# Identification of therapeutic small molecules for treatment of skin fibrosis by modulating epidermal pro-inflammatory signaling

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2023 · $211,200

## Abstract

Project Summary/Abstract
Repurposing of drugs (also called drug repositioning) has advantages over traditional drug development, since
it has shorter pathways to FDA approval and reduced development costs. Drugs have sometimes been
repurposed serendipitously through discovery of side effects or multiple effects. Recent comprehensive
transcriptomic, proteomic, and metabolomic analyses have generated much large-scale data. Connectivity
Map (CMap) is a computational approach that utilizes signature matching to compare unique transcriptome
patterns (i.e., signatures) of certain conditions. CMap has been harnessed for drug repurposing by selecting
candidates whose signatures show inverse relationships with disease signatures, indicating therapeutic
potential through reversing the signature associated with a disease state.
Fibrosis refers to a pathological form of tissue repair that results in replacement of damaged tissue with
nonfunctional scar tissue, rather than regenerating functional pre-injury tissue. In particular, dermal fibrosis is a
common outcome of various skin pathologies including hypertrophic scars, keloids, and burn wounds. In
serious cases, severe dermal fibrosis can lead to substantial cosmetic disfigurement, pain, loss of mobility, and
difficulty regulating temperature. However, therapeutic options for treatment of pathologic scarring are limited.
Mucosal wounds undergo accelerated healing, exhibit less inflammation, and heal with minimal scarring
compared to cutaneous wounds. Much of the difference between mucosal and cutaneous healing is attributed
to the moist mucosal environment. We showed that occluded skin wounds, by application of polyurethane
dressings to mimic a mucosal environment and to augment barrier function of the skin, healed faster and with
less scarring compared to non-occluded skin wounds. Transcriptomic analysis of the epidermis showed a
unique signature in non-occluded skin wounds, which we refer to as the reduced hydration (RH) signature.
We have previously demonstrated that inhibition of specific pro-inflammatory pathways in the epidermis
reduces fibrosis (hypertrophic scar) in the dermis. We hypothesize that utilizing small molecules predicted by
CMap to revert the RH signature is a promising strategy to reduce fibrosis in the dermis. We identified small
molecule candidates predicted to reverse subsets of the RH signature using CMap. We will validate the
efficacy of small molecules to reduce expression of pro-inflammatory genes in vitro and to reduce dermal
fibrosis in vivo. Interestingly, we have noted similarities between the RH signature and epidermal gene
expression signatures in lesional atopic dermatitis and psoriatic skin, which are also known to demonstrate
epidermal barrier dysfunction. Thus, the outcomes of this proposal will provide opportunities to investigate
novel therapeutic drugs, potentially resulting in translatable approaches to alleviate not only symptoms of
fibrosis, but also of other pat...

## Key facts

- **NIH application ID:** 10673140
- **Project number:** 5R21AR081475-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Seok Jong Hong
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $211,200
- **Award type:** 5
- **Project period:** 2022-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10673140

## Citation

> US National Institutes of Health, RePORTER application 10673140, Identification of therapeutic small molecules for treatment of skin fibrosis by modulating epidermal pro-inflammatory signaling (5R21AR081475-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10673140. Licensed CC0.

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