# Enhancing Forelimb Recovery by Promoting Forelimb Corticospinal Tract Regeneration after Spinal Cord Injury

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2024 · —

## Abstract

The corticospinal tract (CST) is the most important voluntary motor control system in humans.
Spinal cord injury (SCI) irreversibly damages the CST, which leads to loss of voluntary motor
control below the injury, including hand function that is critical for independent daily life for
quadriplegia. Recently we have made great progress in achieving substantial CST regeneration
after SCI using spinal cord neural stem cell or progenitor cell grafts. However, an expected and
important finding recently emerged from our RR&D-funded studies: only hindlimb CST axons
regenerate into grafts placed into sites of cervical SCI; forelimb CST axons rarely regenerate.
These findings raise the hypothesis that enhancing regeneration of forelimb CST axons will
significantly improve functional outcomes after SCI when combined with neural stem cell grafts.
In the renewal of this grant, we propose to elucidate mechanisms underlying the poor
regenerative capacity of the forelimb CST and to test experimental approaches for enhancing
forelimb CST regeneration that we hypothesize will further improve forelimb functional recovery
after SCI. Specific Aim 1: Use RNA Sequencing to identify molecular mechanisms associated
with differences in forelimb-CST and hindlimb-CST axonal regeneration in rats. Understanding
mechanisms why forelimb CST does not regenerate is important to help us designing
experiments to enhance forelimb CST regeneration. Specific Aim 2: Determine whether
transient blockade of forelimb CST synaptic activity enables forelimb CST regeneration. Our
recently study showed that forelimb CST axon is highly collateralized in the brain, but hindlimb
CST does not. We hypothesize that these extensive collaterals and their synaptic connections
of forelimb CST limit their regeneration. Recent studies support this hypothesis since deletion
or suppression of Cacna2d2 gene that involve in synaptic activity promotes axon regeneration.
Specific Aim 3: Explore whether PTEN/SOCS3 deletion or suppression will increase forelimb
CST regeneration and skilled forelimb function recovery. In the previous period of this RR&D
grant we found that PTEN/SOCS3 conditional deletion significantly increased overall CST
regeneration into a stem cell graft after SCI, but we did not separately label forelimb and
hindlimb CST axons. We will determine whether PTEN/SOCS3 genetic deletion or suppression
by antisense oligonucleotide therapy specifically enhances forelimb CST regeneration as an
alternative mechanism.
All studies proposed are supported by preliminary feasibility data and can be conducted by the
PI and his collaborators who have extensive experience in SCI research field. Positive findings
of this work will substantially enhance our knowledge of central nervous system regeneration
mechanisms, and identify paths forward to developing treatments for human SCI.

## Key facts

- **NIH application ID:** 10782977
- **Project number:** 5I01RX003776-02
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Pengzhe Lu
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-11-01 → 2026-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10782977

## Citation

> US National Institutes of Health, RePORTER application 10782977, Enhancing Forelimb Recovery by Promoting Forelimb Corticospinal Tract Regeneration after Spinal Cord Injury (5I01RX003776-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10782977. Licensed CC0.

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