# Reconstituting the oligogenic trait 'Eosinophilic myocarditis to heart disease' in Collaborative Cross lines to understand its genetic architecture

> **NIH NIH R21** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $198,750

## Abstract

Abstract / Project Summary
 From a spontaneous founder mutant, we have established several lines of mice that naturally develop
heart disease (HD), which rapidly progresses to heart failure and premature death. Characterization of affected
mutants revealed eosinophilia in multiple organs, including the heart, lungs, and spleen. Affected mice develop
eosinophilic myocarditis (EM) that leads to extensive fibrosis and right ventricular dilated cardiomyopathy, with
most mice dying by ~15-weeks. Clinically, many of the pathologies in mutant mice coincide with those realized
in patients diagnosed with hypereosinophilic syndrome (HES) or eosinophilic granulomatosis and polyangiitis
(EGPA, aka Churg-Strauss Syndrome), two rare eosinophil-associated diseases with a worse prognosis when
accompanied by HD. We have maintained the EM/HD trait on an inbred A/J strain background (i.e., A/JHD) for
many generations, so we suspected that heritability of the mutant trait is controlled by a small set of genes.
The EM/HD disease could also be transferred to irradiated A/J mice by adoptive transfer of splenocytes from
affected mice, implicating a role for the immune system. Because little is known regarding the genes involved
in most eosinophilic diseases, we sought to map EM/HD in this mutant. For linkage studies, we systematically
backcrossed and intercrossed proven A/JHD mutant males (i.e. previously sired affected offspring) with 4 inbred
strains and identified SJL/J (SJ) mice as the best strain–cross combination to reproduce EM/HD for mapping.
Using QTL analysis of SJ-derived F2 and N2 populations, HD was mapped to 3 highly significant loci (named
Emhd1-3 for ‘eosinophilic myocarditis to heart disease’). Linkage regions included a recessive variant on Chr5
(Emhd1) that is necessary but not sufficient for disease, and 2 separate dominant loci on Chr17 (Emhd2 and
Emhd3). Recently, we found that using a 3-generation N2/F2 mating scheme with A/JHD and SJ breeders could
further improve the rate of producing recombinants that developed HD. With this experience and knowledge
gained from reconstituting EM/HD in several inbred strains, along with a more efficient N2/F2 breeding strategy,
we now propose to recapitulate the oligogenic trait in select CC strains. Our working hypothesis is that the
genetic diversity of CC lines will help refine linkage intervals, identify any additional QTLs and determine the
importance of heterozygous regions (i.e., do they house a dominant variant?) to the trait. The primary goals of
this grant are to validate QTLs and better understand the overall heritability. Specifically, we will reestablish
EM/HD in recombinants generated from select CC lines that carry the desired strain alleles at critical sites of
interest. All N2/F2 CC-recombinants will be phenotyped for EM/HD and an equal number of affected and
unaffected CC-recombinants genotyped, and QTL and haplotype analyses performed. We expect the CC lines
will instill the genetic diversity ...

## Key facts

- **NIH application ID:** 10171771
- **Project number:** 5R21AI152575-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Daniel R Prows
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $198,750
- **Award type:** 5
- **Project period:** 2020-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171771

## Citation

> US National Institutes of Health, RePORTER application 10171771, Reconstituting the oligogenic trait 'Eosinophilic myocarditis to heart disease' in Collaborative Cross lines to understand its genetic architecture (5R21AI152575-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10171771. Licensed CC0.

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