Innovative Models for Mechanistic Studies of Novel Hypertension Genes

描述（由申请人提供）：我们研究的总体目标是鉴定作为高血压致病生物标志物的基因。超过90%的高血压是由于未知的原因而发生的。这种形式，称为原发性高血压，是一个严重的危险因素和预测未来的心血管，肾脏疾病和/或中风。虽然遗传学是已知的原发性高血压的发病率高达30%的负责，赋予高血压的易感性的基因已被优先作为候选基因。这些候选基因的验证是必要的，他们被确定为主要的易感基因引起高血压。此类验证研究通常在哺乳动物模型如大鼠或小鼠中进行。使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。这里描述的建议旨在验证在大鼠和人类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，它是基于大鼠中系统和持续的遗传图谱研究，以高血压研究领域已知的最佳分辨率，并与人类全基因组关联研究中的候选基因发现相一致。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）策略，使用锌指核酸酶靶向三个不同的基因，以实现所提出的三个目标。这些基因是：一种蛋白质编码基因，具有血小板反应蛋白基序16的去整合素样金属蛋白酶（Adamts 16），一种转录因子，核受体亚家族2，F组成员2（Nr 2f 2）和Rififiylin（Rffl）。

DESCRIPTION (provided by applicant): The overall goal of our research is to identify genes as causative biomarkers of 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. Validation of these candidate genes is required for them to be identified as primary susceptibility genes causing hypertension. Such validation studies are typically conducted in mammalian models such as rats or mice. 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 proposal described here seeks to validate the prioritized genetic determinants identified in both rats and humans 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 hypertension research and aligns discovery of candidate genes from human genome-wide association studies. The innovative aspect of the work is that it employs the state-of-the-art targeted gene disruption (knock-out) strategy using zinc-finger nucleases to target three different genes in the three aims proposed. The genes are: A protein-coding gene, A disintegrin-like metalloproteinase with thrombospondin motifs 16 (Adamts16), a transcription factor, Nuclear receptor subfamily 2, group F member 2 (Nr2f2) and Rififylin (Rffl).