Innovative Models for Mechanistic Studies of Novel Hypertension Genes

新型高血压基因机制研究的创新模型

• 批准号: 8775253
• 负责人: BINA JOE
• 金额: $ 64.94万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8775253
• 关键词: Abbreviations; Address; Alleles; Animal Model; Biological Markers; Blood Pressure; Candidate Disease Gene; Cardiac Myocytes; Cardiovascular system; Chromosome Mapping; Code; Confounding Factors (Epidemiology); Congenic Strain; Data; Development; Disintegrins; Essential Hypertension; Extracellular Matrix; Future; Gene Targeting; Genes; Genetic; Genetic Determinism; Genetic Engineering; Genetic Models; Genetic study; Goals; Homologous Gene; Human; Human Genome; Hypertension; Inbreeding; Incidence; Inherited; Kidney Diseases; Knock-out; Laboratories; Link; Maps; Metalloproteases; Methods; Modeling; Mus; Names; Nature; Neck; Pathway interactions; Predisposition; Proteins; Publishing; Quantitative Trait Loci; Rattus; Recycling; Regulation; Renin; Research; Resolution; Risk Factors; Site; Stroke; Structure; Susceptibility Gene; Testing; Validation; Variant; Work; Zinc Fingers; apoAI regulatory protein-1; base; blood pressure regulation; congenic; familial hypertension; genetic element; genome wide association study; innovation; interest; non-genetic; normotensive; novel; nuclease; positional cloning; rat genome; salt sensitive; tool; trait; transcription factor; validation studies

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).

描述（由申请人提供）：我们研究的总体目标是确定基因作为高血压的致病生物标志物。超过 90% 的高血压是由于不明原因而发生的。这种形式称为原发性高血压，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素。尽管已知遗传因素导致原发性高血压发病率高达 30%，但导致高血压易感性的基因仅被优先列为候选基因。需要对这些候选基因进行验证，将其鉴定为引起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。使用高血压的大鼠遗传模型，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。这里描述的提案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，它基于对大鼠进行的系统且持续的基因图谱研究，以达到高血压研究领域已知的最佳分辨率，并结合人类全基因组关联研究中发现的候选基因。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，使用锌指核酸酶来针对所提出的三个目标中的三个不同基因。这些基因是：蛋白质编码基因、具有血小板反应蛋白基序 16 (Adamts16) 的解整合素样金属蛋白酶、转录因子、核受体亚家族 2、F 组成员 2 (Nr2f2) 和 Rififylin (Rffl)。