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: 8589002
• 负责人: BINA JOE
• 金额: $ 64.21万
• 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 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8589002
• 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; 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将基因识别为高血压的致病生物标志物。超过90％的高血压出于未知原因而发展。这种形式称为必不可少的高血压，是严重的危险因素，也是未来心血管，肾脏疾病和/或中风的预测指标。尽管众所周知，遗传学是造成必需高血压发病率的30％，但赋予发展高血压易感性的基因仅优先考虑为候选基因。需要验证这些候选基因，才能将其识别为引起高血压的主要敏感性基因。这种验证研究通常在哺乳动物模型（例如大鼠或小鼠）中进行。使用高血压的大鼠遗传模型，我们将大鼠基因组的几个区域映射为含有血压遗传决定因素的区域。此处描述的建议旨在验证在大鼠和人类中鉴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，它基于在高血压研究领域已知的最佳分辨率基于系统的和持续的遗传图研究研究，并使人类全基因组关联研究发现候选基因的发现。这项工作的创新方面是，它采用最新的靶向基因破坏（敲除）策略，使用锌指核酸酶来靶向三个目标中的三个不同基因。这些基因是：一种蛋白质编码基因，一种具有血小板蛋白基序16（ADAMTS16）的分解蛋白样金属蛋白酶，一种转录因子，核受体亚科2，F组F组成员2（NR2F2）（NR2F2）和Rififylin（RFFFL）。