SCoBIRC FACULTY

George M. Smith, Ph.D.

Professor, Department of Physiology

Ph.D. in Department of Genetics & Anatomy at Case Western Reserve University, 1987.

Dr. Smith and his lab

Research Interests

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:
To use genetic therapy tools to recapitulate the developmental growth program in the injured adult nervous system. During development of the brain and spinal cord, molecular cues support axonal growth and guidance to establish the complex circuitry of the central nervous system (CNS). In the adult spinal cord growth cues are lost and the environment in the injured CNS becomes "non-permissive" to regeneration. In order to provide lesioned axons with a growth supportive pathway, we are using recombinant virus to induce expression of neurotrophic factors and guidance molecules at the injury site. Using this technology, we have successfully induced a subpopulation of sensory axons to regenerate into the spinal cord. This regeneration was extremely robust, and it resulted in recovery of thermal sensation in these animals. However, using neurotrophins alone, these axons failed to re-establish their laminar specific connections. By generating overlapping gradients of neurotrophins and a chemorepulsive molecule (semaphorin 3A), we have been able to target regenerating axons and significantly increase their laminar specific synaptic terminals. Present studies are focused on examining specificity of postsynaptic neuronal connections and appropriate second order circuit reformation.

2) Transplant targeting:
To guide or control the growth of these axons from a neuronal transplant to a specific distant target location. With the increase in transplant technology and the advent of differentiating stems cells into specific neuronal population the need to direct the growth of axons to discrete synaptic targets is becoming apparent. Presently, axonal growth out of neuronal transplants is highly limited to the region adjacent the donor tissue, and axonal outgrowth occurs in random patterns. Such methods are primarily used to augment the function of surviving neural circuits after degeneration or injury. By establishing preformed guidance pathways we can construct "highways" in the brain or spinal cord that direct the growth of axons. We have established pathways that not only direct axons to growth within white matter tracts, but also to make precise turns and leave those tracts to enter a designated target location. We are presently using this method to guide axons from transplants after spinal cord injury and in a rat Parkinson's disease model.

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 segregation of sensory and motor axons, with future experiments to examine further segregation of sensory and motor subpopulations.

Select Publications

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.

Curinga GM and Smith GM. (2007) Molecular/genetic manipulation of extrinsic axon guidance factors for CNS repair and regeneration. Exper Neurol. (in press).

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.