# Regulation of signaling pathways mediating epithelial cell injury in the neonatal intestine

> **NIH NIH K08** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $174,114

## Abstract

PROJECT SUMMARY/ABSTRACT
 Necrotizing enterocolitis (NEC) is a devastating, rapidly progressive gastrointestinal disease of
prematurity that affects ~10% of neonates born at < 1500 grams. The risk of NEC is highest for the most
preterm neonates, and one infant dies from NEC in the United States each day. The mortality rate for NEC
approaches 50% if surgical resection of necrotic bowel is required. Intestinal injury in NEC results from a
dysregulated cycle of unrestrained inflammation and intestinal epithelial cell damage. Despite four decades of
research, outcomes have not improved for neonates with NEC due to critical knowledge gaps in our
understanding of mechanisms underlying disease pathogenesis. The studies outlined in this proposal will
characterize new signaling mechanisms regulating intestinal epithelial injury in NEC, determine how
these pathways are modulated by microbial metabolites, and use this knowledge to identify new
dietary strategies or therapeutic targets. Our laboratory found that activation of the aryl hydrocarbon
receptor (AhR) by the dietary ligand indole-3-carbinol (I3C) downregulates the expression of inflammatory
cytokines and reduces intestinal injury during experimental NEC. We will now advance our understanding of
the anti-inflammatory signaling pathways in the neonatal intestine by examining a pathway closely related to
AhR characterized by activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). In
adult murine colitis models, Nrf2 agonists attenuate intestinal injury. Similarly, our preliminary data reveal that
dietary Nrf2 agonist administration reduces inflammation in our murine model of NEC and our unique and
innovative microfluidic model incorporating patient-derived intestinal epithelial cells and microbiome. Based on
our preliminary data and the published literature, we hypothesize that intestinal epithelial injury will be (1)
exaggerated in the absence of Nrf2 signaling in intestinal epithelial cells, (2) downregulated by Nrf2 agonist
production by intestinal microbes, and (3) significantly attenuated by therapeutic agents activating the Nrf2
pathway. For these studies, we will utilize specialized genetically modified strains of mice, a humanized NEC
model, and our microfluidic model incorporating human neonatal intestinal epithelium.
 The K08 candidate is a neonatologist-scientist who has transitioned her research focus to intestinal
epithelial cell biology and host-pathogen interactions in the developing intestinal tract. Her mentor, Dr. Misty
Good, is an international expert in this field and is completely dedicated to the candidate’s success. The
extensive training plan outlined in his proposal will facilitate the achievement of her goal of leading an R01-
funded laboratory dedicated to improving the health of vulnerable neonates through research focused on
intestinal biology and the pathophysiology of NEC.

## Key facts

- **NIH application ID:** 10949901
- **Project number:** 1K08DK140604-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Lauren Carole Frazer
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $174,114
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10949901

## Citation

> US National Institutes of Health, RePORTER application 10949901, Regulation of signaling pathways mediating epithelial cell injury in the neonatal intestine (1K08DK140604-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10949901. Licensed CC0.

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