Research Interests

My laboratory is interested in the growth and guidance of axons within the adult nervous system. There are two main projects in the laboratory.

1) Gene therapy for axons regeneration and targeting:
To use genetic therapy tools to enhance the growth promoting properties of 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. To this end, we have recently developed new genetic axon tract tracer to identify post-synaptic targets onto which regenerating axons connect. We have also begun examining neurotrophin-signaling pathways (mTor and bRaf) to enhance the regeneration of other sensory axon populations. To date we can induce very good regeneration of nociceptive pathways and we have generated constructs to other neurotrophins (GDNF, Artemin, NT3).

2) Constructing motor relays to enhance functional return after spinal cord injury:
The prospect of inducing regeneration of adult supraspinal axons across the lesion, particularly corticospinal tract axons, has proven very difficult. However, one mechanism of endogenous repair requires the formation of relays between cut supraspinal axons and propriospinal axons that bypass the lesion to induce some functional recovery. Indeed, neurons within transplants of either fetal spinal cord tissue or neural progenitor cells can form relays with lesioned axons and induce good functional return, with some of the best recovery occurring after using a combination of fetal spinal cord grafts and neurotrophins. We propose to establish a motor nucleus-like relay at the injury site using a neural stem cell graft. We hypothesis that refining the connections entering the relay, while directing and targeting axons from relay neurons will greatly improve motor outcomes. 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 mostly 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 will construct molecular highways in the spinal cord to target CST axons to the motor relay transplant. The relay neurons will then be directed along a different molecular pathway to downstream spinal motor neuron areas.

Education, Training & Credentials

• PhD, Neuroscience, Case Western Reserve University, Cleveland, OH, 1987
• BA, BS, Psychology, Chemistry, Lewis University, Romeoville, IL, 1983

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

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

Zhang L, Ma Z, Smith GM, Wen X, Pressman Y, Wood PM, Xu XM. (2009) GDNF-enhanced axonal regeneration and myelination following spinal cord injury is mediated by primary effects on neurons. Glia. 57:1178-91

Yurek DM, Fletcher AM, Smith GM, Seroogy KB, Molter J, Kowalczyk TH, Padegimas L, Cooper MJ, (2009) Long-term Transgene Expression in the Central Nervous System using DNA Nanoparticles. Molecular Therapy Mol Ther.17:641-650

Rao R, Mashburn CB, Mao J, Wadhwa N, Smith GM, Desai NS. (2009) Brain-derived neurotrophic factor (BDNF) in infants < 32 weeks gestational age: Correlation with antenatal factors and postnatal outcomes. Pediatr Res. 65:548-552

Hu X, Cai J, Yang J, Smith GM. (2010) Sensory axon targeting is increased by NGF gene therapy within the lesioned adult femoral nerve. Exp Neurol. 223:153-65