# Uncovering the role of Setbp1 in fibroblast-like synoviocytes during inflammatory arthritis

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $454,476

## Abstract

Project Summary
Fibroblast-like synoviocytes (FLS) play a critical role in the pathology of inflammatory joint diseases such as
rheumatoid arthritis, psoriatic arthritis, and juvenile idiopathic arthritis. Under chronic inflammation, FLS undergo
epigenetic remodeling and are transformed into aggressive cancer-like cells, which evade apoptosis, proliferate,
and produce catabolic factors that degrade the articular cartilage and subchondral bone. Once, transformed, the
FLS are known to retain their aggressive properties despite removing them from the inflammatory
microenvironment. Epigenetic remodeling is suggested as the underlying cause for the persistently transformed
phenotype of the FLS. However, the identity of the factors that drive the epigenetic remodeling of the FLS is
incompletely understood. In this proposal, we will focus on defining the roles of an epigenetic hub protein
SETBP1 (Set binding protein 1) in regulating the switch from a homeostatic epigenomic signature to an arthritic
epigenomic signature of the FLS. SETBP1 is an epigenetic hub protein that recruits various types of histone
remodeling complexes to activate or repress gene expression. Previous studies show that gain-of-function and
loss-of-function mutations or deletions of SETBP1 result in impaired embryogenesis and skeletogenesis. Our
preliminary data suggest that SETBP1 also plays a role in maintaining the homeostasis of FLS in adult joints.
Based on these findings we propose our overarching hypothesis that the downregulation of SETBP1 promotes
joint degeneration in IJD. We propose that SETBP1 acts as an epigenetic switch by repressing pro-inflammatory
genes and by repressing anti-inflammatory gene expression. We will test this hypothesis by the conditional
inactivation of Setbp1 in adult joints in a mouse model of rheumatoid arthritis. In Aim 1 we will use phenotypic
and molecular analysis to show a negative interaction between the inflammation and SETBP1. Under Aim 2 we
will investigate if the level of SETBP1 protein determines the epigenetic status of the FLS and thereby drives
their transformation. Under Aim 3 we will investigate the upstream molecular mechanism for SETBP1
expression. Successful completion of this proposal will establish SETBP1 as an epigenetic switch factor in the
FLS. Our results will suggest that SETBP1 is a therapeutic target to prevent drug resistance and the recurrence
of symptoms in autoimmune joint diseases.

## Key facts

- **NIH application ID:** 10982097
- **Project number:** 2R01AR070736-06A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Pallavi Bhattaram
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $454,476
- **Award type:** 2
- **Project period:** 2017-09-06 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10982097

## Citation

> US National Institutes of Health, RePORTER application 10982097, Uncovering the role of Setbp1 in fibroblast-like synoviocytes during inflammatory arthritis (2R01AR070736-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10982097. Licensed CC0.

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