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. Although factors impacting the risk of stroke occurrence can be studied in human populations, those impacting stroke severity are best studied in experimental models. The BXD mouse strains are derived from parent B6 (C57BL/6) and D2 (DBA) lines, each BXD strain having defined contributions of parent gene sequence at different chromosomal loci. Preliminary data using previously available strains have identified novel quantitative trait loci (QTLs) impacting brain vulnerability to ischemic stroke, with a suggestion of sex- dependent variation in their effects. Strain number is the limiting factor in such analyses. The single aim of this study is to determine infarct volume following permanent focal ischemia for the 60 additional BXD strains that are now available. This expansion of the data set will maximize its power to map gene variants that modulate stroke outcome in these mice. The anticipated results will refine and potentially expand the set of newly identified stroke loci, defining potential candidate genes and molecular networks impacting stroke severity.
Proposed studies will define 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.
