# Estrogen-mediated immune regulation in human and experimental inflammatory bowel disease

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $419,771

## Abstract

Project Summary/Abstract
Regulatory T cell (Treg) immunosuppression is critical for maintaining immune tolerance to a diverse array of
potential antigens in the intestinal mucosa. In patients with inflammatory bowel disease (IBD), chronic intestinal
inflammation overwhelms local Treg function, allowing inflammation to persist. Our previous work and that of
others have identified important roles for 17β-estradiol (estrogen, E2) signaling in promoting Treg differentiation
and function. E2 signals through two nuclear receptors, alpha and beta (ERα, ERβ), to modulate gene
transcription in target cells. Although they share high sequence homology, ERα and ERβ mediate distinct and
often opposing functions on gene regulation. In previously published work, we showed that shifting the balance
of E2 signaling towards ERα is generally pro-inflammatory, whereas shifting towards ERβ is generally protective.
In recent preliminary studies using IBD patient samples, we observed significantly diminished ERβ expression
in intestinal biopsy tissues and peripheral T cells from females with active Crohn’s disease (CD). We also found
that ERβ-deficient T cells are resistant to ex vivo, TGFβ-dependent Treg differentiation, and that deletion of ERβ
in a spontaneous ileitis model (SAMP/YitFC, “SAMP” mice) results in significant impairment of Treg
transcriptional and functional responses, contributing to exacerbated inflammation. Therefore, the goal of this
project is to determine the molecular and cellular mechanism(s) by which altered E2 signaling impacts
Treg differentiation and function, contributing to intestinal inflammation. The mechanisms by which E2
signaling cross-talks with inflammatory signals to influence immune cell function are poorly understood. This
proposal seeks to address this knowledge gap through our central hypothesis that dysregulated E2 signaling
contributes to Treg transcriptional remodeling and loss-of-function, facilitating sustained intestinal
inflammation in IBD. In Aim 1, we propose to delineate the molecular mechanisms by which ERα- and ERβ
cross-talk with signaling downstream of TGFβ in primary T cells, influencing TGFβ-dependent Foxp3 expression
and function. Aim 2 will determine the functional impact of rebalancing Treg-specific E2 signaling on intestinal
inflammation in vivo, testing our hypothesis that augmenting Treg-specific ERβ signaling may prevent and/or
rescue intestinal inflammation. Experiments will include adoptive transfer of ERβ-expressing Tregs to SAMP
mice, as well as in vivo assays using a T cell-dependent colitis model. In Aim 3, we plan to determine the
transcriptional and functional effects of rebalancing E2 signaling in CD patient Tregs using novel MaxCyte
transfection technology, assessing ERα- and ERβ-specific effects on (i) TGFβ-dependent Foxp3 induction in
naïve T cells and (ii) ex vivo suppressive function of Tregs. Successful completion of our proposed Aims
will provide key mechanistic insight into the functional...

## Key facts

- **NIH application ID:** 10182035
- **Project number:** 1R01DK128143-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Wendy Ann Goodman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $419,771
- **Award type:** 1
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10182035

## Citation

> US National Institutes of Health, RePORTER application 10182035, Estrogen-mediated immune regulation in human and experimental inflammatory bowel disease (1R01DK128143-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10182035. Licensed CC0.

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