# Role of apoptosis in the intestinal epithelium during homeostasis and disease

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $381,375

## Abstract

PROPOSAL SUMMARY
The intestinal epithelium protects against food antigens and the luminal microbiota by forming a physical
barrier and actively secreting mucous and anti-microbial peptides. The intestinal epithelium is maintained by a
process of constant renewal through a cycle of cell division, differentiation, and apoptosis. Apoptosis is a
potent inducer of regulatory CD4 T (TREG) cells and immune tolerance. During infection, apoptosis induces a
tailored CD4 T helper 17 (TH17) response. Whether apoptosis of intestinal epithelial cells (IEC) plays any role
in intestinal tolerance and effector response is not known. Professional mononuclear phagocytes (MP), such
as macrophages and dendritic cells (DC), clear microbial pathogens during infection and apoptotic cells during
embryonic development and tissue remodeling. While much attention has centered on MP sampling of
commensal and pathogenic microorganisms within the gut lumen, less attention is directed towards sampling
of apoptotic IEC, despite the prominent role that apoptosis plays in the intestinal epithelium. Interference with
the natural cycle of apoptosis in IEC leads to intestinal inflammation in mouse models. There is increased IEC
death and damage to the intestinal epithelium in patients with inflammatory bowel disease (IBD), and this fuels
intestinal dybsiosis and inflammation. Several international IBD genome wide association studies (GWAS) and
meta-analyses have associated susceptibility to IBD with genes involved in pathways regulating innate immune
responses, immunomodulatory cytokines, and TH17 signaling. Gene expression data from different murine cell
types have shown the strongest enrichment of IBD genes in innate immune cells, particularly DC. Gaining an
understanding of whether and how apoptosis of the intestinal epithelium impacts the processes of tolerance
and immunity within the intestine is therefore of utmost importance.
 Using two novel mouse models, we will determine how increasing or impairing apoptosis of the
intestinal epithelium impacts the homeostatic and immune responses within the intestine. We have compelling
evidence that apoptosis in the small intestinal epithelium is not a bystander event, but actively imprints lamina
propria MP with `suppression of inflammation' and `induction of TREG cell' transcriptional signatures. Notably,
many of the genes differentially modulated in MP after apoptotic IEC uptake overlap with IBD genes. Here we
will examine the identities and profiles of colonic MP during steady state and infection. We will investigate how
apoptosis impacts the functions of intestinal MP as they relate to various mechanisms of immune tolerance
and effector response in the intestine. This includes their response to microbial components, their maintenance
of innate lymphoid cells, and their instruction of TREG and TH17 cell fates. All these parameters are disrupted in
IBD. By the completion of these studies, we will have gained new insights into the role ...

## Key facts

- **NIH application ID:** 9926879
- **Project number:** 5R01DK111862-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Julie Magarian Blander
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,375
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926879

## Citation

> US National Institutes of Health, RePORTER application 9926879, Role of apoptosis in the intestinal epithelium during homeostasis and disease (5R01DK111862-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9926879. Licensed CC0.

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