# Discovery of genetic elements regulating intraepithelial lymphocytes

> **NIH NIH R21** · ROCKEFELLER UNIVERSITY · 2020 · $211,875

## Abstract

PROJECT SUMMARY
Intraepithelial lymphocytes (IELs) are an abundant and heterogeneous population of T cells that reside at the
intestinal epithelium, a critical environmental interface between the intestinal tract and the body core. IELs are
tasked with maintaining tolerance to a high volume of harmless stimuli from food and commensal microbiota
while providing protective immunity against ingested pathogens. Dysregulation of this balance leads to loss of
intestinal barrier integrity, susceptibility to enteric infections, and inflammatory bowel diseases. However, many
key aspects of IEL development, tissue residence, and function remain unclear, and the pursuit of these
questions has been hampered by a lack of genetic targeting strategies for the majority of IEL subsets. We
propose to undertake a trait mapping study using the recently established Diversity Outbred and Collaborative
Cross mouse cohorts to identify novel genetic factors influencing IEL maturation and tissue maintenance.
Recently, we performed quantitative trait loci analysis using these cohorts and identified 78 IEL-associated
genomic regions. To determine which single nucleotide polymorphisms (SNPs) within IEL-associated loci are
most likely to be causative, we will take a rigorous bioinformatics approach including functional characterization
of SNPs, identification of candidate target genes, text mining for published association of candidate genes with
relevant ontologies and cell or tissue types, and intestinal gene expression analysis. Further, for at least one
candidate IEL-associated SNP identified we will use CRISPR/Cas9 gene editing to generate SNP mutants in
C57BL/6 mice, with the goal of generating genetic models of high or low IEL frequency. These mice will be
used to confirm biological relevance of candidate genetic elements in vivo, and will enable extensive future
research into IEL function. The proposed work may promote understanding of how IELs contribute to gut
homeostasis and suggest novel therapeutic targets for gut inflammatory diseases.

## Key facts

- **NIH application ID:** 9948570
- **Project number:** 5R21AI144827-02
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Daniel S Mucida
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $211,875
- **Award type:** 5
- **Project period:** 2019-06-07 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948570

## Citation

> US National Institutes of Health, RePORTER application 9948570, Discovery of genetic elements regulating intraepithelial lymphocytes (5R21AI144827-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9948570. Licensed CC0.

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