# A Novel Pathogenic Pathway for Diabetic Keratopathy

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2020 · $47,143

## Abstract

PROJECT SUMMARY / ABSTRACT
 Diabetic keratopathy is a complication of diabetes and a major cause of vision loss. There are no
effective drugs that can prevent or reverse corneal defects related to diabetes. Two independent longitudinal
clinical studies have shown robust therapeutic effects of fenofibrate, a specific agonist of Peroxisome
Proliferator-Activated Receptor-α (PPARα), on diabetic retinopathy. Our preliminary studies using diabetic
human donor corneas and animal models suggest a role of PPARα in maintaining corneal nerve integrity. In
our preliminary studies, we have fabricated an innervated 3D in vitro human corneal model that demonstrates
basic anatomical and physiological similarities to the corneal tissue in vivo. Using this novel model we began
unravelling PPARα’s role in diabetic keratopathy. Significant downregulation of PPARα expression was seen in
cells from both T1DM and T2DM human donors, in agreement with decreased PPARα levels as shown in
diabetic human corneas. Our in vivo preliminary studies have shown that non-diabetic PPARα knockout
(PPARα-/-) mice have decreased densities of the sub-basal nerve fibers and reduced corneal sensitivity, similar
to what is seen in diabetic humans. Furthermore, to our surprise, aged, non-diabetic PPARα knockout mice
naturally developed more severe corneal ulcerations compared to that in age-matched WT mice. Treatment of
diabetic rats with fenofibric acid, an active metabolite of fenofibrate, alleviates corneal nerve degeneration in
diabetic rats. As shown by Seahorse analysis, mitochondrial function is impaired in PPARα-/- retina. Based on
these preliminary studies, we hypothesize that diabetes-induced down-regulation of PPARα expression plays a
key pathological role in diabetic keratopathy and represents a novel drug target. We propose the following
studies to address the hypothesis. First, we will induce diabetes in PPARα-/- mice and PPARα transgenic mice
over-expressing PPARα in the cornea, to determine if PPARα KO exacerbates while PPARα over-expression
alleviates diabetes-induced decreases of corneal nerve density and sensitivity. We will also treat diabetic mice
with fenofibrate to determine if activation of PPARα arrests progression of corneal nerve fiber degeneration.
Second, we will determine if the neuroprotective effect of PPARα is through attenuation of oxidative stress and
inflammation, protection of mitochondrial functions and up-regulation of neurotrophic factors using PPARα-/-
mice and PPARα transgenic mice as well as the innervated in vitro 3D human corneal model. Third, to
translate the neuroprotective PPARα function into a therapy, we will evaluate therapeutic efficacy of topical
application of a proprietary fenofibrate eyedrop on diabetes-induced nerve fiber degeneration. This study has
potential to identify a new function of PPARα in the cornea. These studies have potential to establish a novel
pathogenic mechanism for diabetic keratopathy and to lead to the developmen...

## Key facts

- **NIH application ID:** 10548571
- **Project number:** 7R01EY028949-04
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Dimitrios Karamichos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $47,143
- **Award type:** 7
- **Project period:** 2018-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10548571

## Citation

> US National Institutes of Health, RePORTER application 10548571, A Novel Pathogenic Pathway for Diabetic Keratopathy (7R01EY028949-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10548571. Licensed CC0.

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