# Effects of systemic disease on corneal epithelial pathophysiology

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $492,956

## Abstract

PROJECT SUMMARY
Corneal complications from diabetes are common, often very painful, can negatively impact quality of life, and
lead to permanent visual impairment. Owing to the vast array of molecular pathways that are altered in the
diabetic cornea, traditional therapies are often not sufficient, due to abnormal cellular responses and the loss of
trophic support from corneal nerves.
Our prior studies have shown that the insulin-like growth factor (IGF) system is altered in diabetes. This
includes a significant increase in the pleiotropic secretory protein, IGF-binding protein-3 (IGFBP-3) in diabetic
human tears that correlates with loss of the corneal subbasal nerve plexus. While corneal epithelial cells do not
require insulin for glucose uptake, our laboratory has found instead that insulin has an essential role in
mediating expression of the IGF type 1 receptor (IGF-1R), insulin receptor (INSR), and IGFBP-3. Further
interrogation of these pathways led to the generation of novel and exciting findings in corneal epithelial cells
(CECs) that form the basis for the current proposal. Of high relevance to this proposal, all of our findings
implicate the IGF-1 system as a mediator of mitochondrial function and stability. This is clinically significant
since mitochondrial damage is a major underlying cause of disease morbidity in diabetes and other
systemic diseases.
Based on these findings, we propose to test two central hypotheses: (1) that insulin and IGFBP-3 regulate
mitochondrial quality control and stability by coordinating mitochondrial-nuclear crosstalk in response
to stress; and, (2) that interactions between the voltage dependent anion channel VDAC1, IGF-1R, and
INSR mediate mitochondrial biogenesis and stability. We will test these hypotheses in the following aims.
Aim 1. Compare the effects of IGF-related ligands, receptors, and IGFBP-3 on signaling, proliferation, and
metabolism in normoglycemic versus hyperglycemic CEC culture in vitro and the diabetic mouse corneal
epithelium in vivo. Aim 2: Compare the effects of IGF-related ligands, receptors, and IGFBP-3 on mitochondrial
biogenesis, stability through interactions with VDAC1, and dynamics (fission/fusion) in CECs in vitro and the
diabetic mouse corneal epithelium in vivo. Aim 3: Compare the effects of IGF-related ligands, receptors, and
IGFBP-3 on mitophagy and apoptosis in CECs in vitro and the diabetic mouse corneal epithelium in vivo.
Mitochondria are well known to regulate signals that drive energy production and cell survival, and their
dysfunction has been implicated in a wide range of diseases. These studies will provide the first
comprehensive picture detailing the role of the IGF family in mediating mitochondrial stability and function in
the healthy cornea and in the pathobiology of disease. The outcomes could represent a major paradigm shift
in our understanding and future treatment of the diabetic corneal epithelium and other corneal
diseases and dystrophies where mitochon...

## Key facts

- **NIH application ID:** 9973660
- **Project number:** 2R01EY024546-05A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** DANIELLE M. ROBERTSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $492,956
- **Award type:** 2
- **Project period:** 2015-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973660

## Citation

> US National Institutes of Health, RePORTER application 9973660, Effects of systemic disease on corneal epithelial pathophysiology (2R01EY024546-05A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9973660. Licensed CC0.

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