# Genetics of stroke vulnerability in C57BL/6 mouse substrains

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2021 · $357,200

## Abstract

Stroke remains a significant human disease, and understanding the genetic factors that
contribute to its impact on specific individuals will ultimately be critical in targeting interventions.
Studies in human populations generally address factors affecting the risk of stroke occurrence.
Impacts on stroke severity are readily examined in experimental models, and parallel mapping
of vulnerability loci in mouse and human populations support the translational potential of such
analyses. We have recently identified marked divergence of stroke vulnerability among closely
related substrains of the C57BL/6 mouse. Smaller infarcts are seen in the J and ByJ substrains,
the latter of which originated early in the N lineage. In contrast, larger infarcts are observed in
subsequently derived NCrSlc, NCrl and NJ substrains. Preliminary results establish that the
larger infarct phenotype is inherited as a dominant trait, indicating a single causal mutation.
These nearly coisogenic substrain populations contain only a limited pool of segregating genetic
variants that could underlie the difference in stroke severity.
 We propose to identify the gene variant that modulates stroke vulnerability among C57BL/6
substrains. Aim 1 will generate comprehensive sequence data for ByJ, NCrSlc and NCrl
substrains, for which such resources are not yet available. Since ByJ and NCrSlc are the most
closely related substrains to differ in stroke vulnerability, this will define the minimum list of
candidate variants. Aim 2 will use high-coverage genomic sequences and a dense marker panel
already available for J and NJ substrains to map the locus impacting infarct volume in reciprocal
populations of JxNJ and NJxJ F2 intercross progeny subjected to permanent focal ischemia.
This locus will be confirmed using F2 crosses of ByJ and NCrl substrains. Aim 3, using CRISPR-
Cas9 methodology to repair each candidate variant, will establish the single genetic factor that is
the main source of variation in stroke vulnerability among C57BL/6 substrains.

## Key facts

- **NIH application ID:** 10213155
- **Project number:** 5R01NS113957-02
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Megan Kathleen Mulligan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $357,200
- **Award type:** 5
- **Project period:** 2020-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213155

## Citation

> US National Institutes of Health, RePORTER application 10213155, Genetics of stroke vulnerability in C57BL/6 mouse substrains (5R01NS113957-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10213155. Licensed CC0.

---

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