# Epithelial Regulation of Chronic Itch

> **NIH NIH F30** · WASHINGTON UNIVERSITY · 2020 · $31,446

## Abstract

Project Summary
Chronic itch is debilitating symptom that severely limits quality of life and affects up to 20% of the population.
Despite this, there are no FDA-approved drugs specifically indicated for the treatment of itch. Our current
understanding of chronic itch pathophysiology largely derives from studying inflammatory disorders such as
atopic dermatitis (i.e. eczema). Thus, how chronic itch arises in conditions that lack overt cutaneous inflammation
is poorly understood. A notable example is chronic pruritius of unknown origin (CPUO), which accounts for 10-
40% of all chronic itch cases and lacks effective treatments. Improper barrier function due to dry, aging skin may
be a key driving factor of chronic itch in CPUO, yet what may mediate this is unknown.
IL-33 is an ‘alarmin’ released from keratinocytes upon damage or stress. Our preliminary data suggests that IL-
33 is elevated in the serum of CPUO patients compared to healthy controls. Furthermore, a recent study has
shown that IL-33 is required for the development of dry skin itch in a murine model that recapitulates several of
key aspects of CPUO. However, the precise mechanisms by which IL-33 promotes itch and how this promotion
is regulated remain largely unexplored. IL-33 is a key inducer of immune cell responses, however, we and others
have found that IL-33 can directly activate sensory neurons. Thus, in Aim 1, I will determine if IL-33 is a key
mediator of a direct epithelial-neuronal axis in dry skin itch using novel mice I have generated. The activity of IL-
33 is dramatically enhanced upon extracellular cleavage by proteases. Our preliminary data suggest that KLK7,
a serine protease that is important for barrier homeostasis, promotes chronic itch through an unknown, indirect
mechanism. In Aim 2, I will evaluate if KLK7 cleaves IL-33, and enhances IL-33’s bioactivity and capacity to
induce itch. Together, this work aims to address a unmet need in medicine by shedding light on novel
mechanisms underlying the poorly understood condition of CPUO.

## Key facts

- **NIH application ID:** 10067025
- **Project number:** 1F30AI154912-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Anna Meredith Trier
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $31,446
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067025

## Citation

> US National Institutes of Health, RePORTER application 10067025, Epithelial Regulation of Chronic Itch (1F30AI154912-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10067025. Licensed CC0.

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