# New models, new approaches, new horizons in corneal nerve regeneration

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $505,273

## Abstract

PROJECT SUMMARY/ABSTRACT
The cornea is the most highly innervated structure in the body, supplied by the ophthalmic branch of the
trigeminal nerve. As part of the peripheral nervous system, corneal nerves respond to pain, temperature,
mechanical and chemical stimuli. They also secrete various trophic and growth factors, which are essential to
the health and function of the cornea. However, corneal nerves are highly susceptible to injury through various
mechanisms that include trauma, infections, metabolic imbalances, and therapeutic interventions such as
refractive surgeries. Once injured, they fail to reestablish their baseline density or morphology, contributing to
corneal dysfunction. Currently, there are no targeted treatments specific for corneal nerve regeneration. The
long-term goal of this proposal is to develop therapies for corneal nerve regeneration. The objective is to
determine key molecular mechanisms involved in corneal nerve regeneration to help inform new experimental
and therapeutic interventions. The central hypothesis is the N-Methyl-D-aspartate receptors (NMDAR), a type of
glutamate receptor, help restore corneal nerve density and morphology, and therefore, corneal function. The
rationale underlying this proposal is that NMDARs have been shown to enhance nerve regeneration in other
analogous peripheral nervous systems. However, their role in corneal nerve regeneration remains unknown.
Additional justification for investigating the role of NMDARs in corneal nerve regeneration is based on other
published findings: 1) NMDARs are expressed throughout the nervous system, including the trigeminal nerves;
2) they have been shown to regulate neuronal maintenance and plasticity; 3) they regulate Schwann cell activity,
which are supporting cells essential to nerve regeneration; and 4) NMDARs cooperate with other signaling
molecules that have been shown to regulate corneal nerve regeneration such as LDL-receptor-related protein-1
and Ephrin type-B receptor 2. Therefore, we propose three aims to support our hypothesis. AIM 1 will determine
the role of NMDAR in corneal nerve maintenance and regeneration by conditionally deleting NMDAR in sensory
nerves and Schwann cells independently. AIM 2 will determine the effect of modulating NMDAR levels on corneal
nerve regeneration. AIM 3 will determine key downstream effectors, including the EphB2-Sox2 axis, with spatial
transcriptomics, correlated with protein levels and morphologic changes during corneal nerve regeneration. We
will pursue these aims using innovative genetic mouse models, intravital imaging, and spatial genomics. The
proposed aims are significant because they will define new molecular pathways that will inform the development
of future therapies. The immediate expected outcome of this work is rigorous interrogation of key pathways in
corneal nerve regeneration in vivo and contribution to our fundamental understanding of peripheral nerve
regeneration. The results will have an impo...

## Key facts

- **NIH application ID:** 10795019
- **Project number:** 5R01EY033291-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Vivian Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $505,273
- **Award type:** 5
- **Project period:** 2022-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10795019

## Citation

> US National Institutes of Health, RePORTER application 10795019, New models, new approaches, new horizons in corneal nerve regeneration (5R01EY033291-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10795019. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*