The overall goal of our research is to identify genetic elements causing hypertension. Over 90% of all hypertension develops for no known reasons. This form, called as essential hypertension, is a serious risk factor and predictor of future cardiovascular, renal diseases and/or stroke. Although genetics is known to be responsible for up to 30% of the incidence of essential hypertension, the genes conferring susceptibility to develop hypertension have been only prioritized as candidate genes in both humans and in animal models. Using rat genetic models of hypertension we have mapped several regions of the rat genome as those that contain genetic determinants of blood pressure. The important aspect of these studies is that they are quite advanced in the sense that the resolutions of mapped locations are within mega- or kilobase segments. We propose to continue these high resolution mapping studies, prioritize candidate variants and validate the prioritized genetic determinants identified in rats as candidate genetic determinants of blood pressure. The significance of this work is that it is based on systematic and sustained genetic mapping studies in rats to the best resolutions known in the field of experimental hypertension research and aligns discovery of candidate genes from human genome-wide association studies.
Four aims are proposed, each of which is focused on blood pressure quantitative trait loci on different rat chromosomes (chromosomes 1, 9, 10 and 5). The innovative aspect of the work is that it employs the state-of-the-art targeted gene disruption (knock-out) and knock-in rescue strategies using zinc-finger nucleases to further validate the prioritized genetic elements, which in at least one case, is potentially a noncoding RNA.
Identifying genetic factors contributing to inheritance of hypertension in humans is difficult give that such factors account for only ~30% whereas the remainder larger component is the highly variable environmental factors. Using unique rat genetic models of hypertension that we have developed, we have identified many regions of the rat genome as those containing blood pressure regulatory genes and prioritized the evaluation of novel genetic elements. The proposal seeks to continue these studies and validate the underlying genetic elements.
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