# Inflammatory Bowel Disease Susceptibility Gene Regulation of Anemia

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2021 · $233,250

## Abstract

SUMMARY
Anemia resulting from iron deficiency is the most frequent extraintestinal manifestation of
inflammatory bowel disease (IBD) and can significantly impact patient health and quality of life.
However, the mechanisms of iron deficiency associated with IBD are poorly understood.
Moreover, the contributions of susceptibility genes associated with increased risk of IBD to the
development of anemia are virtually unknown. Protein tyrosine phosphatase non-receptor type 2
(PTPN2) loss-of-function mutations are genetic markers of increased IBD risk. This proposal
builds on our novel preliminary data identifying that in a proteomic screen of serum from PTPN2-
genotyped IBD patients, altered expression of iron-handling proteins was the #1 pathway modified
in IBD patients harboring the rs1893217 PTPN2 loss-of-function risk allele, independent of
disease severity. We also show that Ptpn2-deficient mice have anemia. We hypothesize that
PTPN2 is a critical regulator of iron handling mechanisms and that loss of PTPN2 activity disrupts
iron homeostasis and metabolism. The goal of this study is to translate patient biomarker
findings into experimental models to mechanistically explore PTPN2 regulation of iron transport,
and understand how PTPN2 loss of function may contribute to iron deficiency in IBD. To dissect
the mechanisms by which PTPN2 regulates iron homeostasis, we will focus on PTPN2 regulation
of two essential cell types that are critically important for iron homeostasis. Intestinal epithelial
cells are responsible for the only entry route for iron into the body: absorption by intestinal
epithelial cells, while macrophages are responsible for capturing and recycling iron from the
breakdown of erythrocytes. In Aim 1, we will identify the role of PTPN2 in regulating intestinal
epithelial iron uptake by measuring iron absorption and exit in vivo and in vitro using enteroids
from constitutive and inducible intestinal epithelial-specific Ptpn2 knockout mice. We will also
determine how PTPN2 regulates molecular pathways involved in iron transport and metabolism.
In Aim 2, we will identify the mechanisms of PTPN2 regulation of macrophage iron handling
by determining how PTPN2 deficiency alters iron recycling and regulation of essential iron-
handling proteins using macrophage-specific PTPN2 knockout mice and CRISPR-modified
human macrophages expressing the clinical PTPN2 loss-of-function rs1893217 risk allele.
Expected Outcomes & Impact: These studies will translate findings in PTPN2-genotyped
patients to complementary in vivo and in vitro model systems. We will not only generate
fundamental and highly novel insights into PTPN2 regulation of iron homeostasis and its potential
role as a complicating factor in anemia associated with IBD, but will also identify novel targets for
intervention.

## Key facts

- **NIH application ID:** 10129137
- **Project number:** 1R21AI152017-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** Declan McCole
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $233,250
- **Award type:** 1
- **Project period:** 2021-03-03 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129137

## Citation

> US National Institutes of Health, RePORTER application 10129137, Inflammatory Bowel Disease Susceptibility Gene Regulation of Anemia (1R21AI152017-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129137. Licensed CC0.

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