# Aberrant DNA Repair and Lupus

> **NIH NIH R35** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $829,417

## Abstract

Project Summary/Abstract:
Over one million Americans suffer from Systemic Lupus Erythematosus, an autoimmune disease for which there
is no cure. Systemic lupus erythematosus (SLE or lupus) is a chronic autoimmune disease. The disease
presentation is heterogenous, women are nine times more likely to develop SLE than men, and lupus is
significantly more prevalent in people of Asian, Hispanic, Native American, and African ancestry than people of
European ancestry. Lupus is a significantly understudied disease. Monozygotic twin concordance is found to be
as low as 25% and familial aggregation studies suggest that lupus results at least in part from genetic
predisposition. Most experts in the field agree that gene-environment interactions are important for lupus
development. Recent work from our laboratory suggests that aberrant DNA repair leads to the development of
lupus in a mouse model of the disease. We originally showed that a mutation in the POLB gene in mice results
in development of lupus as a result of defective VDJ recombination and somatic hypermutation. In collaboration
with Dr. Lindsey Criswell we have now identified a large number of coding germline variants that are enriched in
individuals with lupus. In preliminary research, we have demonstrated that mice harboring one of these variants
within the mismatch repair pathway develop high levels of antinuclear antibodies and lupus-associated lung
disease. We have shown that somatic hypermutation is abnormal in these mice and results in the production of
autoantibodies. Our RIVER project is focused on providing mechanistic insights into the development of lupus
as a result of gene-environment interactions. A challenge in the field is understanding how environmental
exposures influence lupus development. We suggest that many previous analyses may be underpowered
because the genetic predisposition factors of the individuals studied are likely to differ, and that genetic factors
play a significant role in the response of the organism to the environment. Our approach to address this challenge
is to construct mouse models of coding genetic variants in DNA repair genes that are significantly enriched in
individuals with lupus. This will be followed by characterization of the disease pathologies emerging in these
mice in the absence and presence of environmental exposures that are known to be linked to lupus development.
We will then take a combined genetic, molecular, and biochemical approach to elucidate underlying mechanistic
insights into the development of lupus. Our project has significant potential to uncover the genetic and
environmental bases of lupus development and to yield paradigm-shifting results that will impact the treatment
of this devastating disease.

## Key facts

- **NIH application ID:** 11005151
- **Project number:** 7R35ES031708-05
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Joann B. Sweasy
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $829,417
- **Award type:** 7
- **Project period:** 2020-07-06 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11005151

## Citation

> US National Institutes of Health, RePORTER application 11005151, Aberrant DNA Repair and Lupus (7R35ES031708-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11005151. Licensed CC0.

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