# Molecular Dysregulation in Fuchs Corneal Endothelial Dystrophy

> **NIH NIH K99** · TRUSTEES OF INDIANA UNIVERSITY · 2021 · $112,673

## Abstract

Abstract
Fuchs Corneal Endothelial Dystrophy (FECD) is a blinding disease that affects millions of people (4% over the
age of 40) in the U.S, for which there is no cure. Endothelial cell loss, thickening of the extra cellular matrix
(ECM) or Descemet’s membrane, presence of extracellular deposits (guttae) are observed in patients with
FECD. Corneal transplantation is the prevalent treatment approach, and FECD accounts for the majority of
corneal transplantations in the world. On a cellular level, increased oxidative stress, expression of endothelial
to mesenchymal transition (EMT) genes, and an accumulation of unfolded proteins are present in FECD. In the
current proposal, I plan to identify and characterize the reasons for a) the accumulation of unfolded proteins
and other debris in the cells, and b) elevated EMT. Our preliminary data show that the components of two main
protein clearance pathways in eukaryotes; autophagy and the ubiquitin proteasome pathway (UPP), are
significantly reduced in FECD cells. In Aims 1 and 2, I plan to identify whether oxidative stress is the cause for
these decreased activities, use pharmacological agents to restore functions of autophagy and UPP, and
determine whether these can alleviate the disease progression. Increased integrin activity and decreased Wnt
signaling was observed in FECD. Both these signaling pathways are known to regulate EMT, which implicated
in FECD disease progression. In Aim 3, I plan to determine if oxidative stress is the cause for the upregulation
of integrin and repression of Wnt pathways in FECD, and to assess the roles of these signal transductions on
EMT. I plan to conduct Aims 1 and 2 during the K99 phase in Indiana University Bloomington. In addition to
establishing my independence from my current lab, I will also take part in career development opportunities
available at Indiana University Bloomington to prepare for the job market, improve science communication as
well as mentoring skills. Aim 3 will be performed during the R00 phase. Successful completion of these aims
will lead to the identification and characterization of molecular mechanisms that are awry in FECD, and
determine whether restoration of these pathways would suffice in the amelioration of the disease progression.

## Key facts

- **NIH application ID:** 10282153
- **Project number:** 1K99EY032974-01
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** Rajalekshmy Shyam
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $112,673
- **Award type:** 1
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10282153

## Citation

> US National Institutes of Health, RePORTER application 10282153, Molecular Dysregulation in Fuchs Corneal Endothelial Dystrophy (1K99EY032974-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10282153. Licensed CC0.

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