# Mechanisms of axon guidance in laryngeal reinnervation following injury of the recurrent laryngeal nerve

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $603,170

## Abstract

PROJECT SUMMARY: Recurrent laryngeal nerve (RLN) injury occurs in tens of thousands of patients per
year in the United States. It results in synkinetic reinnervation inducing vocal fold paralysis and severe
dysphonia. This produces significant patient morbidity as the voice is a unique and integral part of each
person's identity, impacting virtually every aspect of our daily lives, from speaking to loved ones, to engaging in
business or simply completing daily tasks. Voice dysfunction leads to fear and isolation, as well as impaired
quality of life, disability claims and lost worker productivity similar to severe chronic diseases, resulting in a
significant societal burden. Current therapies are suboptimal and there are no treatments that can restore vocal
fold motion and normal voice. There are critical gaps in our knowledge about the molecular mechanisms
underlying axonal guidance during nerve regeneration. Our long-term goals are to identify the expression and
actions of guidance cues and to manipulate them to guide selective, non-synkinetic reinnervation of the
laryngeal muscles after RLN injury, with restoration of normal vocal fold function and normal voice.
Our previous work has revealed that in both embryologic development and post-RLN injury, laryngeal muscles
are innervated in similar sequences. Yet, post-RLN injury reinnervation is disordered, resulting in synkinesis
with vocal fold dysfunction. Our laboratory has identified Netrin-1 and GDNF as the factors most likely to play a
central role in axon guidance during RLN regeneration. We have shown that their expression in laryngeal
muscles and the expression of their receptors in the nucleus ambiguus (NA) are chronologically coordinated
with axonal reinnervation. We have demonstrated that manipulation of these guidance cues can alter the
pattern of reinnervation.
These findings suggest a controlled but dysfunctional expression of guidance cues resulting in synkinetic
reinnervation and vocal fold paralysis after RLN injury. In comparison, developmental innervation, which is
also tightly controlled chronologically, results in normal vocal fold function. Our central hypothesis is that
Netrin-1 and GDNF are critical guidance cues in laryngeal reinnervation. Further, manipulation of their
pathways post-RLN injury to mimic those seen during normal development will in result in selective, non-
synkinetic reinnervation with restoration of normal vocal fold function. Guided by strong preliminary data, we
seek to pursue the following three Specific Aims: 1) to describe the patterns of expression of GDNF, Netrin-1,
and their receptors during innervation of the larynx in development 2) to describe the pathways that modulate
the function of GDNF, Netrin-1 and their receptors during innervation in development and during reinnervation
post-RLN injury and 3) to evaluate in vitro the effects of modulating pathways in the NA and muscle. This
research will broadly impact the field of nerve regeneration, a...

## Key facts

- **NIH application ID:** 10200760
- **Project number:** 5R01DC018060-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Michael Pitman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $603,170
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200760

## Citation

> US National Institutes of Health, RePORTER application 10200760, Mechanisms of axon guidance in laryngeal reinnervation following injury of the recurrent laryngeal nerve (5R01DC018060-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10200760. Licensed CC0.

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