Genetics of Hypertension

描述(申请人提供)：我们研究的总体目标是确定导致高血压的遗传因素。超过90%的高血压患者的发病原因不明。这种形式被称为原发性高血压，是未来心血管、肾脏疾病和/或中风的严重危险因素和预测因子。尽管众所周知，遗传学导致了高达30%的高血压发病率，但在人类和动物模型中，导致高血压易感性的基因只被优先列为候选基因。利用高血压的大鼠遗传模型，我们已经将大鼠基因组的几个区域定位为包含血压遗传决定因素的区域。这些研究的重要方面是，它们相当先进，因为测绘位置的分辨率在兆基或千基范围内。我们建议继续这些高分辨率的作图研究，确定候选变异的优先顺序，并验证在大鼠中被确定为血压候选遗传决定因素的优先遗传决定因素。这项工作的意义在于，它基于系统和持续的大鼠基因图谱研究，以实验性高血压研究领域已知的最佳分辨率为基础，并对从人类基因组范围的关联研究中发现候选基因进行比对。提出了四个目标，每个目标都集中在不同大鼠染色体(第1、9、10和5号染色体)上的血压数量性状基因座上。这项工作的创新之处在于，它采用了最先进的靶向基因中断(敲除)和敲入抢救策略，使用锌指核酸酶来进一步验证优先排序的遗传元素，这至少在 一种情况是潜在的非编码RNA。

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.