# Investigating how platelet-derived growth factor receptors direct synovialfibroblast-mediated pathology in inflammatory arthritis

> **NIH NIH R56** · UNIVERSITY OF WASHINGTON · 2020 · $388,300

## Abstract

PROJECT SUMMARY/ABSTRACT
There is a fundamental gap in understanding of how different types of synovial fibroblasts contribute to
rheumatoid arthritis (RA) pathology, restricting the ability to block fibroblast-mediated joint inflammation and
cartilage erosions. The long-term goal driving this proposal is to identify ways to specifically target fibroblast
function in inflammatory arthritis. The objective of this proposal to investigate platelet-derived growth factor
receptors (PDGFRs) as one of these targets. Although PDGFRs are potent stimulators of fibroblast
proliferation and migration and are known to be upregulated in RA, PDGFR research in inflammatory arthritis
has lagged behind other disease fields. The rationale for this study is that it will advance new therapeutic
approaches in autoimmune inflammatory arthritis by both developing preclinical data to support an arthritis
indication for newly developed anti-PDGFR therapeutics and by discovering novel fibroblast pathways for
future clinical targeting. The central hypothesis shaping this proposal is that that PDGFRα and PDGFRβ
independently contribute to the development of inflammatory arthritis and fibroblast-mediated joint pathology.
This hypothesis is built on preliminary data showing different functional outcomes following PDGFRα or
PDGFRβ activation in RA synovial fibroblasts and demonstrating that different fibroblast subpopulations can be
isolated directly from the synovium based on PDGFRα and PDGFRβ expression. This hypothesis will be tested
in three specific aims: (1) Determine how PDGFRα and PDGFRβ expression regulates inflammatory arthritis
development; (2) Determine how PDGFRα and PDGFRβ activation is regulated in synovial fibroblasts; and (3)
Test anti-PDGFR treatment combinations in a preclinical inflammatory arthritis model. Aim 1 uses inducible
genetic deletion of PDGFRs to test their function in arthritis development in a mouse model and correlates this
function with the transcriptional profiles of PDGFR-expressing fibroblast populations isolated directly from the
synovium. Aim 2 isolates differential effects of PDGFRα and PDGFRβ activation in synovial fibroblasts by
examining gene expression, membrane interactions, and ligand availability. Aim 3 uses the preclinical serum
transfer mouse arthritis model to test how anti-PDGFR antibodies may augment arthritis treatment when
combined with other types of therapies. This approach is innovative, in the applicant's opinion, because it
reenergizes PDGFR research in RA by combining genetic tools developed for other diseases with new flow
cytometric and bioinformatic methods to analyze fibroblast function both in vitro and directly ex vivo. The
proposed research is significant because determining how PDGFRα and PDGFRβ expression and signaling
regulates fibroblast and synovial biology is expected to assess how new PDGF-specific drugs can be used to
treat RA and to increase our fundamental understanding of how different synovial fibro...

## Key facts

- **NIH application ID:** 10247966
- **Project number:** 1R56AR073844-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Jan Christian Lood
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,300
- **Award type:** 1
- **Project period:** 2020-09-10 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247966

## Citation

> US National Institutes of Health, RePORTER application 10247966, Investigating how platelet-derived growth factor receptors direct synovialfibroblast-mediated pathology in inflammatory arthritis (1R56AR073844-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10247966. Licensed CC0.

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