# Eph-ephrin signaling in the lens

> **NIH NIH R01** · TRUSTEES OF INDIANA UNIVERSITY · 2021 · $456,650

## Abstract

Project Summary
According to the World Health Organization, age-related lens pathologies are the leading cause of visual
impairment in the world. Cataracts, defined as any opacity in the eye lens, remain the leading cause of
blindness in the world. Presbyopia is caused by a reduction in the lens’ ability to change shape during focusing
(accommodation), and, by extension, the need for reading glasses. Unaddressed presbyopia is the leading
cause of visual impairment globally. Decades of study have focused on congenital lens pathologies, and thus,
very little is known about the underlying cellular and molecular mechanisms that facilitate lifelong lens
homeostasis. Recent studies have reported that mutations of the EphA2 receptor or the ephrin-A5 ligand are
associated with variable congenital and age-related cataracts in humans and mice, and these bidirectional
signaling molecules are key components for regulating lens cell organization and stability.
 Our mouse models reveal that loss of EphA2 leads to age-related cortical cataracts similar to human
patients with EphA2 dysfunction. We will evaluate cataract progression in our mouse line to study the cellular
and molecular changes that occur during cortical cataract formation. We hypothesize that loss of EphA2 results
in changes in cytoskeletal structures or cell-cell adhesion of peripheral fiber cells leading to optical
discontinuities in the lens cortex.
 Our new data show that the lens utilizes both canonical ligand-mediated EphA2 bidirectional signaling and
non-canonical ligand-independent EphA2 signaling pathways. We hypothesize that canonical EphA2 signaling
is required in equatorial epithelial cells while non-canonical EphA2 activation is required for fiber cell
differentiation and maturation and that this segregation of receptor activity may explain the large variety of
human congenital and age-related cataracts caused by EphA2 mutations. We will evaluate the activation
pattern of EphA2 spatially and temporally and determine the activity of known downstream pathways in
different lens cell populations. We will apply EphA2 agonist and antagonist peptides to primary culture mouse
lens epithelial cells to generate mini lenses as an in vitro model for lens development.
 Increased size and stiffness of the lens center or nucleus has been hypothesized to be a key factor for not
only age-related increases in overall lens stiffness and presbyopia, but also poor nutrient and waste transport
leading to age-related nuclear cataracts. Our new preliminary data shows that loss of EphA2 leads to softer,
smaller lens nuclei. We hypothesize that Eph-ephrin signaling is required for normal cell-cell adhesion and
cytoskeleton rearrangement that drives nuclear fiber cell membrane re-organization and compaction. This data
will provide a better understanding of coordinated signaling mechanisms for maintaining homeostasis during
normal aging and in lenses with changes in transparency and biomechanical properties, wh...

## Key facts

- **NIH application ID:** 10095178
- **Project number:** 1R01EY032056-01
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** Catherine Kehsin Cheng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $456,650
- **Award type:** 1
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10095178

## Citation

> US National Institutes of Health, RePORTER application 10095178, Eph-ephrin signaling in the lens (1R01EY032056-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10095178. Licensed CC0.

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