# Regulation of TH17 Cell Development and Function by the REV-ERBs

> **NIH NIH R01** · SCRIPPS FLORIDA · 2020 · $480,000

## Abstract

Project Summary / Abstract
Under homeostatic conditions, TH17 cells have essential roles in protective immunity against extracellular
pathogens at mucosal barriers. However, TH17 cells have also been associated with the pathogenesis of
several autoimmune diseases, suggesting that failure of TH17 cell homeostasis may give rise to disease states.
A significant amount of work has identified key factors that drive TH17 cell development and pathogenicity,
including both the nuclear receptors (NRs) RORα and RORγt. However, cell-intrinsic mechanisms that
negatively regulate TH17 cell development and associated inflammatory responses have received less
attention. Therefore, a more comprehensive understanding of this cell type is needed to better understand
TH17 cell biology and autoimmunity in order to identify novel therapeutic targets to treat TH17-mediated
diseases. The REV-ERBs (REV-ERBα and REV-ERBβ), two other members of the NR superfamily, are often
co-expressed in the same tissues as the RORs and bind the same DNA response elements, which suggest
mutual cross talk and co-regulation of their target genes. The REV-ERBs regulate a number of physiological
processes and are best known for their roles in the circadian rhythm and metabolic processes. While much is
known about the roles for ROR regulation of TH17 cell development and function, the biology of the REV-ERBs
in this process is completely unexplored. Our preliminary studies indicate that the REV-ERBs have distinct
roles in the regulation of TH17 cell development. Overexpression of the REV-ERBs inhibits TH17 cell
development, whereas genetic deletion of each receptor results in increased RORα/γt and CD4+IL-17A
expression. Using novel REV-ERB-specific synthetic ligands that we have developed, we demonstrate that
pharmacological modulation of REV-ERB activity inhibits TH17 cell development and function both in vitro and
in vivo. Based on our data, we hypothesize that the REV-ERBS are key negative regulators of TH17 cell
development and function and REV-ERB-specific synthetic ligands may provide novel therapeutics for the
treatment of TH17-mediated autoimmune diseases. To test our hypothesis we propose to 1) Identify the roles
for the REV-ERB in the regulation of TH17 cell development and function; 2) Demonstrate that the REV-ERBs
are negative regulators of TH17 cell development and autoimmune disease progression in vivo; 3) Determine
how REV-ERB-specific pharmacological modulation affects REV-ERB activity, TH17 cell functional responses,
and autoimmunity. Successful completion of these studies will uncover key roles for the REV-ERBs in TH17
cell biology and reveal that REV-ERB-specific ligands may be a novel therapeutic strategy for the treatment of
TH17-mediated autoimmune diseases.

## Key facts

- **NIH application ID:** 9821180
- **Project number:** 5R01AI116885-05
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Laura A Solt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $480,000
- **Award type:** 5
- **Project period:** 2015-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9821180

## Citation

> US National Institutes of Health, RePORTER application 9821180, Regulation of TH17 Cell Development and Function by the REV-ERBs (5R01AI116885-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9821180. Licensed CC0.

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