# Wnt5a, a New Diabetic Corneal Marker Related to Wound Healing

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2023 · $417,477

## Abstract

Diabetes is the most widespread blinding disease in working-age adults. Up to 70% of diabetic patients suffer
from corneal problems including neuropathy and epithelial keratopathy (impaired wound healing, ulcers,
recurrent erosions) that impair vision and cause pain and discomfort. Diabetic keratopathy is underdiagnosed,
and therapy remains symptomatic. We previously identified markers altered in human diabetic corneas and
normalized their levels in human corneal organ cultures by gene and nano therapy, which also restored normal
stem cell phenotype and corneal wound healing. Epigenetic changes may contribute to diabetic complications.
Therefore, we examined epigenetic DNA methylation in human diabetic corneas and found a set of genes
abnormally methylated vs. normal corneas. WNT5A gene, a noncanonical member of Wnt regulators of cell
motility, proliferation and differentiation, was hypermethylated in diabetic corneas. Its expression was reduced in
diabetic corneas and stem cell-enriched epithelial cultures. Wnt5a addition accelerated wound healing in
diabetic (but not in normal cells), with stem cell marker expression increase. Inhibition of diabetes-increased
miRNA-203a targeting WNT5A increased Wnt5a and wound healing in diabetic cells. miRNA-203a inhibitor and
WNT5A siRNA reduced wound healing in normal cells. We will identify mechanisms of action of new diabetic
marker Wnt5a, its effects on diabetic corneal cell populations, and normalize its levels in diabetic corneal cells.
We hypothesize that normalization of diabetes-impaired stem cell phenotype and epithelial wound
healing may be achieved by restoring normal expression of noncanonical Wnt5a by blocking its
inhibiting microRNA with a novel nanoconjugate and using demethylating agents.
Specific Aim 1. To identify Wnt5a receptor(s) mediating its effects on diabetic epithelial cells and corneas. Wnt5a
receptors in diabetic limbal cells and corneas will be identified by imaging and functionally, by siRNAs, focusing
first on ROR2. This will allow modulating their expression and signaling in diabetic cells to boost Wnt5a effects.
Specific Aim 2. To examine Wnt5a effects on epithelial wound healing and limbal cell populations in human
organ-cultured diabetic corneas. In these corneas, we will confirm normalizing Wnt5a effects using wound
healing and stem cell marker expression. Changes in limbal epithelial differentiated and stem cell populations
upon Wnt5a (or inhibitors) treatment will be examined by single cell RNA-seq vs. control normal cells.
Specific Aim 3. To test the efficacy of therapies aimed at increasing Wnt5a expression using cultured diabetic
cells and organ-cultured corneas. Diabetic limbal epithelial cells and corneas will be treated with nanoconjugate
with miR-203a specific antagonist and/or with demethylating 5-Aza-2′-deoxycytidine (Decitabine) or Zebularine.
Our aims fit well the priorities set in the NEI Vision Research: Needs, Gaps, and Opportunities. These
priorities inclu...

## Key facts

- **NIH application ID:** 10682429
- **Project number:** 5R01EY031377-04
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Alexander V Ljubimov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $417,477
- **Award type:** 5
- **Project period:** 2020-09-30 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10682429

## Citation

> US National Institutes of Health, RePORTER application 10682429, Wnt5a, a New Diabetic Corneal Marker Related to Wound Healing (5R01EY031377-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10682429. Licensed CC0.

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