# Modeling xenobiotic-induced autoimmunity using Collaborative Cross strains.

> **NIH NIH R21** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $221,875

## Abstract

Autoimmunity is thought to result from a combination of genetics, environmental triggers, and stochastic events.
Although the role of environmental/xenobiotic agents in triggering autoimmunity is well established, it is unclear
if idiopathic and experimentally induced disease arise by common genetic, molecular and cellular pathways.
Genetic studies have suggested that idiopathic and xenobiotic-induced animal models of systemic autoimmunity
share common requirements as well as significant differences, such as the importance of the inflammasome and
type I interferons. The lack of genetic and phenotypic criteria for discriminating between idiopathic and
environmental/xenobiotic-induced systemic autoimmune disease is a critical barrier to our understanding of
autoimmunity in general. Inbred laboratory mouse strains have proven vital for autoimmune disease research
because the inbred genotype provides a genetically uniform animal for experimental purposes. However, the
restricted genetic heterogeneity among the common laboratory strains that is primarily derived from two original
Asian and European fancy mice, limits the diversity of common variants that are currently thought to play the
major role in complex diseases such as systemic autoimmunity. We propose that the Collaborative Cross (CC)
mouse panel is better suited to model the range of phenotypes in complex disease because it is the only
mammalian resource with genome-wide genetic variation randomized across a large, heterogeneous and
reproducible population and it incorporates the genomes of three strains of wild mice from different continents.
Consequently, CC mice strains provide a powerful tool to model environmental/xenobiotic-induced autoimmunity
in a genetically heterogeneous population. To test this, we will examine the response of CC strains to crystalline
silica and HgCl2. These two agents have been chosen because HgCl2 induces features of autoimmunity
(autoantibodies, kidney disease), but not overt disease in humans and mice, while crystalline silica induces
systemic autoimmune disease in both. We hypothesize that the genetic diversity of the CC panel of recombinant
inbred (RI) strains will allow us to show that exposure to HgCl2 and silica leads to different profiles of immune
mediators, inflammation, autoantibodies, and pathology which explain their disparate levels of disease severity.
Additionally, we argue that use of the CC RI strains will not only significantly improve our ability to identify genetic
loci, but to also determine specific genes and molecular pathways that discriminate HgCl2- and silica-induced
systemic autoimmune disease from each other as well as from idiopathic systemic autoimmunity. We will address
this in three aims. Specific aim 1: Analysis of baseline serum biomarkers in CC RI strains, Specific Aim 2:
Induction and analysis of xenobiotic-induced autoimmunity in CC RI mice, and Specific Aim 3: Genetic mapping
of xenobiotic-induced autoimmunity in CC RI mice...

## Key facts

- **NIH application ID:** 10111516
- **Project number:** 5R21ES031454-02
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Kenneth Michael Pollard
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $221,875
- **Award type:** 5
- **Project period:** 2020-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10111516

## Citation

> US National Institutes of Health, RePORTER application 10111516, Modeling xenobiotic-induced autoimmunity using Collaborative Cross strains. (5R21ES031454-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10111516. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*