The overall objective of this proposal is to identify the genes controlling blood pressure, that is, the blood pressure quantitative trait loci (QTL). The Dahl salt sensitive (S) rat is used as an animal model. At this point, most of the blood pressure QTL under study have been localized on linkage maps by the use of congenic strains in which a QTL-containing chromosomal segment from a (donor) strain is introgressed by a selective breeding paradigm into the (recipient) S strain. Such a congenic strain carrying a substituted low blood pressure QTL allele has a lower blood pressure than S rats. In this proposal, the QTL containing congenic segments on rat chromosomes 5, 9 and 10 will be reduced to chromosomal intervals of less than 1 centiMorgan by substitution mapping. Substitution mapping consists of systematically reducing the size of the introgressed congenic chromosomal segment. A series of congenic substrains containing progressively shorter overlapping donor chromosomal segments is constructed. It is determined which strains do, or do not, show a blood pressure different from S rats, and thus which strains do, or do not, contain the substituted QTL allele. From this information one can deduce the QTL containing chromosomal region which will generally be less than 1 centiMorgan. Candidate genes in this interval will be evaluated for DNA sequence variation and expression differences between the donor and recipient (S) strain. From this a strong candidate gene can be expected, which is logically the causative blood pressure gene. Blood pressure genes thus identified in the rat provide new candidate genes for understanding physiological/biochemical pathways of blood pressure control. Such genes are likely to provide targets for therapeutic intervention in human hypertension.
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