We will carry out crosses between inbred mouse strains that differ in blood pressure to find the regions carrying genes that affect this trait. The location of these regions will be used to predict homologous regions that will be tested in human pedigrees segregating for hypertension and affected sib pairs in other projects of this proposal. The first set of mouse crosses will be between a hypertensive strain and a normotensive strain; the second set between a strain with low blood pressure and a normal strain, and the third between a strain with salt-sensitive hypertension and a normal strain. The number of progeny collected for each cross will be a minimum of 282. The progeny will be tested for blood pressure by the tail cuff method and the upper and lower 25% of the range will be retested for direct arterial pressure. Blood pressure measurements will be carried out at Boston University in the animal core. Genotyping will use SSLP markers or probes based on interspersed repetitive elements, a method called IRS-PCR. Analysis will be by the statistical procedures for quantitative trait loci (QTL) mapping utilizing interval mapping and the computer program Mapmaker if blood pressure measurements are norinally distributed or a modified interval mappmg computer progrrn if the measurements are not normally distributed or if significant donunance or epistatic interactions occur. Subsequent experiments depend on the results of the testing in humans. If candidate genes are suggested, then transgenic or knockout mice may be constructed to test such candidates. If a region contains a gene affecting hypertension in both mouse and human but no candidate gene is obvious, then an extended mouse cross will be started in an attempt to positionaIly clone the gene. If these latter studies are not required by the results from the human studies, additional crosses in the mouse to fmd genes affecting blood pressure are described.
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