Mechanistic characterization of genes for hypertension and renal disease.

描述(由申请人提供)： 复杂的人类疾病，如高血压和肾脏疾病，是主要的健康问题 在美国。美国国家心脏、肺和血液研究所(NHLBI)已经投资于许多全基因组关联研究(GWAS)和其他类型的遗传和基因组研究，以提供对复杂人类特征和疾病背后的分子病理生理机制的理解。尽管许多基因和区域与高血压有关，但这些基因中的许多在潜在机制中的作用尚未得到严格的测试。动物模型提供了分析多种风险因素和环境因素之间复杂相互作用的能力。这项建议将结合我们在研究控制血压的血管和肾脏机制的生理学研究中的经验，结合一种强大的、新的大鼠定点突变方法。在大鼠中进行基因敲除(KO)的新技术将使我们能够敲除GWAS提名的大量基因，并将这些基因敲除与高血压、遗传易感性和正常血压的大鼠品系相结合。具体地说，我们提出了以下目标。目的1-研究这些基因与高血压和肾脏疾病的已知发病机制之间的机制关系。将使用两级系统来调查 长期维持血压和高血压的机制。第一级研究了20株KO菌株的血压、压力感受器反射、氧化应激、血管反应性和对盐负荷的反应。第二级将学习治疗药物遗传学、血压-利尿剂-利尿剂的关系和肾脏血流动力学，以及血管机制。目的2-在致敏菌株中敲除100个基因。目标基因将由一个委员会选择，标准包括人类基因研究中的复制、对基因及其途径缺乏了解、比较基因组学，以及可能引起研究界的兴趣。目的3-生物信息学组成和基因特征，将来自大鼠、小鼠和人类的基因信息与我们的生理学研究数据相结合。所有动物模型和数据都将提供给研究界进行进一步研究。 公共卫生相关性： 高血压和肾脏疾病可能导致中风、心脏病发作以及心脏和肾脏衰竭。全基因组关联研究已经确定了与高血压和其他复杂疾病相关的潜在基因和区域，但对这些基因的分子机制几乎没有提供验证。这个项目的总体目标是使用一种新的技术来敲除高血压和正常血压动物的基因。 测试这些基因在控制血压的血管和肾脏机制中的作用的模型。这一独特的策略将从机制上理解GWAS基因在高血压和肾脏疾病中所起的病理生理学作用。

DESCRIPTION (provided by applicant): Complex human diseases, such as hypertension and renal disease, are major health problems in the United States. The National Heart, Lung, and Blood Institute (NHLBI) has invested in many genome-wide association studies (GWAS) and other types of genetic and genomic studies to provide an understanding of the molecular pathophysiological mechanisms underlying complex human traits and diseases. Although many genes and regions have been associated with hypertension, the roles of many of these genes in the underlying mechanisms have not been rigorously tested. Animal models provide the ability to dissect the complex interactions between multiple risk factors and environmental factors. This proposal will combine a powerful, new methodology for site directed mutagenesis in the rat with our experience in physiological studies investigating vascular and renal mechanisms controlling blood pressure. The novel technology for gene knock-outs (KO) in the rat will allow us to knock-out a large number of genes nominated by the GWAS and combine these gene knock-outs with hypertensive, genetically susceptible and normotensive rat strains. Specifically, we propose the following aims. Aim 1 - Investigate the mechanistic relationships between the genes and known mechanisms of hypertension and renal disease. A two tier system will be used to investigate the mechanisms involved in long-term maintenance of blood pressure and hypertension. Level one investigates blood pressure, baroreceptor reflex, oxidative stress, vascular reactivity, and response to salt load in 20 KO strains. Level two will study therapeutic pharmacogenetics, pressure-natriuretic-diuretic relationships and renal hemodynamics, and vascular mechanisms. Aim 2 - Knock-out 100 genes in a sensitized strain. The genes to be targeted will be selected by a committee using criteria focusing on replication in human genetic studies, lack of knowledge of the gene and its pathway, comparative genomics, and likely interest from the research community. Aim 3 - Bioinformatics component and Gene Characterization to integrate gene information from rat, mouse, and human with the data from our physiological studies. All animal models and data will be made available to the research community for further studies. PUBLIC HEALTH RELEVANCE: Hypertension and renal disease can lead to stroke, heart attack, and failure of the heart and kidneys. Genome wide association studies (GWAS) have identified potential genes and regions that are associated with high blood pressure and other complex diseases, but have provided little validation of the molecular mechanisms of these genes. The overall goal of this project is to use a novel technique to knockout genes in hypertensive and normotensive animal models to test the role of these genes in the vascular and renal mechanisms controlling blood pressure. This unique strategy will provide a mechanistic understanding of the pathophysiological role played by GWAS genes in hypertension and kidney disease.