George Smith, PhD
Department of Neuroscience
Center for Neurovirology
Shriners Hospitals Pediatric Research Center
My laboratory is interested in the growth and guidance of axons within the adult nervous system. There are three main projects in the laboratory.
1) Gene therapy for axons regeneration and targeting:
2) Transplant targeting:
3) Peripheral nerve regeneration and guidance:
Unlike the central nervous system, the peripheral nervous system has a high capability to regenerate. This regeneration fails, however, if axons need to regenerate over large traumatic injuries. In addition, regenerating axons often become misrouted during regeneration, greatly reducing overall functional recovery. To aid regeneration across large lesion gaps and correct misrouting we are 1) developing biodegradable scaffolds to improve nerve repair, and 2) expressing guidance molecules at nerve branch point to aid pathway selection of sensory and motor axons. For the first set of experiments, we have engineered biodegradable microfilaments and linear foams that support cell attachment, direct migration and will allow the slow release of drugs to further improve repair mechanisms. These materials are presently being explored to investigate nerve and spinal cord repair. In the second series of experiments, we are using viral vectors to express developmentally important molecules that influence sensory or motor axons guidance in Schwann cells at branch points caudal to the lesion site. Initial experiments are examining general segregation of sensory and motor axons, with future experiments to examine further segregation of sensory and motor subpopulations.
Tanelian, D.L., M.A. Berry, S.A. Johnston, T. Le, and G.M. Smith (1997) In vivo repulsion and inhibition of a-delta and c-fiber sensory afferents after expression of semiphorin III. Nature Medicine 3:1398-1401.
Smith, G.M. and J. Hale (1997) Macrophage/microglia regulation of astrocytic tenascin: synergistic action of transforming growth factor-beta and basic-fibroblast growth factor. J. Neurosci. 17:9624-9633.
Romero M.I. and G.M. Smith (1998) Adenoviral gene transfer into the normal and injured spinal cord: enhanced transgene stability by combined administration of temperature-sensitive virus and transient immune blockade. Gene Therapy 5:1612-1621.
Romero M.I., N. Rangappa, L. Li, E. Lightfoot, M.G. Garry, G.M. Smith. (2000) Extensive sprouting of sensory afferents and hyperalgesia induced by conditional expression of NGF in the adult spinal cord. J. Neurosci. 20:4435-4445.
Rangappa, N., A. Romero, K. Nelson, R. Eberhart, and G.M. Smith. (2000) Laminin coated poly-l-lactide filaments support robust axon growth while providing directional orientation. J. Biomed. Mater. Res. 51:625-634.
Roy S., Coffee P., Smith, G.M., Brady, S.T., and Black M.M. (2000) Neurofilaments are transported rapidly but intermittently in axons: implications for slow axonal transport. J. Neurosci. 20:6849-6861.
Romero M.I., N. Rangappa, M.G. Garry, G.M. Smith. (2001) Functional regeneration of chronically-injured sensory afferents into adult spinal cord following neurotrophin gene therapy. J. Neurosci. 21:8408-8416.
Tang X.Q., D.L. Tanelian, and G.M. Smith. (2004) Semaphorin3A inhibits nerve growth factor-induced sprouting of nociceptive afferents in adult rat spinal cord. J. Neurosci. 24:817-827.
Tang X.Q., J. Cai, K.D. Nelson, X.J. Peng, and G.M. Smith (2004) Functional repair of dorsal root injury by guidance conduits and neurotrophin. Eur. J. Neurosci. 20:1211-1218.
Smith G.M. and C. Strunz (2005) Growth Factor and Cytokine Regulation of Chondroitin Sulfate Proteoglycans by Astrocytes. Glia 52:209-218.
Cai J., Peng X., Nelson K.D., Eberhart R., G. M. Smith. (2005) Permeable guidance channels containing microfilament scaffolds enhance axon growth and maturation. J Biomed Mater Res A. 75:374-386.
Cameron A.A., G.M. Smith, D.C. Randall, D. Brown, A.G. Rabchevsky (2006) Genetic manipulation of intraspinal plasticity after spinal cord injury alters the severity of autonomic dysreflexia. J. Neurosci. 26:2923-32.
Nakamura T.Y., A. Jeromin, G.M. Smith, H. Kurushima, H. Koga, Y. Nakabeppu, S. Wakabayashi, J. Nabekura. (2006) Novel role of neuronal Ca2+ sensor-1 as a survival factor up-regulated in injured neurons. J Cell Biol. 172:1081-91.
Chaudhry N, de Silva U, Smith GM. (2007) Cell adhesion molecule L1 modulates nerve-growth-factor-induced CGRP-IR fiber sprouting. Exp Neurol. 202:238-249.
Curinga GM, Snow DM, Mashburn C, Kohler K, Thobaben R, Caggiano AO, and Smith GM. (2007) Mammalian produced chondroitinase AC mitigates axon inhibition by chondroitin sulfate proteoglycans. J. Neurochem. 102:275-288.
Tang XQ, Heron P, Mashburn C, Smith GM (2007) Targeting sensory axon regeneration in adult spinal cord. J. Neurosci. 27:6068-6078.
Silva, AS, Fairless R, Frame MC, Montague P, Smith GM, Toft A, Riddell JS, Barnett SC. (2007) FGF/heparin differentially regulates Schwann cell and olfactory ensheathing cell interactions with astrocytes; a role in astrocytosis. J. Neurosci. 27:7154-7167.
Ziemba K.S., Chaudhry N., Jin Y., Rabchevsky A.G. and Smith G.M. (2008) Targeting axon growth from neuronal transplants in the adult central nervous system along preformed guidance pathways. J. Neurosci.;28 340-348
Jin, Y., Ziemba, K.S., and Smith G.M. (2008) Axon growth across a lesion site along a preformed guidance pathway in the brain. Exper. Neurol. 210:521-530