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Genetic & Functional Analyses of Hypertension Susceptibility Genes

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基本信息

批准号：
9309009
负责人：
YEN PEI CHRISTY CHANG
金额：
$ 45.76万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9309009
关键词：
Address Adult Affect Alanine Alternative Splicing Biochemistry Bioinformatics Biological Biology Blood Pressure Cardiovascular Diseases Chronic Clinical Coronary heart disease Data Detection Diet Disease Elements Essential Hypertension Excretory function Fatty acid glycerol esters Follow-Up Studies Funding Gene Expression Genes Genetic Genetic Transcription Genetic study Genotype Goals Grant Heritability Human Human Genome Hypertension International Kidney Kidney Diseases Knock-in Mouse Knowledge Lead Lysine Messenger RNA Meta-Analysis Molecular Biology Mus Mutation Nephrons Obesity Pathogenesis Pathway interactions Pattern Pharmacogenetics Phenotype Phosphotransferases Physiological Physiology Play Post-Transcriptional Regulation Predisposition Prevalence Proline Protein Isoforms Protein-Serine-Threonine Kinases Proteins Public Health Publishing Quantitative Reverse Transcriptase PCR RNA Splicing Regulatory Element Renal function Research Personnel Risk Factors Role Signal Transduction Sodium Sodium Chloride Stress Stroke Susceptibility Gene Technology Therapeutic Intervention Thiazide Diuretics Tissues Transcript Transcriptional Regulation Untranslated RNA Variant Work absorption base blood pressure regulation design driving force effective therapy familial hypertension genetic variant genome wide association study hypertension treatment in vitro Assay insight interdisciplinary approach interest member mouse model non-genetic novel personalized care physical inactivity prevent promoter public health relevance response screening symporter targeted treatment thiazide transcriptome transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Essential hypertension (HTN) affects more than 25% of adults worldwide, and is a significant risk factor for coronary heart disease, stroke, and renal disease. Non-genetic factors such as obesity, high fat/sodium diet, stress, and physical inactivity contribute to a steady increase in the prevalence of HTN despite remarkable improvement in HTN screening and treatment options. This phenomenon, termed Hypertension paradox, underscores the importance of understanding the genetic factors underlying HTN, so that personalized care can be developed to prevent and treat HTN. Variants that play a role in determining blood pressure (BP) and HTN susceptibility have been uncovered by recent genome-wide association studies (GWAS), but the biological underpinning of such signals is often unclear. This proposal aims to uncover the functional significance of such GWAS signals through a multi-disciplinary approach. Our prior GWAS effort demonstrated that variants in the serine-threonine kinase, STK39, are associated with BP and highlighted an incompletely understood network of kinases and co-transporters critical for normal salt excretion and BP control. Mouse models indicated that members of this network, such as with no lysine kinases (WNKs) and STK39-encoded Ste20-related proline-alanine-rich kinase (SPAK), might have unknown isoforms that are renal-segment specific and the distribution and interaction of these isoforms are crucial for proper renal function. Therefore we will generate cortex- and medulla-enriched human and mouse kidney transcriptomes by RNA sequencing, which is suitable for the detection of novel isoforms and rare transcripts. We will validate and characterize transcript and protein isoforms of these kinases and co-transporters to obtain a better understanding of how they work together to regulate renal sodium handling. Our objectives are to identify and characterize isoforms of this specific network of kinases and co-transporters that are functionally distinct. In doing so, we will also provide high quality human and mouse nephron segment-specific transcriptomes for investigators interested in other aspects of renal gene expression. In a parallel but complementary aim, we will also examine novel GWAS signals yet to be characterized by combining our expertise in transcriptional regulation and bioinformatics to mine the ever-expanding annotation of regulatory elements in the human genome. Initially we will focus on replicated HTN and BP-associated variants, but our long-term objective is to build a bioinformatics pipeline designed to convert signals from large genetic studies, such as GWAS, to functional elements in the human genome so that the underlying biology of any phenotype or disease can be examined. To accomplish these goals, we have brought together investigators who are experts in hypertension genetics, transcriptional regulation, bioinformatics, molecular biology, biochemistry, and renal physiology.

描述（由申请人提供）：原发性高血压（HTN）影响全球超过25%的成年人，是冠心病、中风和肾脏病的重要危险因素