# Mechanisms Governing Nerve-Mediated Control of Corneal Wound Healing: New Hope for Patients with Neurotrophic Keratopathy

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $581,295

## Abstract

PROJECT SUMMARY:
Overview: The molecular mechanisms by which corneal nerves regulate limbal stem cells (LSCs), required for
corneal epithelial maintenance and wound healing, and ultimately critical for vision, are unknown. When corneal
nerves are impaired or absent, patients develop nonhealing corneal wounds that lead to permanent blindness,
a condition known as neurotrophic keratopathy (NK). Our objective is to determine the mechanisms by which
corneal nerves govern epithelial renewal. In this research proposal we plan to define key cellular and molecular
regulators of LSCs that will broaden our knowledge of stem cell biology and will enable development of topical
therapeutics for patients with NK. The central hypothesis is that corneal Schwann cells (SCs) are key trophic
regulators of LSC, that, in turn, regulate ocular surface health.
Preliminary studies: In our reported preliminary studies, we combined surgical manipulations, single cell
expression analysis (scRNA-seq) and locally-induced selective cell ablation to identify candidate molecular
mechanisms. We observed that corneal nerve-associated SCs appear to serve as “paracrine factories,”
producing multiple secreted proteins that support corneal epithelial maintenance.
Innovation: To unequivocally determine the mechanisms governing the interactions between SCs and LSCs,
we developed a set of comprehensive approaches using dynamic tracking of corneal cell populations. We
developed a unique NK animal model in which we rescued corneal clarity by surgically introducing a distinct
population of donor nerve cells into denervated corneas, enabling us to probe the role and chronicity of corneal
innervation in epithelial renewal. To track changes in the cells populating the LSC niche, we performed scRNA-
seq analyses comparing healthy, denervated, and de-epithelialized corneas. We observed that SCs regulate
innervation-depended corneal epithelial renewal, forming the basis for a new conceptual model of paracrine
interactions between SCs and LSCs. Based on these preliminary studies, we will (i) define the extent to which
SCs trophically regulate LSC activity, (ii) validate the computationally-predicted library of candidate paracrine
interactions and, among those, define the particular SC-derived trophic factors that directly regulate LSC activity,
and (iii) develop novel comprehensive topical therapeutic strategies to treat patients with NK, for which our
institution has filed a US Patent application.
Impact and Significance: We anticipate that the studies in this proposal will define the mechanisms by which
corneal nerves regulate LSC activity during corneal epithelial wound healing and maintenance. NK, a leading
cause of corneal blindness in Americans, has historically defied definitive treatment. The mechanistic insights
gained will be leveraged clinically in the development of novel, effective topical therapeutics for NK.

## Key facts

- **NIH application ID:** 10860087
- **Project number:** 1R01EY036047-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Gregory Howard Borschel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $581,295
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10860087

## Citation

> US National Institutes of Health, RePORTER application 10860087, Mechanisms Governing Nerve-Mediated Control of Corneal Wound Healing: New Hope for Patients with Neurotrophic Keratopathy (1R01EY036047-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10860087. Licensed CC0.

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