Contact Information

Department of Pharmacology

Uniformed Services University of the Health Sciences
Department of Pharmacology
4301 Jones Bridge Road
Bethesda, Maryland 20814-4799
Phone: (301) 295-3223
FAX: (301) 295-3220

NCBI Biography

Aviva Symes, Associate Professor, Department of Pharmacology

Aviva Symes, Ph.D.

Associate Professor

  • Ph.D. Biochemistry, University College, London, UK
  • Postdoctoral Fellowship: Neurology, Massachusetts General Hospital/ Harvard Medical School

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-β 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-β 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?β signals within the CNS after injury. TGF?β 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-β after traumatic injury (Both TBI and SCI) and the mechanisms through which they do so.

Smad3 null mice form a more rapid and smaller glial scar after SCI. Sections from wildtype (+/+) and Smad3 null (-/-) spinal cord 8 days after a dorsal hemisection SCI. These data show that the absence of Smad3 has a profound influence on the recovery from SCI, and that altering Smad3 levels may prove beneficial to the recovery process.

In the peripheral nervous system, axotomy induces the expression of several neuropeptides, in sensory and sympathetic ganglia. Expression of one of these neuropeptides, vasoactive intestinal peptide, is induced by members of the gp130 cytokine family, specifically leukemia inhibitory factor (LIF). We have studied the mechanisms through which LIF and related cytokines induced transcription of the VIP gene. We have also shown that TGF-β synergizes with LIF to upregulate expression of this gene. Signaling by both cytokine families (gp130 cytokines and TGF-βs) is mediated by a 180 bp element in the VIP promoter, the cytokine response element through activation of pathway specific transcription factors. We are interested in determining the pathways and transcription factors through which these and other cytokines regulate VIP gene expression as a model of highly adaptive neuronal gene expression.