# Elucidating the molecular mechanisms underlying ligand-dependent REV-ERB activity in Th17 cells

> **NIH NIH F31** · UNIVERSITY OF FLORIDA · 2022 · $24,646

## Abstract

Project Summary/Abstract
Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis are characterized by an
inappropriate immune response to commensal gut flora that causes chronic damage to the gastrointestinal (GI)
tract. Genome-wide association studies showing genes associated with T helper 17 (Th17) immune responses
are strongly implicated in IBD susceptibility together with clinical evidence of Th17 cells in GI tissues of IBD
patients have identified a central role for Th17 cells in IBD pathogenesis. Although Th17 cells are characterized
by the production of IL-17A, they also produce many other molecules each with critical roles in regulating the
immune response. This could explain why IL-17A-neutralizing antibodies have had little success in treating IBD,
while targeting factors within Th17 cells that broadly regulate their expression of effector molecules may be a
more effective strategy. To this end, we recently demonstrated that the closely related REV-ERB (REV-ERBa
and REV-ERBb) nuclear receptors (NRs) are cell-intrinsic repressors of Th17 cell pathogenicity. Transcriptional
repression of signature Th17 cell genes by the REV-ERBs is essential for limiting disease severity in mouse
models of chronic inflammatory disease and treatment with synthetic REV-ERB ligands developed at Scripps
Florida enhanced the protective effect. The porphyrin, heme, is the endogenous ligand for the REV-ERBs and
my preliminary data indicate that heme is important for REV-ERB activity in Th17 cells. Since NR ligands evolved
to transmit extracellular or intracellular signals into changes in gene expression, understanding the source and
effects of heme-dependent REV-ERB activity in Th17 cells may reveal signaling pathways underlying IBD
pathogenesis that could be exploited for therapeutic benefit. At the same time, although the basis for ligand-
dependent NR activity is in their regulation of NR structure, contradictory evidence between published cell-based
and structural studies has prevented understanding of the molecular basis for heme-dependent REV-ERB
activity. My preliminary data reveal a potential solution to this conflict. My overarching hypothesis is that heme
produced intracellularly in Th17 cells enhances REV-ERB repression of a pathogenic Th17 cell
phenotype by stabilizing the REV-ERBs’ interaction with a transcriptionally repressive coregulator
(corepressor) protein. I will test this hypothesis through two central aims: 1) I will identify the role of heme as a
REV-ERB-dependent signaling molecule in Th17 cells and 2) I will define the heme-dependent structural
changes that influence REV-ERB activity. I expect the results of these aims to characterize an underexplored
signaling pathway in Th17 cells that could be targeted to treat IBD. In the process, I will receive comprehensive
training in immunology and structural biology approaches from a unique, interdisciplinary mentorship team.
Together with the extensive professional d...

## Key facts

- **NIH application ID:** 10592012
- **Project number:** 6F31DK127643-03
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Sarah Mosure
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $24,646
- **Award type:** 6
- **Project period:** 2021-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10592012

## Citation

> US National Institutes of Health, RePORTER application 10592012, Elucidating the molecular mechanisms underlying ligand-dependent REV-ERB activity in Th17 cells (6F31DK127643-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10592012. Licensed CC0.

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