The general objective of the proposed work is the identification and characterization of genetic loci that are involved in the pathogenesis of stroke. The studies will be carried out in an animal model of genetically determined hypertensive cerebrovascular disease, that shares many features with the human disease, viz. the stroke-prone, spontaneously hypertensive rat (SHRSP). Elucidation of disease- associated genes in this model will provide the basis for subsequent studies in humans. The relevance of the proposed studies is evidenced by the importance of stroke as public health issue. As in previous, related work on the genetics of hypertension, both anonymous and sequence-specific markers will be used for the mapping of quantitative trait loci in F2 hybrids derived from cross-breeding SHRSP with stroke- resistant SHR, a strategy that will allow us to avoid blood pressure as a confounding factor in the analysis. Because of the genetic proximity between the two strains, special efforts will be directed towards the development of informative genetic markers. Once a locus is identified, further characterization by both classical genetic (congenics) and molecular (positional cloning) approaches will be pursued.
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