An Inducible Receptor Tyrosine Kinase for Axonal Regeneration
Armin Blesch, Ph.D., UCSD
Associate Professor, Department of Neurosciences, Center for Neural Repair

In the proposed studies we are planning to determine whether the inducible activation of a novel hybrid trk receptor (i-trk) can prevent neuronal atrophy and enhance axonal regeneration after spinal cord injury. In preliminary studies, we have constructed and characterized viral vectors for an inducible tyrosine kinase receptor (i-trk) that can be activated by a small cell-permeable dimerizing molecule, AP20187. This chimeric trk receptor consists of 1) a trkA intracellular domain 2) an amino-terminal myristoylation signal and 3) two tandem FK506 binding domains. Our data demonstrate that i-trk activation can mimic neurotrophin signaling in a dose and time-dependent fashion. We will now test the hypothesis that the activation of this inducible trk in injured, virus-transduced neurons can mimic neurotrophin signaling and
thereby prevent neuronal atrophy and enhance axonal growth in vivo. We will test our hypothesis with 2 different neuronal populations (corticospinal neurons and dorsal root ganglion neurons) in adult rats: First, we will determine whether inducible tyrosine kinase receptor (i-trk) AAV gene transfer and receptor activation can prevent lesion-induced cell death and atrophy of corticospinal neurons. Second, we will investigate whether regulated i-trk activation can enhance axonal growth and guide regenerating dorsal column sensory axons across lesions in the injured spinal cord. Taken together, the proposed experiments will develop a practical means of transient tyrosine receptor kinase signaling in specific subsets of neurons without affecting non-targeted CNS structures, to enhance the intrinsic growth capacity of injured neurons.

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