# Skin Barrier Adaptation

> **NIH NIH R56** · WASHINGTON UNIVERSITY · 2020 · $328,783

## Abstract

ABSTRACT
The skin epidermis provides a critical first line of environmental defense. However, the mechanisms mediating
how epidermal keratinocytes adapt and respond to the external environment are poorly understood. Involucrin
(IVL) is the major scaffold protein of the cornified envelope surrounding the differentiated keratinocyte. Our
previous work supports a functional role for involucrin in epidermal adaptive responses to the environment,
acute microbial exposure, and inflammation. (1) We discovered recent selective sweep for an IVL haplotype in
the northern European (CEU) population. This IVL CEU haplotype is associated with increased IVL expression
in sun-exposed skin compared to that in non-sun-exposed skin [according to Genotype-Tissue Expression
Project (GTEx) data]. Positive selection of IVL CEU is directly correlated with increasingly northern latitudes,
suggesting a fitness benefit of increased IVL expression in northern clines. (2) IVL was the only large
Epidermal Differentiation Complex (EDC)-encoded skin barrier protein that exhibited significantly higher levels
in the epidermis of conventionally raised (CR) lab mice compared to those in germ-free (GF) and reconstituted
skin microbiome (RSM) mice (GF mice acutely exposed to CR commensal microbiota), suggesting an adaptive
keratinocyte response to microbial interactions. (3) Ivl-/- mouse skin exhibited a protective effect against
MC903-induced inflammation with reduced vitamin D receptor expression, suggesting a regulatory role for IVL
in vitamin D signaling in the epidermis. We hypothesize that IVL levels are specifically calibrated to generate
an adaptive skin barrier that is finely tuned in response to the environment. We will test this hypothesis by
performing three aims. Aim 1. Determine the causative genetic variants that increase IVL gene expression
levels. IVL CEU includes enhancer 923 that is required for involucrin target gene expression as evidenced by
loss of Ivl expression in 923-/- mice. Cellular and molecular assays in keratinocytes will be performed to identify
the molecular mechanisms by which enhancer variation(s) modulate target gene expression. Aim 2. Determine
the role of involucrin in the skin adaptive response to commensal microbiota. We will examine the skin and
inflammatory responses in rederived Ivl-/- CV mice as a functional measurement of skin adaptation. Aim 3.
Determine the molecular mechanism by which involucrin regulates Vitamin D receptor expression and
signaling in the epidermis. MC903-treated Ivl-/- ear skins did not exhibit severe inflammation and exhibited
reduced Vdr expression. We hypothesize a role for Involucrin to positively regulate Vdr expression and
signaling via phosphorylated p38δ, a known VDR activator in other human cell types. Our hypothesis will be
rigorously tested using constitutively active p38δ and knockdown in vitro studies with anticipated results for
increased and decreased Vdr expression and signaling, respectively. This stud...

## Key facts

- **NIH application ID:** 10241614
- **Project number:** 1R56AR075427-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Cristina de Guzman Strong
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $328,783
- **Award type:** 1
- **Project period:** 2020-09-10 → 2022-09-20

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241614

## Citation

> US National Institutes of Health, RePORTER application 10241614, Skin Barrier Adaptation (1R56AR075427-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10241614. Licensed CC0.

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