) In a congenic strain of spontaneously hypertensive rat (SHR) that carries a segment of chromosome 1 from the Brown Norway (BN) rat, the applicant found that systolic blood pressure is 10 mmHg lower than in the SHR progenitor strain. The SHR congenic and progenitor strains are genetically identical except for a segment of chromosome 1 that contains several prominent candidate genes for hypertension, including the SA gene and the genes for the beta and gamma subunits of the renal epithelial sodium channel. This new congenic strain represents an important advance in gene mapping in spontaneous hypertension and provides unique opportunities for isolating quantitative trait loci (QTL) regulating blood pressure in the SHR. To definitively test the hypothesis that a major blood pressure QTL exists on chromosome 1 in the vicinity of the SA and Scnn1b genes and to begin fine genetic mapping of this QTL, the applicant will use the strategy of complementation by genetically mediated chromosome transfer. Radiotelemetry techniques will be used to measure blood pressure in a series of congenic sublines derived by backcrossing the existing congenic SHR strain to the progenitor SHR strain. Using a series of > 25 polymorphic markers which map to the chromosome region of interest, she will narrow the chromosome 1 region containing the blood pressure ATL to approximately 5-10cM. As she maps the blood pressure QTL to a more restricted (-5 cM) chromosome region in the congenic sublines of SHR, she will develop additional polymorphic markers as needed using single strand conformation polymorphism analysis and other molecular techniques. Although the ultimate identification of a specific blood pressure QTL is beyond the scope of the current application, the substitution mapping approach proposed will provide the critical groundwork necessary for the eventual cloning of genes on chromosome 1 that regulate blood pressure in the SHR. Continued collaboration with Dr. Kurtz offers her a unique environment where she can receive training in both molecular genetics and cardiovascular physiology and at the same time be able to reap the research opportunities that stem from these unique congenic strains of SHR. The K08 award will allow her to complete a research training program crucial to her career goal of becoming a fully independent investigator studying the genetic determinants of multifactorial cardiovascular diseases.
| Ewy, G A; Felner, J M; Juul, D et al. (1987) Test of a cardiology patient simulator with students in fourth-year electives. J Med Educ 62:738-43 |
