# Investigating a rare pediatric enteropathy caused by ADAM17 loss of function using iPSC-derived human intestinal organoids

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2023 · $39,353

## Abstract

Project Summary
ADAM17 loss of function (LOF) is the cause of a pediatric enteropathy termed Neonatal Inflammatory Skin and
Bowel Disease 1 (NISBD1), which is associated with intestinal inflammation and diarrhea. While little is known
about NISBD1, two patient biopsies revealed abnormal intestinal crypt/villus morphology. The crypt/villus
structure is the fundamental repeating intestinal unit lined by an epithelium that contains crypt restricted intestinal
stem cells (ISCs). ISCs give rise to differentiated cells and are integral to maintaining epithelial function. ISCs
are supported by specialized epithelial cells and underlying mesenchymal cells that provide ISC niche signals,
including EGF-like ligands. ADAM17 is a ubiquitously expressed protease that cleaves and sheds proteins from
the cell membrane. Its substrates include EGF-like ligands, suggesting a role for ADAM17 in the ISC niche.
Recent work has revealed that ErbB3 ligand neuregulin 1 (NRG1) promotes human ISC maturation and
differentiation. Human fetal intestinal tissue sections reveal mesenchyme restricted expression of NRG1 and
epithelium restricted expression of its receptor ErbB3. This suggests a pattern of ADAM17 mediated
mesenchyme to epithelium signaling crosstalk. I will test the hypothesis that ADAM17 mediates cellular
crosstalk, regulating human intestinal epithelial development. First, I am establishing a matched isogenic
set of NISBD1 patient iPSC lines with one CRISPR corrected to be ADAM17 proficient. I will differentiate both
lines into human intestinal organoids containing organized epithelium and mesenchyme. Then, I will interrogate
the ADAM17 LOF phenotype using cellular, transcriptomic, and functional analyses. Next, I will investigate
ADAM17 mediated cellular crosstalk in a targeted approach by studying NRG1-ErbB3 signaling. To identify
additional candidate ADAM17 substrates, I will take an unbiased mass spectrometry and proteomics approach
to determine all human intestinal ADAM17 substrates, i.e. the sheddome. This analysis will establish datasets
for future targeted investigation of ADAM17 substrates in the human ISC niche. In summary, I will perform an
innovative patient specific disease modeling study using iPSC-derived organoids to characterize NISBD1 and
study the role of ADAM17 in the developing human intestine.

## Key facts

- **NIH application ID:** 10823723
- **Project number:** 1F31DK138753-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Shane Williams
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $39,353
- **Award type:** 1
- **Project period:** 2023-09-11 → 2026-09-10

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10823723

## Citation

> US National Institutes of Health, RePORTER application 10823723, Investigating a rare pediatric enteropathy caused by ADAM17 loss of function using iPSC-derived human intestinal organoids (1F31DK138753-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10823723. Licensed CC0.

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