George Smith, PhD

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.

Educational Background

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