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确定作为高血压致病生物标志物的基因。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%，但赋予高血压易感性的基因仅作为候选基因被优先考虑。需要对这些候选基因进行验证，才能确定它们是引起高血压的主要易感基因。此类验证性研究通常在大鼠或小鼠等哺乳动物模型中进行。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。本文所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，它是基于在大鼠中进行的系统和持续的遗传作图研究，以达到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发现的候选基因相一致。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，使用锌指核酸酶在三个目标中靶向三个不同的基因。这些基因包括：一个蛋白质编码基因，一个带血栓反应蛋白基序的崩解素样金属蛋白酶16 (Adamts16)，一个转录因子，核受体亚家族2，F组成员2 （Nr2f2）和Rififylin （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).