# Regulation of Mucosal Lymphocytes

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $683,655

## Abstract

PROJECT SUMMARY/ABSTRACT
CEACAM1 is a single-pass type I transmembrane protein and the primordial member of the carcinoembryonic
antigen (CEA) family of immunoglobulin molecules that is expressed on the apical and basolateral surfaces of
intestinal epithelial cells (IEC) and on a wide range of immune cell types. However, its functions on intestinal
epithelial cells (IECs) are unknown. The current research proposal addresses the unanswered question of
whether CEACAM1 acts to convert microbial or host signals from the apical and/or basolateral surface into the
production of antimicrobial peptides (AMP) by IECs. The ability of the IEC to sense the presence of microbes
and deliver antimicrobial peptides (AMP) into the lumen represents a major mechanism of mucosal defense. Our
long-term goals are to determine whether CEACAM1-mediated stimulation of AMPs protects from commensal
and pathogenic microbe invasion of the IEC and susceptibility to colitis, the vectoral direction required for this
stimulation (apical and/or basolateral), whether it is specifically dependent upon CEACAM1 isoforms with a short
(S) cytoplasmic tail and if high-affinity ligands for CEACAM1 can be developed to stimulate these protective
activities. The objective of this research is to elucidate how CEACAM1 stimulates AMP production and whether
this information together can be co-opted for therapeutic purposes. Our central hypothesis is that CEACAM1
functions as a novel microbial sensor that responds to specific microbes or host ligands with production of AMPs
that are important to barrier protection. This rationale is derived from recent studies that a specific deficiency of
CEACAM1 in mouse IEC in vivo leads to decreased AMP expression by IECs coupled to increased susceptibility
to colitis and invasion by pathogenic microbes. Our central hypothesis will be tested with three specific aims: 1)
Determine whether IEC-associated CEACAM1 regulates the production of AMP and host susceptibility to colitis
and enteropathogens; 2) Determine whether specific CEACAM1 isoforms are responsible for delivering activat-
ing signals to induce AMPs, and; 3) Define a therapeutic strategy to enhance human CEACAM1 ligands that
interact homophilically to induce these protective responses. In Aim 1, we will determine the innate and/or adap-
tive origins of the intestinal inflammation that ensues from CEACAM1-deficiency in the IEC and whether this
involves increased bacterial translocation of founding populations in the lumen. Aim 2 will determine whether
CEACAM1-S isoforms can stimulate IECs to produce AMPs in response to pharmacologic and microbial signals
and whether such stimulation can occur in response to ligation of CEACAM1 on the apical and basolateral sur-
faces. In Aim 3, we seek to generate human CEACAM1 variants with enhanced ability to stimulate IEC produc-
tion of AMP in vitro and in vivo and as such provide protection from experimental colitis. Overall, this proposal is
significant because...

## Key facts

- **NIH application ID:** 10818467
- **Project number:** 5R01DK051362-26
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Richard S Blumberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $683,655
- **Award type:** 5
- **Project period:** 1998-09-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10818467

## Citation

> US National Institutes of Health, RePORTER application 10818467, Regulation of Mucosal Lymphocytes (5R01DK051362-26). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10818467. Licensed CC0.

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