# Breaking down barriers: defining the role of EphA2 in building epidermal tight junctions in atopic dermatitis

> **NIH NIH K01** · NORTHWESTERN UNIVERSITY · 2020 · $90,045

## Abstract

PI: Bethany E. Perez White
Re: Project Summary/Abstract
Tight junctions are a vital component of the epidermal barrier and are required for skin function. While we know
these structures are disrupted in skin diseases such as atopic dermatitis, we do not fully understand the normal
signaling contributing to their function. This knowledge gap makes finding therapies to restore tight junction
activity difficult. Therefore, defining the signaling pathways responsible for establishing tight junctions would
serve not only to advance our basic understanding of skin biology, but also may provide leads for drug
targeting and disease intervention. Our preliminary evidence indicates that EphA2 receptor tyrosine kinase
(RTK) contributes to the formation and function of tight junctions in 2D cultures. Genetic manipulation of these
cultures to remove EphA2 results in a loss of the localization of tight junction proteins from the stratum
granulosum in which they reside. In addition, we have found a loss of tight junction function by measuring
electrical resistance and the permeability of large molecules in 2D keratinocyte cultures. Based on these
changes in epidermal integrity after loss of EphA2, we hypothesize that EphA2 is a positive regulator of
tight junctions in the epidermis and can be targeted to improve tight junction barrier function. We
specifically will determine how EphA2 is regulating tight junctions and if EphA2 could be targeted
pharmacologically to enhance skin barrier function. Our initial studies implicate the structural protein afadin,
downstream of EphA2 signaling, as a positive regulator of the formation and function of tight junctions in
epidermal keratinocytes. Our studies have found that EphA2 loss leads to the mislocalization of afadin from
cell borders to the cell's interior regions, and a loss in afadin and tight junction proteins. Therefore, we will first
test the effect of EphA2 and afadin loss on the assembly and functionality of tight junctions in 3D reconstituted
human epidermis (3D RHE). We will next test the mechanism by which EphA2 alters afadin expression,
leading to tight junction defects. We have also uncovered novel EphA2/EGFR RTK crosstalk that is integral to
TJ morphogenesis. Finally, we will use 3D RHE and animal models of atopic dermatitis to determine if EphA2
ligand activation with ephrin-A1 can enhance tight junction barrier function and either prevent or reverse the
manifestations of this disease. Atopic dermatitis is a prevalent skin disease primarily affecting infants and
young children characterized by an epidermal barrier defect in association with skin inflammation. This chronic
condition severely decreases the quality of life of patients and their families, and causes a significant lifelong
economic burden. By understanding the biology of tight junctions, a critical structural component of the skin
that is dysfunctional in atopic dermatitis, we can seek new therapies to alleviate this disease. We have
propos...

## Key facts

- **NIH application ID:** 9983609
- **Project number:** 5K01AR072773-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Bethany E Perez White
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $90,045
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983609

## Citation

> US National Institutes of Health, RePORTER application 9983609, Breaking down barriers: defining the role of EphA2 in building epidermal tight junctions in atopic dermatitis (5K01AR072773-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9983609. Licensed CC0.

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