mice heal a stab wound to the cerebral cortex more quickly than do wild type mice, with less infiltration of inflammatory cells and less deposition of extracellular matrix. We also have similar data for scar formation in Smad3 null mice after SCI. Our data suggest that inhibition of Smad signaling may be beneficial to recovery from TBI and SCI. Using genetic mouse mutants, primary glial culture, imaging and viral expression of smad specific shRNAs we are exploring the identity of the cells that respond directly to TGF- after traumatic injury (Both TBI and SCI) and the mechanisms through which they do so.
 
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