Hypertension is a polygenic disease. Although rat models of genetic hypertension have been useful in the studies of pathophysiology of this disease, the actual genetic basis for their extreme phenotypes remains unknown. We propose to undertake the first systematic genetic dissection of the major polygenic factors causing in hypertension in two important inbred rodent model systems: 1) Spontaneously Hypertensive Rat (SHR) vs. Wistar Kyoto inbred (WKY); and 2) Dahl Salt Sensitive (SS/JR) vs. Dahl Salt Resistant (SR/JR). By mapping these gene,s it should become possible to cone them, to study them, and to determine what role that their human homologue products play in the etiology of human essential hypertension. Specifically, we propose to: a) Construct a genetic linkage map of the laboratory rat consisting of DNA polymorphisms. By comparing DNAs from SHR, WKY, SS/JR and SR/JR, we will identify a collection of 250 DNA polymorphisms (simple RFLPs detected by single-copy probes storable by Southern blots; or tandem repeats of the CA dinucleotide storable by the Polymerase Chain Reaction (PCR)). b) Map the major polygenic factors underlying the striking genetic differences in blood pressure between SHR and WKY. We will breed 200 males F2 intercross progeny between the strains. The progeny will be scored for blood pressure and for various Mendelian-inherited phenotypes known or believed to be closely related to hypertension. The progeny will then be scored with the genetic markers. Segregation of the quantitative physiological phenotypes will then be compared with the segregation of the genetic markers in order to determine the approximate genetic positions of the major quantitative trait loci (QTLs) causing the phenotypic differences. c) Map the major polygenic factors underlying the striking genetic difference in blood pressure between SS/JR and SR/JR. The experiments will be parallel to those in (b) above. The QTL positions in the two crosses will be compared to determine whether major factor occur in similar locations. d) Initiate experiments directed at the molecular cloning of the major OTLs causing hypertension. Once the QTLs are localized to specific regions between flanking RFLPs, we will initiate their molecular cloning based on position (through chromosome walking etc). These experiments will probably not be completed in the grant period, but we intend to continue them in a subsequent project. These studies should identify the genetic loci responsible for hypertension in the rat and may provide insight into the pathogenesis of human genetic hypertension.
Showing the most recent 10 out of 45 publications