# Genetics of organ-specific lupus disease sequelae

> **NIH NIH R21** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $207,565

## Abstract

SUMMARY/ABSTRACT
Systemic lupus erythematosus (SLE or lupus) is a deadly and incurable autoimmune disease characterized by
widespread inflammation and rampant production of autoantibodies. Clinical disease presents as a
heterogeneous spectrum of symptoms and damage to organ systems, including the kidneys and heart. Despite
decades of robust insights into the genetic factors contributing to risk for development of SLE, the functional
genetic mechanisms governing specific disease manifestations remain undefined. Therefore, accurate disease
prognosis and effective prevention of life-threatening organ damage remain challenging. Notably, disease
severity and involvement of specific organs in SLE varies amongst different ethnic groups and between disparate
strains of inbred mice, strongly suggesting that genetic cues may determine pathogenesis of disease. However,
limited genomic variation and restricted recombination rates associated with intercrosses between inbred mouse
strains have complicated dissection of these genetic drivers of disease pathogenesis. To better model human
disease, the collaborative cross was generated from eight founder strains to capture the tremendous genetic
variation present across the mouse genome. The diversity of allele combinations among collaborative cross lines
prompts a broader spectrum of disease phenotypes than commonly observed in inbred mice, thereby facilitating
high resolution mapping of genetic loci influencing complex polygenic traits.
In this proposal, we endeavor to demonstrate that the collaborative cross resource is a powerful tool capable of
identifying specific genetic loci linked to clinically important organ-specific manifestations of SLE. We will apply
a cutting-edge mouse model of SLE that we find differentially provokes cardiac and renal damage in different
inbred mouse strains. The innovative combination of an inducible model of SLE-like disease with the
collaborative cross resource will facilitate qualitative and quantitative comparison of disease outcomes among
individual strains of mice. The breadth of genetic variation captured in these mice will enable mapping of
quantitative trait loci even for small phenotypic variations in disease pathogenesis. This study represents a
promising and original approach to address critical, unanswered questions regarding the genetic origins of
heterogeneous organ-specific manifestations of SLE. The results of the proposed experiments will open new
avenues of basic and translational research into clinically-targetable pathways identified as risk factors for
development of life-threatening cardiac and renal pathologies in SLE. Moreover, these results will likely promote
additional futures attempts at genetic dissection of other heterogeneous manifestations of SLE, including
musculoskeletal, mucocutaneous, neuropsychiatric and pulmonary pathologies.

## Key facts

- **NIH application ID:** 10007204
- **Project number:** 1R21AI145304-01A1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Stephen N. Waggoner
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $207,565
- **Award type:** 1
- **Project period:** 2020-07-22 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10007204

## Citation

> US National Institutes of Health, RePORTER application 10007204, Genetics of organ-specific lupus disease sequelae (1R21AI145304-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10007204. Licensed CC0.

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