CONGENIC STRAINS IN EXPERIMENTAL HYPERTENSION

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The spontaneously hypertensive rit (SHR) is the most widely studied model of essential hypertension. however the primary genetic factors responsible for increased blood pressure in the SHR remain to be identified. In linkage studies in recombinant inbred strains and in F2 and backcross populations derived from the SHR, multiple genetic markers have been reported to be linked to the inheritance of increased blood pressure (BP). In the current studies, we will derive and characterize a library of congenic strains of SHR to: 1) determine which of these linkages reflect molecular variants necessary for full expression of spontaneous hypertension and 2) use the strains to map major blood pressure regulatory genes to narrow chromosome regions. To accomplish these goals, we will create multiple congenic strains of SHR. Each of these new strains will differ from the SHR progenitor with respect to a single chromosome region. We will then measure BP in these strains under a range of environmental conditions. Differences in BP between the SHR progenitor strain and the congenic strains will allow for the identification and isolation of narrow chromosome regions involved in the primary pathogenesis of hypertension. Specifically, we will: 1) Use backcross breeding and genomic selection techniques to replace selected chromosome segments in the SHR with corresponding chromosome segments from the normotensive Brown-Norway (BN) rat. In this fashion, a panel of at least 10 congenic strains will be created in which each strain differs from the SHR progenitor in only a single chromosome region. 2) Determine which of the transferred chromosome segments contain genes relevant to hypertension by comparing the BP of the congenic strains to the BP of the SHR progenitor strain. Radiotelemetry transducers will be used to continuously measure heart rate and aortic pressures during different stages of development and under different environmental conditions (normal dietary NaCl; high dietary NaCl: high stress (restraint). high NaCl combined with high stress). 3) Map the cost potent BP regulatory genes to more restricted chromosome regions by measuring BPs in recombinant congenic strains that carry different overlapping segments of the chromosome regions of interest. We will also test for interaction effects of these genes by measuring blood pressures in hybrid lines derived by the cross-breeding of selected congenic strains. QTLs regulating cardiac mass will be mapped in a similar fashion. Thus, the new congenic strains will enable us to definitively test hypotheses about the role of specific chromosome regions in the pathogenesis of spontaneous hypertension and lay the groundwork required for the eventual positional cloning of molecular variants responsible for the increased blood pressure.