Innovative Models for Mechanistic Studies of Novel Hypertension Genes

描述(申请人提供)：我们研究的总体目标是确定基因是高血压的致病生物标记物。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，遗传因素导致了高达30%的高血压发病率，但导致高血压的易感性基因只被优先考虑为候选基因。需要对这些候选基因进行验证，才能确定它们是导致高血压的主要易感基因。此类验证研究通常在大鼠或小鼠等哺乳动物模型中进行。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。这里描述的建议试图验证在大鼠和人类中被确定为血压候选基因决定因素的优先基因决定因素。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，以高血压研究领域已知的最佳分辨率为基础，并将从人类基因组范围的关联研究中发现的候选基因进行比对。这项工作的创新之处在于，它采用了最先进的靶向基因干扰(敲除)策略，使用锌指核酸酶来靶向所提出的三个目标中的三个不同基因。这些基因是：蛋白编码基因，带有血栓反应蛋白基序的去整合素样金属蛋白酶16(Adamts16)，转录因子，核受体亚家族2，F组成员2(Nr2f2)和核糖体蛋白(Rff1)。

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).