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.
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.
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