# Role of healthy skin molecular phenotype in the switch to specific skin diseases

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2023 · $182,121

## Abstract

The risk of atopic dermatitis (AD), hidradenitis suppurativa, and lupus erythematosus is significantly
higher in African American (AA) population, while White Non-Hispanic (WNH) subjects have a greater
risk of psoriasis. The mechanisms that underlie disparity in susceptibility to different inflammatory skin
diseases are poorly understood. In our pilot experiments, using extensively validated RNA-seq analysis
we revealed striking differences in gene expression in healthy AA versus WNH skin, enriched for
proinflammatory signaling. In addition, 3D human skin equivalent cultures (HSE) made from human
primary keratinocytes seeded on collagen matrix, appeared to have a much more robust response to
the pro-inflammatory effects of TNFa, a prototype cytokine involved in multiple inflammatory skin
diseases. These results suggested that intrinsic pro-inflammatory circuits in AA skin/keratinocytes may
contribute to the increased development of certain inflammatory skin diseases in the AA population
including AD. However, the molecular mechanisms that trigger the shift of this “ambivalent” pre-disease
inflammatory signaling towards specific inflammatory skin diseases remain to be investigated. 3D HSE
made from primary human keratinocytes and immune cells as well as skin explant cultures treated with
Th1/Th17 cytokines (TNFa, IL17, IL22) or Th2 cytokines (IL4, IL13) have been successfully used to
induce in vitro morphological and molecular changes typical for psoriasis and AD. Thus, we
hypothesized that different molecular phenotypes of AA and WNH healthy skin define molecular switch
towards either pro-AD or pro-psoriasis signaling and that we could delineate the initial significant stages
in this process using AA and WNH 3D HSE and skin explant cultures treated with Th1/Th17
(TNFa+IL17+IL22) or Th2 (IL3+IL14) cytokines. We propose to use in vitro skin models: 3D HSE made
from AA and WNH adult skin cells (keratinocytes, fibroblasts and T cells from the same donor) and
explant cultures of AA and WNH human skin provided by STEM Core at Northwestern SBDRC for
cytokine treatment. We propose to use comprehensive approach including RNA-seq, Q-PCR, proximity
extension immuno-PCR assay (Olink proteomics), confirmed by immunostaining with Vectra
Multispectral Imager to identify onset of changes in 3D HSEs/skin explants gene/protein expression
during the treatment with AD- or psoriasis-related cytokines. We will compare these changes to already
identified/published molecular signatures of non-lesional and lesional skin in AD and psoriasis patients.
We will also determine changes in epidermal barrier that are an integral part of psoriasis and AD
pathophysiology. We expect that the obtained results will reveal whether and potentially how the
molecular phenotype of healthy skin defines the switch to specific skin diseases and will set the stage
for the development of personalized prevention approaches for different minority populations,

## Key facts

- **NIH application ID:** 10709874
- **Project number:** 5R21AR081520-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Irina Budunova
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $182,121
- **Award type:** 5
- **Project period:** 2022-09-23 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10709874

## Citation

> US National Institutes of Health, RePORTER application 10709874, Role of healthy skin molecular phenotype in the switch to specific skin diseases (5R21AR081520-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10709874. Licensed CC0.

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