# Chronic Neuromodulation of Phrenic Sympathetics to Rescue Diaphragm Function Following Cervical Spinal Cord Injury

> **NIH NIH R03** · EMORY UNIVERSITY · 2021 · $156,292

## Abstract

Abstract/Project Summary (30 lines of text)
Life expectancy of ventilator-dependent cervical spinal cord injury (cSCI) patients is significantly reduced by
respiratory complications. Despite recent advances in pulmonary medicine, including phrenic nerve stimulation
and diaphragm pacing, there are no long-term solutions for cSCI-induced ventilator dependency. This project
addresses this profound therapeutic gap by testing and developing translational principles to amplify diaphragm
contraction strength via selective neuromodulation of phrenic sympathetic innervation to reduce or eliminate
ventilator dependency. While sympathetic fibers are widely associated with vasomotor control, recent studies
provide compelling evidence that sympathetic innervations of skeletal muscles provide essential trophic support
for maintaining healthy neuromuscular junctions (NMJs) and facilitates neurotransmission. In humans and in
animals, the phrenic nerve is a conduit for sympathetic fibers innervating the diaphragm. Phrenic sympathetics
(PS) originate from extra-spinal post-ganglionic neurons and are undamaged with direct injuries to the spinal
cord. Notably, the diaphragm compared to all muscles studied, has among the richest supply of sympathetic
axonal terminals colocalizing with NMJs. This study will develop principles to translation for PS neuromodulation,
a biologically-based but untested therapeutic strategy, for enhancing or restoring diaphragm function following
cervical spinal cord injury. In Aim 1, the effects of chronic selective PS stimulation on long-term diaphragm
function and NMJ health will be studied in an optogenetic C4-5 hemocontusion cSCI mouse model with
photoexcitable PS fibers. Chronic in-vivo photostimulation of diaphragm PS fibers with blue-light will be delivered
by an implanted miniature optoelectronic device. Terminal experiments will be performed to assess diaphragm
contractile properties and phrenic-diaphragm histology to evaluate the extent to which chronic PS recruitment
can mitigate observed cSCI-induced physiological and histological changes. Aim 2 will develop a recombinant
adeno-associated virus (rAAV) gene-therapy approach using luminopsin technology to impart selective opto-
chemogenetic control over PS neuronal activity. Luminopsins are fusion proteins with a light-sensing
channelrhodopsin ionotropic channel and a light-emitting luciferase imparting two modes of neuronal control;
1) photoactivation of opsin and 2) molecular-activation of luciferase generating opsin-activating bioluminescence
light. The luminopsin approach permits photoactivation control over neuronal activity but obviates the need for
internal light source. Survival surgeries will be performed to deliver the engineered rAAV to the diaphragm via a
transabdominal approach. Terminal experiments, 2 weeks following transduction, will compare the effects of
photo- and molecular luminopsin activation on diaphragm contraction force and recruited PS activity. Histolog...

## Key facts

- **NIH application ID:** 10138207
- **Project number:** 1R03HD104276-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** NICHOLAS AU YONG
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $156,292
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10138207

## Citation

> US National Institutes of Health, RePORTER application 10138207, Chronic Neuromodulation of Phrenic Sympathetics to Rescue Diaphragm Function Following Cervical Spinal Cord Injury (1R03HD104276-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10138207. Licensed CC0.

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