# Skin Barrier Adaptation

> **NIH NIH R01** · HENRY FORD HEALTH SYSTEM · 2022 · $355,548

## Abstract

ABSTRACT
The epidermis provides skin barrier function against the harsh external environment and is the primary site of
vitamin D production. Deficiencies in epidermal keratinocyte function lead to increased risks for skin infection
and inflammation. The expression of genes encoded within the Epidermal Differentiation Complex (EDC)
locus is critical for epidermal function that must adapt to different environments to further ensure survival. We
discovered recent evolution in the human epidermis. We report a recent selective sweep for increased
involucrin (IVL) expression in the epidermis of individuals from European populations in contrast to African
populations. Our finding reveals functional diversity and adaptation in the human epidermis associated with
human migration out of Africa. Yet the mechanisms for involucrin dosage and the functional impact for
adaptive epidermal function are not known. Here we aim to rigorously understand the mechanisms by which
IVL modulates Vitamin D receptor (VDR) function in the epidermis, an emerging paradigm based on our in
vivo mouse and human population studies. Ivl knockout (Ivl-/-) mice express lower levels of vitamin D receptor
expression in the epidermis resulting in decreased ligand-bound vitamin D receptor signaling and dampened
Tslp-mediated inflammation. This newly discovered phenotype for Ivl-/- mice highlights a functional role for Ivl
to modulate Vdr signaling for epidermal immune crosstalk in contrast to previous work that found involucrin to
be dispensable for skin barrier development. This finding is significant as IVL and VDR are both increased in
the epidermis of individuals of European ancestry in contrast to relatively decreased IVL and VDR expression
in the epidermis of individuals of African ancestry. Together, our discoveries in mice and human reveal a
functional regulatory axis for IVL/VDR that underlies the evolutionary selection and diversity of the human
epidermis. We will test the following overarching hypothesis in this study. Involucrin modulates vitamin D
receptor function and epidermal crosstalk for adaptive epidermal function that underlies human skin diversity
and evolution. We will test this hypothesis in the following specific aims. Aim 1. Identify the regulatory
mechanisms for increased IVL. Aim 2. Identify the mechanisms for Involucrin-mediated regulation of vitamin
D receptor. Aim 3. Identify the involucrin pathway for adaptive epidermal immune crosstalk. Completion of the
aims will generate new knowledge for IVL/VDR axis function that underlies human skin diversity and
evolution. This knowledge will facilitate precision medicine initiatives designed for population-specific skin and
critical for achieving global skin health.

## Key facts

- **NIH application ID:** 10467695
- **Project number:** 1R01AR079888-01A1
- **Recipient organization:** HENRY FORD HEALTH SYSTEM
- **Principal Investigator:** Cristina de Guzman Strong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $355,548
- **Award type:** 1
- **Project period:** 2022-07-19 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10467695

## Citation

> US National Institutes of Health, RePORTER application 10467695, Skin Barrier Adaptation (1R01AR079888-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10467695. Licensed CC0.

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