PRIMARY FACULTY

Aviva Symes, Ph.D.
Associate Professor
Pharmacology
 
4301 Jones Bridge Road
Bethesda MD 20814
Office: 301-295-3234
Fax: 301-295-1996
asymes@usuhs.mil

Cytokine regulation of gene expression in the nervous system.
 
In the nervous system cytokines influence neuronal and glial survival and differentiation: protecting cells when injured or stressed and altering phenotype in response to environmental signals. Cells constantly receive environmental information, yet respond uniquely to each signal, carrying out a distinct program dependent upon the signal received and the responding cell. Understanding how neurons and glia recognize these signals and respond appropriately is a vital component of understanding how the nervous system functions. This laboratory investigates the molecular mechanisms through which cytokines mediate long term changes in nervous system function through altering neuronal and glial gene expression. We are particularly interested in the mechanisms through which cytokines act on neurons and glia after injury to regulate genes important to the functional recovery of the nervous system.
 
We are concentrating on the regulation of gene expression in the nervous system by two cytokine families: the gp130 cytokines and the TGF-beta family of cytokines. The gp130 cytokines, including interleukin-6, ciliary neurotrophic factor, leukemia inhibitory factor and cardiotrophin 1, perform a variety of significant developmental and maintenance functions in the nervous system. The second cytokine family, the TGF-beta cytokine superfamily, also have many neuroprotective and neurotrophic functions. Expression of members of both cytokine families are elevated after injury and may regulate neuronal and glial actions to promote recovery.
 
There are two main projects within the laboratory. The first investigates regulation of the neuropeptide vasoactive intestinal peptide (VIP) gene which is elevated after injury to the peripheral nervous system. Interestingly, both cytokine families induce expression of the neuropeptide, vasoactive intestinal peptide (VIP), through the same 180bp element in the VIP promoter, which we have called the cytokine response element (CyRE). We are characterizing the signaling pathways and transcription factors, activated by each cytokine family, which interact with this element, and mediate these cytokine signals. TGF-beta and CNTF synergistically activate VIP transcription through the cytokine response element. We believe that this synergistic action results from transcription factors activated by each pathway, interacting on the DNA to produce combinatorial effects. Synergism gives the cells the versatility to produce a large response to a relatively small increase in cytokine signal. Synergism between these two cytokine families may exist in the regulation of a number of biological processes.
 
The second major project in the laboratory is the investigation of the role of TGF-beta in the response of the central nervous system to traumatic injury. Viable axotomized neurons fail to regenerate because of both the poor regenerative capacity of many adult CNS neurons together with the the inhibitory environment of the CNS. The glial cells at the site of injury determine the permissiveness of the environment for axonal regrowth. Thus, in order to achieve maximal neuronal regeneration in victims of traumatic brain and spinal cord injuries, we need simultaneously to promote neuronal growth while removing the endogenous glial barriers to this growth. TGF-beta promotes deposition of extracellular matrix proteins, some of which are inhibitory to axon regrowth. We are investigating how inhibition of TGF-beta signaling contributes to deposition of components of the glial scar, after spinal cord and traumatic brain injury. Determining the molecular pathways that lead to formation of the glial scar after traumatic injury to the CNS is a critical step in our search for pharmacological interventions aimed at restoring neuronal function.

Selected Publications

Resources