GENETIC BASIS OF STROKE IN STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

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The aim of this project is to define the genetic basis of stroke in the stroke-prone spontaneously hypertensive rat (SHRSP). SHRSP were developed by selective inbreeding of substrains of the Okamoto-Aoki spontaneously hypertensive rat to produce a model in which a predisposition to stroke is reliably genetically transmitted. Comparisons of SHRSP and inbred normotensive controls (WKY) using a standardized ischemic test paradigm, acute occlusion of the middle cerebral artery (MCA-occlusion), have implicated inadequate capacity of the anastomoses bridging the MCA and the anterior and posterior cerebral arteries as the critical determinant of stroke, although the gene product mediating the stroke diathesis is unknown. The present proposal seeks to extend these observations to the genetic level by using genetic linkage analysis to identify genomic sites linked to the phenotype of MCA-occlusion stroke. Using a map of the rat genome constructed from simple sequence repeats typed by the polymerase chain reaction, we will perform linkage analyses treating stroke as both a qualitative (presence vs. absence) and a quantitative (volume of infarcted brain) trait in F2 animals derived from SHRSP X WKY crosses. We will use linked markers to identify possible candidate genes for further study as well as to direct development of congenic strains for study of the genomic locus of interest. In addition, we will examine several other phenotype features of SHRSP, including phasic accelerations in growth and blood pressure and in vitro vascular characters for linkage with genomic markers.