Grants and Contracts Details
Description
Abstract
Recent advances in spinal cord injury (SCI) medicine have revealed the potential for neuromodulation to
target spared spinal tracts to elicit a restoration of function in chronic stages of SCI. Leveraging growth
and intrinsic properties of spared axons can therefore be an effective approach to recover function in
chronic SCI. Our group has optimized the use of retrogradely transported AAVs (AAVrg) to target spared
axons in chronic SCI and demonstrated that augmenting the mTOR pathway via PTEN-knockout using
AAVrg''s can improve locomotor abilities in mice with chronic injuries. Several outstanding questions
remain regarding the mechanisms and long-term effects of sustained mTOR pathway hyperactivity in
neurons including: 1) are locomotor improvements contingent upon sustained hyperactivity in the mTOR
pathway (i.e. do locomotor improvements manifest from changes to intrinsic properties that would
reverse upon removal of mTOR pathway stimulation, or are they a manifestation of structural axon
growth); and 2) what are the long-term effects of sustained mTOR pathway hyperactivity on neuronal
health and metabolism? To address these outstanding questions, we have developed an AKT InducibleVector-
Expression system (AKTIVE) to temporally control the intensity and duration of mTOR pathway
hyperactivity. We will use our AKTIVE system to toggle on/off increased activity in the mTOR pathway by
expressing a constitutively active AKT (myrAKT) in a doxycycline-inducible manner in spared spinal tracts
and determine the effects on locomotor recovery, axon growth and sprouting, as well as elucidate the
effects of sustained vs transient myrAKT expression on neuronal health and metabolism. We hypothesize
that a transient expression of myrAKT will result in sustained locomotor improvements, increased axon
growth below the lesion, and that limiting the expression of myrAKT to a few weeks will restore normal
metrics of metabolism in neurons (autophagy, mitophagy, and mitochondrial function) relative to
permanent and sustained myrAKT expression. Results from our experiment will provide invaluable
insights into the role of the mTOR pathway in ongoing neuronal functions in chronic SCI, as well as
demonstrate the ability for transient AKT hyperactivity to affect locomotor abilities through spared axon
tracts. Further, we will have demonstrated the safety and feasibility of combining inducible gene-therapy
approaches for use in chronic SCI in a manner applicable to any mammalian species. Our collective
efforts will set the foundations for future studies aimed at testing and optimizing our AKTIVE genetherapy
approach in larger animal models.
Status | Active |
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Effective start/end date | 2/1/24 → 1/31/27 |
Funding
- KY Spinal Cord and Head Injury Research Trust: $200,000.00
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