# The Role of an MSH6 Gene Variant and UV Radiation in Systemic Lupus Erythematosus

> **NIH NIH K99** · UNIVERSITY OF ARIZONA · 2021 · $87,463

## Abstract

PROJECT SUMMARY/ABSTRACT
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease that involves the combination of
both genetic and environmental risk factors for disease in humans. This disease afflicts over 3 million people
worldwide, and there is currently no cure for SLE. Recently, I have developed a novel mouse model that has a
knockin of a human SLE-associated gene variant (GV) in the mismatch repair gene MSH6. Interestingly,
preliminary data indicate that mice homozygous for the MSH6 GV have significantly increased serum titers of
anti-nuclear antibodies, a hallmark criterion of SLE, as compared to wildtype mice. The main objective of this
study is to analyze two human-associated factors, one environmental and the other genetic, to understand the
underlying mechanism of SLE pathogenesis. Importantly, this study is significant because the use of two human-
associated factors, the human-derived GV and UV radiation, will closely mimic the multifactorial pathoetiology
seen in human SLE. Therefore, this mouse study can potentially provide insight into human SLE that cannot be
derived from other models. This proposal is divided into 3 aims to elucidate the role of UV radiation and DNA
repair in SLE pathogenesis. The first aim will seek to understand if the MSH6 GV and UV radiation leads to
decreased latency and/or increased severity of lupus in mice by analyzing the onset of SLE phenotypes—such
as anti-nuclear antibodies, glomerulonephritis, and dermatitis—in MSH6 GV mice un/treated with UV radiation.
The second aim will seek to understand the immunological effects induced by the MSH6 GV and UV radiation.
This will be determined by utilizing high-throughput sequencing and in vitro assays to elucidate how the MSH6
GV and UV radiation influences antibody diversification and the removal of autoreactive B cells. Lastly, the third
aim will utilize in vitro assays to determine the binding affinity of the MSH6 variant to its cognate substrate and
determine if the MSH6 GV and UV radiation promote an aberrant DNA response and cell death, which can
potentially induce the production of anti-nuclear antibodies by manipulating antibody diversification and
autoantigen release, respectively. The first aim will be initiated and completed during the mentored phase, and
the second and third aims will be initiated during the mentored phase to gain expertise in specific techniques
and completed during the independent phase. To achieve the aims of this proposal, I assembled a team of
mentors with expertise in human and murine autoimmunity, inflammation, immunology, and DNA repair. This
team will also provide me the guidance and tools to transition into independence and to establish a successful
lab. Additional opportunities to attend and present at conferences and to mentor students and postdoctorates
will be complementary for my long-term goal of establishing an independent research program. Collectively,
each of these individuals and opportunities...

## Key facts

- **NIH application ID:** 10236530
- **Project number:** 5K99ES030748-02
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Rithy Meas
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $87,463
- **Award type:** 5
- **Project period:** 2020-08-12 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10236530

## Citation

> US National Institutes of Health, RePORTER application 10236530, The Role of an MSH6 Gene Variant and UV Radiation in Systemic Lupus Erythematosus (5K99ES030748-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10236530. Licensed CC0.

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