# Novel approaches for corneal haze/fibrosis elimination

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2021 · $374,007

## Abstract

Abstract
Corneal fibrosis (haze) after injury, infection, or trauma causes blindness in 1.3 million Americans each year and
accounts for 7% of the world’s blindness. Current drugs often fail to cure severe and established corneal haze.
At present, cornea transplant surgery is the standard of care. A normal clear cornea do not contain
myofibroblasts. After insult, quiescent transparent keratocytes are activated by transforming growth factor b
(TGFb) to become corneal stromal fibroblasts (CSFs), which then transdifferentiate into corneal myofibroblasts
(CMFs) to do corneal repair. Excessive and prolonged formation of CMFs during early-stages and persistence
of CMFs in stroma in late-stages of wound healing are the primary causes of haze in vivo. Recently, we
uncovered 2 novel mechanisms regulating this process: (a) haze production involves the intermediate-
conductance Ca2+-activated K+ channel, KCa3.1 whereas (b) haze elimination in vivo can be induced via selective
apoptosis in CMFs by a dual therapy. This study provided the first evidence that haze can be cleared by directing
the fate of CMFs in vivo. CMFs are not terminally differentiated cells and can be reverted to CSFs in vitro.
Myofibroblast formation, reversal, and de-differentiation are tissue-specific events, and no cornea-specific data
exists currently. This premise led to a central hypothesis that novel epigenetic approaches used to direct the fate
of CMFs in vivo will eliminate established and severe haze in vivo, and provide a non-surgical means of vision
restoration. This project aims optimizing non-surgical method to treat haze pursuing 3 specific aims. Aim-1 tests
a hypothesis that TRAM-34 (a KCa3.1 specific inhibitor) limits CMF formation in early-stages of wound healing in
vivo by inhibiting KCNN4 gene transcription via upregulation of Restrictive element-1 silencing transcription
factor (REST) reducing AP1 (Activator protein-1). Aim-2 tests a hypothesis that epigenetic reprogramming in
late-stages of wound healing by Sodium butyrate (NaB) will efficiently de-differentiate CMFs to precursor CSFs
in vitro and keratocytes in vivo by enhancing DNA methyl transferases (DNMTs), methyl CpG binding protein 2
(MeCP2) and DNA methylation of CpG islands on the promoter on alpha-smooth muscle actin gene. Aim-3 tests
a hypothesis that TRAM-34+NaB dual therapy will fully abolish severe/established haze in vivo in rabbits without
significant side effects by (a) limiting TGFb-driven excessive and prolonged CMFs formation in early-stage
wound healing by reducing KCa3.1 by TRAM-34, and (b) promoting CMFs reversal to precursor cells in late-stage
wound healing by NaB via epigenetic reprogramming. Our pilot studies strongly support hypotheses. Proposed
studies will be accomplished employing established in vitro human and in vivo (rabbit and KCa3.1-/- mice) corneal
fibrosis models, clinical eye exams, molecular, and cellular assays and following our published method. The
successful conclusion of pr...

## Key facts

- **NIH application ID:** 10178035
- **Project number:** 5R01EY030774-03
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Rajiv Ravindra Mohan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $374,007
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10178035

## Citation

> US National Institutes of Health, RePORTER application 10178035, Novel approaches for corneal haze/fibrosis elimination (5R01EY030774-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10178035. Licensed CC0.

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