# Promoting targeted reinnervation of phrenic motor neurons and restoration of respiratory function using cell-specific expression of BDNF after cervical spinal cord injury

> **NIH NIH F30** · THOMAS JEFFERSON UNIVERSITY · 2020 · $50,520

## Abstract

PROJECT SUMMARY
We are testing a novel strategy to regenerate damaged descending bulbospinal respiratory axons and
reinnervate phrenic motor neurons (PhMN) after cervical spinal cord injury (SCI) in rats. SCI is caused by trauma
to the spinal cord, and more than half of all cases occur in the cervical region, leading to breathing compromise
by damaging circuits involved in respiratory control. Restoration of functional deficits caused by SCI is limited
due to the low intrinsic drive of neurons to regenerate axons and a lack of guidance cues to signal growing axons
to appropriate targets, among others. The C3-C5 mid-cervical spinal cord levels house the PhMNs, which are
responsible for diaphragm activation. PhMNs are predominately mono-synaptically innervated by supraspinal
respiratory neurons located in a brainstem nucleus called the rostral Ventral Respiratory Group (rVRG). We are
seeking to reverse respiratory dysfunction after SCI by restoring the crucial circuit controlling PhMNs, and thus
diaphragm activation. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of growth
factors, promotes axonal growth and acts as a guidance cue. Phosphatase and tensin homolog (PTEN) is a
negative regulator of mammalian target of rapamycin (mTOR), which is responsible for pro-growth pathways
including axon growth. Downregulation of PTEN has been shown to induce axon regeneration. We aim to
promote targeted reinnervation of PhMNs and restore diaphragm function by systemically inhibiting PTEN with
antagonist peptides to induce axon growth through the injury, followed by BDNF overexpression selectively in
PhMNs via an adeno-associated virus (AAV) to direct growing axons. In Aim 1, we will determine whether
providing a PhMN-specific source of the axon guidance molecule, BDNF, promotes targeted PhMN reinnervation
by rVRG axons following cervical SCI. We will assess rVRG axons using an AAV vector expressing a dual
anterograde/trans-synaptic tracer, examining regrowth and collateral sprouting, and identify synaptic
reconnection with spared PhMNs by post-synaptic accumulation of the trans-synaptic marker. In Aim 2, we will
determine whether rVRG-PhMN circuit re-connectivity promotes diaphragmatic recovery after cervical SCI. We
will assess the ability of rVRG-PhMN reconnection to restore diaphragm function by testing in vivo diaphragm
activation via electromyography (EMG). Excitingly, we can distinguish between modes of recovery, i.e. ipsilateral
regrowth versus contralateral sprouting, by selectively silencing unilateral rVRG neurons with inhibitory Designer
Receptor Exclusively Activated by Designer Drugs (DREADDs) and recording any subsequent changes in
EMGs. BDNF overexpression is associated with neuropathic pain and abnormal motor function. We will test for
unintended consequences of BDNF, including pain phenotypes and motor gains/deficits. We aim to use the
strategy proposed here to reconnect motor neurons responsible for diaphragm ac...

## Key facts

- **NIH application ID:** 9917847
- **Project number:** 5F30NS103436-03
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Brittany Charsar
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2018-05-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9917847

## Citation

> US National Institutes of Health, RePORTER application 9917847, Promoting targeted reinnervation of phrenic motor neurons and restoration of respiratory function using cell-specific expression of BDNF after cervical spinal cord injury (5F30NS103436-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9917847. Licensed CC0.

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