Activation of mTor Signaling by Gene Transduction to Induce Axon Regeneration in the Central Nervous System Following Neural Injury
Final rept. 21 Feb 2013-20 Feb 2014
COLUMBIA UNIV NEW YORK MEDICAL CENTER
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A longstanding concept in neuroscience has been that the mature mammalian brain is incapable of axon regeneration. However, we have shown that it is possible to achieve long range axon growth by re-activation of intrinsic genetic programs that are active during development. We have found that activation of AktmTor signaling by AAV-mediated transduction with either the kinase Akt or the GTPase Rheb in a model of retrograde axonal degeneration induces axon growth by dopamine neurons. However, these molecules cannot be directly used in therapeutics because they are oncogenes. The goal of this proposal therefore is to develop a strategy to circumvent this problem. We have hypothesized that mediators downstream of mTor may diverge in their effects, making it possible to achieve axon growth without oncogenic risk. In Year 01 we had shown that one mTor target, p70S6K, is able to induce new axon growth. In Year 02 we have assessed the ability of a second mTor target, eIF4E, to induce new axon growth. We have found that transduction of dopamine neurons of the SN by AAV eIF4E at three weeks after axonal destruction with the neurotoxin 6OHDA does not induce new axon growth. This conclusion was reached by assessments based on three techniques immunostaining for tyrosine hydroxylase-positive axons in the medial forebrain bundle MFB quantification by confocal optical dissection of either GFP-positive axons in the MFB in transgenic THGFP mice or of Tomato-positive axons following transduction with anterograde tracer Tomato-Tau. As anticipated, based on anatomical evidence showing an inability of AAV eIF4E to re-establish anatomical contact, we found no reversal of a toxininduced behavioral deficit. We conclude that of the two mTor targets, p70S6K and eIF4E, only p70S6K is an effective mediator of new axon growth. It will therefore be the focus of a refined, axon-targeting strategy in Year 03 of this proposal.
- Anatomy and Physiology
- Medicine and Medical Research