# Project 3: The role of DNASE1L3 and its DNA substrate in lupus

> **NIH NIH P50** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $284,978

## Abstract

ABSTRACT
The hallmark of systemic lupus erythematosus (SLE) is the production of antibodies to nuclear antigens such
as ribonucleoproteins and DNA. Antibodies to double-stranded DNA (dsDNA) and/or chromatin represent an
important transition from benign to overt clinical SLE and may predict flares and the severity of tissue damage.
The mechanisms of tolerance to chromatin/DNA and of its breakdown in SLE are poorly understood. We
explored these mechanisms by focusing on DNASE1L3, a unique secreted DNase whose null mutations are
associated with an early-onset familial SLE. Our studies showed that chromatin in microparticles derived from
apoptotic cells represented a specific substrate of DNASE1L3 in vitro and in vivo. They also demonstrated that
the chromatin and/or other antigens were exposed on the surface of microparticles and recognized by
autoantibodies in a DNASE1L3-sensitive manner. We hypothesize that DNASE1L3-sensitive DNA/protein
complexes on microparticles are important self-antigens in human SLE, and that that DNASE1L3 can be used
to target them for therapeutic purposes. The collaborative nature of the project and unique patient samples and
technologies available from our co-investigators will be leveraged to develop and test this hypothesis. In Aim
1, the incidence and clinical relevance of antibodies to DNASE1L3-sensitive antigens in SLE patients will be
explored. In Aim 2, DNASE1L3-sensitive antigens on microparticles and the antibodies targeting them will be
characterized at the molecular level. In Aim 3, the utility of DNASE1L3 as a therapeutic agent will be tested in
animal models of SLE. Collectively, these studies would provide insights into the origin and mechanisms of the
pathogenic responses to DNA and associated antigens in human SLE, and facilitate novel approaches towards
their therapeutic blockade.

## Key facts

- **NIH application ID:** 10249217
- **Project number:** 5P50AR070591-05
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Boris Reizis
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $284,978
- **Award type:** 5
- **Project period:** 2017-09-22 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249217

## Citation

> US National Institutes of Health, RePORTER application 10249217, Project 3: The role of DNASE1L3 and its DNA substrate in lupus (5P50AR070591-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10249217. Licensed CC0.

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