# Role of epoxy fatty acids - soluble epoxide hydrolase axis in intestinal mucosal barrier defense

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $667,022

## Abstract

Overarching objective of this project is to elucidate whether and how cytochrome p450 (CYP)-derived epoxy
fatty acid metabolites (EpFAs) and soluble epoxide hydrolase (sEH)-hydrolyzed EpFAs metabolites (called diol
oxylipins) in sustaining gastrointestinal (GI) mucosa barrier homeostasis and to develop the efficient therapeutic
approach against GI mucosa barrier damage. More than 80% polyunsaturated fatty acids (PUFA)/eicosanoids
are metabolized through CYP pathway and GI mucosa has the highest expression levels of CYP epoxygenase
and sEH. We found that sEH inhibition or knockout against nonsterol anti-inflammatory drugs (NSAIDs) or
aflatoxin B1 (AFB)-induced GI mucosa damage via strengthening mucosa barrier defense and preserving levels
of EpFAs to limit inflammation in vivo. We have developed novel sEH inhibitors with excellent pharmacokinetics
and low toxicity, including the IND approved inhibitor EC5026. This sEH inhibitor has a strong effect on blocking
inflammation, eicosanoid/cytokine storms, and NSAIDs or aflatoxin B1-induced GI mucosa damage or ulcer.
PPARγ’s anti-inflammatory activities are well-known, and EpFAs are PPARγ agonist or PPARγ is a possible
EpFAs-binding receptor. Our hypothesis is that enhancement of EpFAs via sEH inhibition is crucial in sustaining
Gl mucosa barrier for their defense and restitution to mucosa damage, and mechanistically EpFAs block NSAIDs
or AFB-induced GI mucosa injury through its binding protein/receptor - PPARγ and its mediated signaling
pathway/s to i) enhance the GI mucosa barrier defense by increasing goblet cell mucin production and enterocyte
tight junction and by enhancing mucosa restitution/regeneration by activating enterocyte progenitor cell
proliferation/migration/regeneration process, and ii) inhibit endoplasmic reticulum (ER)/mitochondrial stress, and
iii) inhibit eicosanoid/cytokine storms and inflammatory activity. We have established and used numerous novel
genetically engineered mouse models and in vitro intestinal organoids, and showed a critical role of sEH
knockout in epithelial regeneration. We proposed the following three aims: 1) to determine the independent roles
of sEH specific cell-lineage knockout compared to global sEH inhibition in strengthening intestinal mucosa barrier
defense and restitution against NSAIDS/toxin-induced GI mucosal injury using powerful Villin-Cre/sEHfl/fl, Cdh5-
Cre/sEHfl/fl and LysM-Cre/sEHfl/fl mouse models that have specific sEH knockout in intestinal epithelium,
endothelium, and macrophages, respectively; 2) to determine how sEH inhibition/knockout or EpFAs enhances
intestinal mucosa restitution/regeneration process responded to injury via activating the PPARγ-mediated
signals and regulating the key related transcriptome profile in intestinal epithelium using our novel 3xTg-iEAP
intestinal epithelial injury-healing mouse model and in vitro intestinal crypt organoids; and 3) to determine
whether the key EpFAs-binding protein - PPARγ is a central player ...

## Key facts

- **NIH application ID:** 10777394
- **Project number:** 1R01DK137885-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Guang-Yu Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $667,022
- **Award type:** 1
- **Project period:** 2024-02-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10777394

## Citation

> US National Institutes of Health, RePORTER application 10777394, Role of epoxy fatty acids - soluble epoxide hydrolase axis in intestinal mucosal barrier defense (1R01DK137885-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10777394. Licensed CC0.

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