The primary goal of this project is to identify genes and loci involved in hypertension and related phenotypes. Identification of genes involved in Mendelian disorders can rely heavily on genetic mapping and positional cloning strategies cloning strategies. However, identification of genes involved in complex inherited disorders (such as hypertension) by positional cloning alone is not likely to be highly successful. The multiple genes contributing to a complex phenotypes can allow genetic mapping, but prevent refinement of loci because recombinants cannot be unequivocally resolved from the influences of unlinked loci. Thus, identifications involved in complex phenotypes requires the use of all available information and a combination of research approaches. Such information includes the temporal-spatial expression patterns of genes, studies of gene function, knowledge of sequence polymorphism of genes, data obtained from physiological studies in animal models, as well as positional information gained from genetic studies in humans and animal models. In this study, we will take a multifaceted approach to the identification of genes and loci potentially involved in hypertension and hypertension-related phenotypes.
In specific aim 1, we will use expression data from rat models of hypertension and gene-expression profiles, along with human and rat positional data to identify high- probability candidate genes for human gene-expression profiles, along with human and rat positional data to identify high-probability candidate genes for human hypertension.
Inj specific aim 2, the human orthologues of the high-probability candidate genes identified in specific aim I will be isolated and evaluated for allelic association with hypertension in human populations.
In specific aim 3, we will verify and refine putative loci influencing body size phenotypes and blood pressure, and in aim 4, we will identify a gene causing a human Mendelian disorder influencing blood pressure. The study design is built upon our past successes and resource development. We will take full advantage of existing genomic resources, as well as resources that are rapidly becoming available including: the complete draft sequence of the human genome; the discovery efforts of our NIH-funded """"""""Rat Gene Discovery and Mapping Program"""""""" at the University of Iowa; human/rat syntenic maps; extensive rat and human cDNA libraries enriched for full -length clones; microarray hybridization capabilities with a comprehensive set and human cDNA libraries enriched for full-length clones; microarray hybridization capabilities with a comprehensive set of rat ESTs; and efficient sequencing team; expertise in all facets of genotyping and genetic mapping; outstanding information management expertise; well- characterized rat hypertension models; and carefully-phenotyped human subjects. All of these resources will be used toward ensuring the successful completion of this project.
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