Genetics of stroke vulnerability in C57BL/6 mouse substrains
Project Number5R01NS113957-05
Contact PI/Project LeaderNOWAK, THADDEUS S. Other PIs
Awardee OrganizationUNIVERSITY OF TENNESSEE HEALTH SCI CTR
Description
Abstract Text
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.
Public Health Relevance Statement
Proposed studies will identify novel genetic loci that determine stroke vulnerability in mice. In
view of the conserved genome structures and physiologies of mice and humans, this will
ultimately contribute to the discovery of genes and gene networks that impact the human
disease. More complete understanding of genetic factors contributing to variation in stroke
severity, expected to result from this study, should help guide future prevention and therapeutic
approaches.
National Institute of Neurological Disorders and Stroke
CFDA Code
853
DUNS Number
941884009
UEI
X1M1PN3KG3E7
Project Start Date
15-July-2020
Project End Date
30-June-2025
Budget Start Date
01-July-2024
Budget End Date
30-June-2025
Project Funding Information for 2024
Total Funding
$277,187
Direct Costs
$182,360
Indirect Costs
$94,827
Year
Funding IC
FY Total Cost by IC
2024
National Institute of Neurological Disorders and Stroke
$277,187
Year
Funding IC
FY Total Cost by IC
Sub Projects
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