# Dysregulation of inflammation resolution as therapeutic target for IBD

> **NIH NIH K01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $161,566

## Abstract

ABSTRACT
Promoting inflammation resolution and resolution-dependent intestinal epithelial wound healing are recent
therapeutic concepts for IBD. During inflammation resolution, macrophages phagocytose apoptotic neutrophils
(efferocytosis), thereby preventing secondary necrosis. Macrophage efferocytosis also stimulates the secretion
of various resolving and reparative factors that can trigger intestinal epithelial wound healing. I previously
reported that dysregulation of macrophage efferocytosis and efferocytosis-dependent intestinal epithelial wound
healing contributed to pathogenesis in a murine model of Crohn’s disease (CD). The overall goal of this project
is to build upon my prior work to advance human pre-clinical research into resolution-based therapies for CD.
First, I seek to leverage innovative human models and unbiased analytical techniques to determine the cell-cell
communication between efferocytic macrophages and human small intestinal epithelium that drives epithelial
wound healing following inflammatory injury. This work will fill important knowledge gaps, identify potential
resolution-specific therapeutic targets, and define a physiological baseline against which to assess disease-
dependent dysregulation of this resolution/repair module. Towards this first goal, I have recently modeled
inflammatory injury in human ileal and jejunal intestinal epithelial organoid culture systems and shown that
human macrophage efferocytosis rescues this injury. I will interrogate this model with multi-omic techniques in
order to reconstruct potential ligand-receptor interactions and receptor-signaling pathways. Second, I seek to
investigate and translationally target potential disease-dependent dysregulations of macrophage efferocytosis
and efferocytosis-dependent human small intestinal epithelial wound healing. I have observed, consistent with
prior reports, that mucosal oxidized polyunsaturated fatty acids including 12- and 15- hydroxyeicosatetraenoic
acid (HETE) correlate with disease in murine models of IBD and in IBD patient biopsies. In my human models,
these HETEs act as potential dysregulators of resolution—suppressing both macrophage efferocytosis and
efferocytosis-dependent small intestinal epithelial wound healing. I will investigate the mechanisms of these
dysregulations. Nonetheless, I had previously observed that the apolipoprotein A1 mimetic peptide 4F rescues
murine CD-like disease by enhancing mucosal excretion of disease-elevated HETEs. Pilot data show that 4F
inhibits HETE-dependent human macrophage dysregulation and enhances the clearance of HETEs across
human small intestinal primary epithelium. 4F thus appears to be a promising therapy against HETE-dependent
dysregulation of resolution and resolution-repair. After this study, I anticipate that I will have characterized novel
dysregulations of inflammation resolution and resolution-dependent intestinal epithelial repair that may amplify
disease in IBD but that can nonetheless...

## Key facts

- **NIH application ID:** 10849740
- **Project number:** 5K01DK133666-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** David Meriwether
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $161,566
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10849740

## Citation

> US National Institutes of Health, RePORTER application 10849740, Dysregulation of inflammation resolution as therapeutic target for IBD (5K01DK133666-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10849740. Licensed CC0.

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