# Role of protein citrullination in rheumatoid arthritis

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $388,300

## Abstract

Project Summary/Abstract
Despite several new treatment options, many patients with rheumatoid arthritis (RA) continue
to suffer from poorly controlled disease. To enable the urgently needed development of better
therapies, the molecular mechanisms that underpin the pathogenesis of RA need to be better
understood. The newest hypothesis postulates that abnormally citrullinated proteins become
`neo'-self-antigens and stoke direct autoimmunity against this modified self. Key questions now
are why and how excessive and/or abnormal citrullination occurs in RA patients.
The research proposed here will provide novel insights into how pathological citrullination
occurs in RA patients. This work will help elucidate the molecular mechanisms by which the
citrullinating enzymes PAD2 and/or PAD4 act in triggering RA. This will, in turn, be invaluable
for evaluating them as drug targets, and will provide biomarker opportunities to monitor the
activity of the disease and possibly stratify RA patients into different subpopulations that may
require different therapies. The Specific Aims are:
AIM 1. The mechanism(s) of increased citrullination in RA patients.
AIM 2. A novel function of PAD4 in oxidative burst regulation.
The first Aim directly seeks evidence in patient samples of the five proposed mechanisms of
pathological citrullination to determine which are operational in vivo. Their contributions
individually, or in combinations, to protein citrullination of disease-relevant substrates,
including substrate mixtures and cells relevant to RA pathogenesis will be investigated.
The second Aim explores the discovery of a novel link between PAD4 and the cytosolic
components of the NADPH oxidase machinery (NOX2) in human neutrophils. The citrullination
of NOX2 components may contribute to the pathogenesis of RA by blocking a protective
oxidative burst response. The molecular details of PAD4 interaction with NOX2 will be
examined and the citrullination of specific arginine residues and the functional consequences of
these sites on the oxidative burst response tested, as this response has been reported to be
involved in tempering autoimmunity.

## Key facts

- **NIH application ID:** 9883195
- **Project number:** 1R01AR074939-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Tomas M Mustelin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,300
- **Award type:** 1
- **Project period:** 2020-02-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9883195

## Citation

> US National Institutes of Health, RePORTER application 9883195, Role of protein citrullination in rheumatoid arthritis (1R01AR074939-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9883195. Licensed CC0.

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