Genetics of Hypertension

描述（由申请人提供）：我们研究的总体目标是确定引起高血压的遗传因素。超过90%的高血压发病原因不明。这种形式，被称为原发性高血压，是一个严重的危险因素和预测未来心血管疾病，肾脏疾病和/或中风。虽然已知遗传因素占原发性高血压发病率的30%，但在人类和动物模型中，赋予高血压易感性的基因仅作为候选基因被优先考虑。利用大鼠高血压遗传模型，我们绘制了大鼠基因组的几个区域，这些区域包含血压的遗传决定因素。这些研究的重要方面是，它们在地图位置的分辨率在百万或千碱基段的意义上是相当先进的。我们建议继续进行这些高分辨率的制图研究，优先考虑候选变异，并验证在大鼠中确定的优先遗传决定因素作为血压的候选遗传决定因素。这项工作的意义在于，它是基于在实验性高血压研究领域已知的最佳分辨率的大鼠中进行的系统和持续的遗传作图研究，并与人类全基因组关联研究中发现的候选基因相一致。提出了四个目标，每个目标都集中在不同大鼠染色体（染色体1、9、10和5）上的血压数量性状位点。这项工作的创新之处在于，它采用了最先进的靶向基因破坏（敲除）和敲入拯救策略，使用锌指核酸酶来进一步验证优先的遗传元件，至少

DESCRIPTION (provided by applicant): 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.