# Ocular Surface Functions of KLF4 and KLF5

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $411,626

## Abstract

PROJECT SUMMARY
Corneal epithelium (CE) is a self-regenerating stratified squamous tissue that protects the rest of the eye by
serving as the anterior-most barrier.1, 2 Our long-term goal is to identify the regulatory networks that govern the
CE stratification and homeostasis, facilitating better understanding of the molecular basis for sight-threatening
corneal disorders. Previously, we demonstrated that the Krüppel-like factors Klf4 and Klf5 play crucial non-
redundant roles in maturation and maintenance of the ocular surface.2-17 In this proposal we seek to determine
their role in regulating distinct cellular and molecular pathways of CE stratification and homeostasis, and
elucidate how defects in these pathways affect CE plane of division and genetic stability, causing ocular
surface diseases. We will employ complementary and innovative cell culture and imaging systems, transgenic
mouse models and Next-Gen sequencing approaches to test the novel central hypothesis that `Klf4 and Klf5
orchestrate CE cell stratification and homeostasis by coordinating the CE cell plane of division and genetic
stability in a TGF-, BMP6-, and Pard3-dependent manner'. This hypothesis was formulated based on our
published work, 2-16 and exciting preliminary results. We will test this hypothesis by pursuing three Specific
Aims. In Aim 1, we will test if KLF4 and KLF5 play key roles in regulating CE cell shape, apical-basal polarity
(ABP) and plane of division, thereby elucidating the link between these transcription factors and the cellular
processes that regulate CE stratification. In Aim 2, we will test if CE stratification is driven by a crosstalk
between transcription factors Klf4 and Klf5, and signaling network involving TGF and BMP6 pathways,
thereby elucidating the molecular mechanisms that regulate CE stratification and homeostasis. In Aim 3, we
will test if Klf4 is a key regulator of genome stability that protects the CE from radiation-induced DNA damage
and tumor development by upregulating the ABP gene Pard3 (also called Par3) expression. By delineating the
regulatory pathways of corneal epithelial differentiation, stratification and carcinogenesis, and elucidating the
molecular underpinnings of ocular surface disorders such as pterygium and ocular surface squamous
neoplasia (OSSN), this proposal directly addresses the NIH mission of `seeking fundamental knowledge about
the nature and behavior of living systems' and offers the potential for translation to ocular surface disorders
which account for considerable healthcare burden in the world. The proposed research is significant as its
anticipated outcomes will identify the molecular factors and pathways important for normal growth and function
of CE cells, and their deficiencies that lead to sight-threatening corneal disorders.

## Key facts

- **NIH application ID:** 10375722
- **Project number:** 2R01EY026533-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Shivalingappa Kottur Swamynathan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $411,626
- **Award type:** 2
- **Project period:** 2016-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375722

## Citation

> US National Institutes of Health, RePORTER application 10375722, Ocular Surface Functions of KLF4 and KLF5 (2R01EY026533-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10375722. Licensed CC0.

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