The goal of this study is to investigate genetic contributions to stroke vulnerability, taking advantage of a robust stroke model as well as availability of a unique mouse resource. We have extended to mice our longstanding experience with tandem surgical occlusion of the middle cerebral artery (MCA) and ipsilateral common carotid artery (CCA) in rats. This permits even permanent occlusions with essentially no mortality, and with experience the procedure has become sufficiently rapid to be suitable for large scale screening studies. The animal resource consists of a panel of recombinant inbred mouse strains derived from C57BL/6J and DBA/2J parents. The specific contribution of parental genomes (chromosomal location and sequence) is defined for each of these BxD hybrids, and they have been widely used to map genetic contributions to complex traits. Of the lines currently in existence, 50 were derived at this institution and will be the source of animals for the proposed studies.
In Aim 1, male and female mice of individual BxD strains will be subjected to permanent MCA occlusions. Cortical infarct volumes will be assessed at 24 h, providing the primary data for Quantitative Trait Locus (QTL) analysis of strain and gender differences in stroke vulnerability. Acute cerebral blood flow (CBF) changes will be compared using speckle contrast imaging in Aim 2, to provide a preliminary assessment of the relative roles of perfusion variation vs. intrinsic tissue vulnerability, and of CBF responses to peri-infarct depolarization, in determining differences in infarct volume among strains. These experiments would provide the foundation for more expansive studies including the full complement of BxD lines, as well as other rat and mouse reference populations, to comprehensively define the genetics of vulnerability to ischemic stroke.
Stroke is a major cause of death and disability in this country and around the world. As the potential to obtain complete genome sequence data for any individual becomes progressively more feasible, so does the goal of optimizing individual risk assessment and treatment for a range of diseases, including stroke. The proposed studies will employ state-of-the-art techniques in mouse stroke modeling, a unique resource of recombinant inbred mouse strains, and powerful analytical tools to identify genetic influences on stroke outcome which, if successful, could ultimately impact the individualized care of stroke patients.
