# Manipulating NeuroD1 expression by MicroRNAs to Optimize Neuronal Conversion for Spinal Cord Injury Repair

> **NIH NIH R21** · AUGUSTA UNIVERSITY · 2022 · $192,500

## Abstract

Project Summary:
Spinal cord injury (SCI) represents a devastating central nervous system (CNS) injury that impairs mobility and
sensory function of afflicted patients. A significant challenge in treating SCI is to replenish the neurons lost during
the pathological process. In vivo reprogramming is a recently developed technology and represents a major
breakthrough in regenerative medicine. This innovative technology literally converts endogenous glial cells into
functional neurons for repair purposes. In vivo reprogramming reactive astrocytes into functional neurons has
been successfully demonstrated in several reports including one from the PI’s lab by using a single transcription
factor, NeuroD1, in the injured brain (Guo et al, 2014, Cell Stem Cell). The PI’s ongoing research programs is to
determine if this in vivo reprogramming technology can regenerate functional neurons in the injured spinal cord.
Their preliminary results have already shown that NeuroD1 can efficiently convert reactive astrocytes into new
neurons in the spinal cord. However, the neurons converted by highly and continuously expressed NeuroD1 are
almost exclusively of the glutamatergic (i.e. excitatory) neuronal subtype, which is consistent with the fact that
NeuroD1 is a glutamatergic neuron-lineage determination factor during development. In reality, both excitatory
and inhibitory neurons would be needed to rebuild optimal neuronal circuitry for functional repair. The PI believes
that high level of NeuroD1 in newly converted neurons drive them into the glutamatergic subtype, and reason
that they can generate inhibitory neurons using NeuroD1 by modulating NeuroD1 expression level during the
neuronal conversion process. Toward that, they have engineered a new NeuroD1-expression viral construct that
contains a microRNA (miRNA)-responsive element. In particular, they have inserted a tandem repeat of miR-
124 (a neuronal miRNA) target sequence at the 3’-end of the NeuroD1-coding sequence (ND1-124T), so that
NeuroD1 expression can be regulated by the inhibitory mechanism of miR-124. Thus, we can achieve a high
level of NeuroD1 expression in astrocytes (low in miR-124) for neuronal reprogramming to occur, and a much
reduced level of NeuroD1 in converted neurons (high in miR-124) thereby allowing generation of inhibitory
neuronal subtypes. In this proposal, the PI will determine the efficiency of neuronal conversion by ND1-124T in
the injured spinal cord. More importantly, they will determine the specific subtypes of the converted neurons and
whether such conversion improves functional recovery after SCI. Their central hypothesis is that controlled
NeuroD1 expression during neuronal conversion is beneficial in generating diversified neuronal subtypes and
improving animal’s behavioral outcomes after SCI. The PI proposes two specific aims: 1) To determine neuronal
conversion efficiency of ND1-124T and neuronal subtypes of converted neurons in the injured spinal cord; 2) To
determi...

## Key facts

- **NIH application ID:** 10358514
- **Project number:** 5R21NS119732-02
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** HEDONG LI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $192,500
- **Award type:** 5
- **Project period:** 2021-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10358514

## Citation

> US National Institutes of Health, RePORTER application 10358514, Manipulating NeuroD1 expression by MicroRNAs to Optimize Neuronal Conversion for Spinal Cord Injury Repair (5R21NS119732-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10358514. Licensed CC0.

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