Multigene Kinase Network, Kidney Transport and Salt in Essential Hypertension

原发性高血压中的多基因激酶网络、肾脏转运和盐

基本信息

批准号：
7938618
负责人：
Paul A Welling
金额：
$ 49.99万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-25 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7938618
关键词：
Affect Aldosterone Alleles Animal Model Antibodies Blood Pressure Cardiovascular system Carrier Proteins Cells Complex Development Dietary Sodium Disease Distal End stage renal failure Essential Hypertension Excretory function Familial disease General Population Genes Genetic Polymorphism Genetic Predisposition to Disease Heart failure Human Hypertension Intervention Kidney Knowledge Light Mineralocorticoids Modeling Molecular Genetics Morbidity - disease rate Mus Mutate Mutation Myocardial Infarction Nephrons Pathway interactions Phenotype Phosphorylation Phosphotransferases Physiological Planets Potassium Predisposition Protein-Serine-Threonine Kinases Public Health Reagent Regulation Renal function Signal Transduction Sodium Sodium Chloride Stress Stroke Susceptibility Gene System Testing Thiazide Diuretics Transgenic Animals Transgenic Mice Variant Work gene environment interaction genome wide association study hyperkalemia mortality mouse model novel novel therapeutics public health relevance response salt balance symporter tool

项目摘要

DESCRIPTION (provided by applicant): Essential hypertension is a major threat to public health, affecting over a billion people in the world and contributing to kidney and cardiovascular mortality and morbidity in 5 million people annually. Like other complex disorders, multiple genes with variant alleles and different environmental stresses are thought to contribute to the disease. Using a genome-wide association strategy, we recently identified the first essential hypertension susceptibility gene, STK39 (aka SPAK serine/threonine kinase), illuminating a newly described, multi-gene kinase network and a specific environmental trigger--dietary salt-- in the genesis of hypertension. Available evidence from our group and others suggests: 1) STK39 interacts with the products of the WNK genes, serine/threonine kinases that are mutated in a rare familial disorder of hypertension and hyperkalemia, to control kidney salt excretion and maintain blood pressure; 2) Dietary sodium and potassium differently trigger signaling through the STK39/WNK pathway to regulate the activity of a key renal salt transport protein, the thiazide diuretic sensitive sodium chloride co- transporter (NCC); 3) Aberrant gain-of-STK39 signaling causes an inappropriate increase in NCC activity, leading to sodium retention and hypertension. Here we bring together a mutlidisciplinary team to develop and apply novel transgenic animal models and reagents to test these exciting new ideas about gene-gene and gene-environment interactions in the development of hypertension, building on our recent discoveries. Development of these new tools and knowledge will shed light on the underlying molecular and genetic mechanisms of the disease. It also will provide much-needed models to study and identify new therapeutic strategies for intervention. PUBLIC HEALTH RELEVANCE: Essential hypertension is a major threat to public health, affecting over a billion people in the world and contributing to kidney and cardiovascular mortality and morbidity in 5 million people annually. Like other complex disorders, multiple genes with variant alleles and different environmental stresses are thought to contribute to the disease. Here we bring together a mutlidisciplinary team of experts in the field to develop and apply novel transgenic animal models and reagents to test exciting new ideas about a multi-kinase gene network and a specific environmental trigger--dietary salt--in the genesis of hypertension, building on our recent GWA discovery of STK39 kinase as an essential hypertension susceptibility gene.

描述（由申请人提供）：原发性高血压是对公共健康的主要威胁，影响着世界上超过 10 亿人，每年导致 500 万人因肾脏和心血管疾病死亡和发病。与其他复杂疾病一样，具有变异等位基因的多个基因和不同的环境压力被认为是导致这种疾病的原因。利用全基因组关联策略，我们最近鉴定了第一个原发性高血压易感基因 STK39（又名 SPAK 丝氨酸/苏氨酸激酶），阐明了新描述的多基因激酶网络和特定环境触发因素（膳食盐）高血压的发生。我们小组和其他人的现有证据表明：1）STK39 与 WNK 基因的产物（在一种罕见的家族性高血压和高钾血症中发生突变的丝氨酸/苏氨酸激酶）相互作用，以控制肾脏盐排泄并维持血压； 2) 饮食中的钠和钾通过 STK39/WNK 通路不同地触发信号传导，从而调节关键的肾盐转运蛋白（噻嗪类利尿剂敏感的氯化钠协同转运蛋白 (NCC)）的活性； 3) STK39 信号传导异常导致 NCC 活性异常增加，导致钠潴留和高血压。在这里，我们聚集了一个多学科团队，以我们最近的发现为基础，开发和应用新型转基因动物模型和试剂，以测试这些关于高血压发展中基因-基因和基因-环境相互作用的令人兴奋的新想法。这些新工具和知识的开发将揭示该疾病的潜在分子和遗传机制。它还将提供急需的模型来研究和确定新的干预治疗策略。公共健康相关性：原发性高血压是公共健康的主要威胁，影响着世界上超过十亿人，每年导致 500 万人因肾脏和心血管疾病死亡和发病。与其他复杂疾病一样，具有变异等位基因的多个基因和不同的环境压力被认为是导致这种疾病的原因。在这里，我们汇集了该领域的多学科专家团队，开发和应用新型转基因动物模型和试剂，以测试有关多激酶基因网络和特定环境触发因素（膳食盐）在高血压发病过程中的令人兴奋的新想法，基于我们最近 GWA 发现 STK39 激酶作为一种重要的高血压易感基因。