# Targeted therapeutic modulation of inflammatory cytokines through manipulation of noncoding RNA regulation of innate immunity in atopic dermatitis

> **NIH NIH R61** · STANFORD UNIVERSITY · 2021 · $370,214

## Abstract

Atopic Dermatitis (AD), the most common chronic inflammatory skin disorder worldwide,
is driven by both terminal keratinocyte differentiation defects and strong type 2 immune
responses. What controls AD disease activity? Why is its response to therapy different from
patient to patient? These are poorly understood problems and presents a large unmet need for
both effective and safe therapeutics. In this project we seek to provide a molecular handle to
explain some of these fundamental questions, by addressing a potentially under-explored
source of immune regulation represented by epigenetic mechanisms. Our paradigm-shifting
hypothesis centers on the epigenetic regulation of the immune response implicated in the
pathogenesis of AD, and on a newly identified class of long noncoding RNAs (lncRNAs), the
immune gene priming lncRNAs (IPLs), that exploit pre-formed chromatin topology at specific
cytokine nuclear compartments to facilitate their epigenetic priming and activation. We propose
to test and expand our hypothesis using technological advances that only now make this
possible. I outline here a plan to pursue this opportunity with 3 specific aims. In Aim 1 (the R61
phase), we will establish the upstream molecular events that coordinate the epigenetic state of
inflammatory genes. We hypothesize that IPLs are critical mediators that directly interact with
the 3-dimensional chromatin architecture to prime chemokine promoters and enhance the pro-
inflammatory responses in innate immune cell activation. We will characterize the mechanisms
through which IPLs regulate IL-4 and IL-13, keystone interleukins critical to the induction and
perpetuation of the Type 2 response in AD. In Aim 2, we will identity novel protein components
that directly interact with the IPLs to modulate the chromatin landscape. We will also perform
chromosome conformation capture across the IL-4/IL-13 locus to establish whether changing
levels of IPL-IL4/13 alters chromosomal looping across the locus. Lastly, in Aim 3 (R33 phase)
we will test inhibitors that specifically target IPL-4/13 in established murine AD-like models that
recapitulate human AD. The IPL inhibitors will also be evaluated for their effects on the sensory
responses known to influence AD behavior, to modulate direct neuronal priming by Type 2
cytokines shown to be a key step in the pathogenesis of AD. Taken together, our data will
directly establish how IPLs and 3-dimensional chromatin architecture act in a cooperative
manner to reduce gene-intrinsic noise, and allow robust activation of innate immune genes. A
more precise fine-tuning of chemokine transcription through direct manipulations of IPL activities
represents a highly valuable therapeutic strategy to achieve tailored immunomodulation in AD.

## Key facts

- **NIH application ID:** 10021394
- **Project number:** 5R61AR076815-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Kevin Chun-Kai Wang
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $370,214
- **Award type:** 5
- **Project period:** 2019-09-19 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10021394

## Citation

> US National Institutes of Health, RePORTER application 10021394, Targeted therapeutic modulation of inflammatory cytokines through manipulation of noncoding RNA regulation of innate immunity in atopic dermatitis (5R61AR076815-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10021394. Licensed CC0.

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