# Atg5-dependent regulation of Notch ligands in intestinal inflammation

> **NIH NIH P20** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2022 · $220,642

## Abstract

Immune dysregulation and intestinal barrier defects are key pathogenic factors driving inflammatory bowel
disease (IBD). These pathogenic factors are influenced by both genetic and environmental factors and have
been the target of numerous therapeutic agents which have had limited clinical success. Given the current
therapeutic options and recent failures, it’s critical that we enhance our understanding of the basic science
behind immune dysregulation and intestinal barrier defects to identify new therapeutic targets. The studies
proposed in this grant application seek to bridge this gap in IBD knowledge and provide insight into possible
novel therapeutic targets. The goals of this application are to investigate how inflammatory macrophages
contribute to barrier dysfunction through Notch signaling and to determine the efficacy of targeting Notch
ligands to prevent and treat IBD. Our preliminary data show macrophages in the inflamed gut upregulate Notch
ligands, Notch is activated in colonocytes, and inflammatory macrophages alter organoid differentiation and
barrier integrity. Based on our preliminary data, we advance a novel hypothesis that inflammatory
macrophages through Notch signaling i) alters intestinal stem cell (ISC) differentiation; ii) disrupts intestinal
tight junction permeability and cellular metabolism; and iii) that autophagy plays a role in regulating cell surface
Notch ligand expression in macrophages. Additionally, we hypothesize the in vivo targeting of Notch ligands in
animal models of IBD will ameliorate intestinal inflammation. The following are the specific aims of the project:
In aim 1, we will delineate the pathogenic role of Notch ligand-positive macrophages in intestinal barrier
differentiation and function and the therapeutic efficacy of targeting Notch ligands in limiting intestinal
inflammation.
In aim 2, we will determine the mechanism behind increased Notch ligand expression. Specifically, we will
determine the role of autophagy in regulating Notch ligand expression.
The information generated from this project will provide a ground-breaking step with important long-term
implications in understanding how inflammatory macrophages affect intestinal barrier integrity through
modulation of both ISC and differentiated epithelium functions.
Project Summary Page

## Key facts

- **NIH application ID:** 10496982
- **Project number:** 2P20GM121176-06
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Eliseo F Castillo
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $220,642
- **Award type:** 2
- **Project period:** 2017-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10496982

## Citation

> US National Institutes of Health, RePORTER application 10496982, Atg5-dependent regulation of Notch ligands in intestinal inflammation (2P20GM121176-06). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10496982. Licensed CC0.

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