# Mechanisms of Regeneration:  Facial Nerve Injury and Repair

> **NIH NIH K08** · STANFORD UNIVERSITY · 2020 · $166,536

## Abstract

Project Summary/Abstract
This proposal presents a five-year research career development program focused on the study of Hedgehog
(Hh) pathway signaling in facial nerve injury response. The candidate is currently an Assistant Professor of
Otolaryngology at the Stanford School of Medicine. The outlined proposal builds on the candidate’s previous
research and clinical experience under the supervision of a world-renowned expert in Hh pathway signaling,
Dr. Phil Beachy. The proposed experiments and didactic work will position the candidate with a unique set of
skills that will enable his transition to independence as a physician scientist in the mechanisms of nerve injury
response and nerve fibrosis.
Facial paralysis results in significant disability for affected patients, impacting both facial function and overall
quality of life. For patients with permanent paralysis, surgery is the most effective treatment to improve facial
symmetry and – in some cases – restore partial movement. However, existing treatments do not completely
restore normal facial movement. Clinically, the injured facial nerve becomes fibrotic, which can impede
recovery and treatment. Despite the clinical importance of this, the mechanism underlying nerve fibrosis is
poorly understood. Given the critical role of the hedgehog pathway in perineurial development, we explored the
function of hedgehog-responsive elements in the murine facial nerve after injury. We first verified the presence
of hedgehog-responsive fibroblasts (Gli1+) within the murine facial nerve. Gli1+ fibroblasts within the facial
nerve expand impressively after injury and compose the majority of the perineurium of the regenerating nerve.
These cells closely associate with activated Schwann cells and regenerating axons and appear to promote
angiogenesis in the first two weeks after injury. By 10 weeks after injury, however, Gli1+ fibroblasts appear to
form fibrotic tissue within the nerve. Following on these findings, we hypothesize that Hh signaling promotes
early nerve regeneration after injury but transitions to a pro-fibrotic state at later time points after injury. To
assess these hypotheses, we propose the following aims: 1) Characterize the role of Hh signaling after facial
nerve injury using powerful genetic and pharmacologic models, 2) Describe changes in Gli1+ cells during facial
nerve regeneration and fibrosis via Next Generation Sequencing. Completion of the research in this proposal
will enable a thorough dissection of the role of Hh signaling in facial nerve injury, vet this pathway as a
mediator of both regeneration and fibrosis after injury, and reveal new therapeutic targets for clinical use.

## Key facts

- **NIH application ID:** 10013199
- **Project number:** 5K08DE028364-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Jon-Paul Pepper
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $166,536
- **Award type:** 5
- **Project period:** 2019-09-09 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10013199

## Citation

> US National Institutes of Health, RePORTER application 10013199, Mechanisms of Regeneration:  Facial Nerve Injury and Repair (5K08DE028364-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10013199. Licensed CC0.

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