Genetic & Functional Analyses of Hypertension Susceptibility Genes

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• 批准号: 8506323
• 负责人: YEN PEI CHRISTY CHANG
• 金额: $ 56.97万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8506323
• 关键词: Accounting; Address; Adult; Affect; Alanine; Alternative Splicing; Biochemistry; Bioinformatics; Biological; Biology; Blood Pressure; Cardiovascular Diseases; Caring; Clinical; Coronary heart disease; Data; Detection; Diet; Disease; Essential Hypertension; Excretory function; Fatty acid glycerol esters; Functional RNA; Funding; Gene Expression; Gene Expression Profile; Genes; Genetic; Genotype; Goals; Grant; Heritability; Human; Human Genome; Hypertension; Hypotension; Indium; International; Kidney; Kidney Diseases; Knock-in Mouse; Knowledge; Lead; Lysine; Messenger RNA; Meta-Analysis; Mining; Molecular Biology; Mus; Mutation; Nephrons; Obesity; Pathogenesis; Pathway interactions; Pattern; Pharmacogenetics; Phenotype; Phosphotransferases; Physiology; Play; Post-Transcriptional Regulation; Predisposition; Prevalence; Process; Proline; Protein Isoforms; Protein-Serine-Threonine Kinases; Proteins; Public Health; Publishing; RNA Sequences; 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; Variant; Work; absorption; base; blood pressure regulation; design; driving force; effective therapy; familial hypertension; follow-up; genetic variant; genome wide association study; in vitro Assay; insight; interest; member; mouse model; non-genetic; novel; prevent; promoter; public health relevance; response; screening; symporter; thiazide; transcriptome sequencing

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）：基本高血压（HTN）影响了全球25％以上的成年人，并且是冠心病，中风和肾脏的重要危险因素 疾病。非遗传因素，例如肥胖，高脂肪/钠饮食，压力和身体不活跃 尽管HTN筛查和治疗选择显着改善，但HTN的患病率稳定增加。这种现象称为高血压悖论，强调了理解HTN遗传因素的重要性，因此可以开发个性化的护理来预防和治疗HTN。最近全基因组关联研究（GWAS）发现了在确定血压（BP）和HTN敏感性中发挥作用的变体，但是这种信号的生物学基础通常尚不清楚。该建议旨在通过多学科方法来揭示此类GWAS信号的功能意义。我们先前的GWAS努力表明，丝氨酸 - 苏氨酸激酶STK39中的变体与BP相关，并强调了一个不完全理解的激酶网络和对正常盐分排泄和BP控制至关重要的共同转运蛋白。鼠标模型表明，该网络的成员（例如没有赖氨酸激酶（WNK）和STK39接管的Ste20与丙啉 - 丙氨酸 - 丙氨酸 - 富含丙氨酸 - 富含丙氨酸的激酶（SPAK）的成员可能具有肾脏特异性的肾脏特异性和相互作用，并且这些同工型的分布和相互作用可能是适当的肾脏功能。因此，我们将通过RNA测序产生富含皮层和髓质的人和小鼠肾脏的转录组，这适用于检测新型同工型和稀有转录本。我们将验证和表征这些激酶和共发蛋白的转录本和蛋白质同工型，以更好地了解它们如何一起工作以调节肾脏钠处理。我们的目标是识别和表征该特定激酶和共发器的特定网络的同工型，它们在功能上是 清楚的。在此过程中，我们还将为对肾脏基因表达其他方面感兴趣的研究者提供高质量的人类和小鼠肾脏段特异性转录组。在一个相似但互补的目标中，我们还将检查新颖的GWAS信号，尚未通过将我们在转录调节和生物信息学方面的专业知识结合起来来挖掘人类基因组中调节元素的不断扩展的注释。最初，我们将专注于复制的HTN和与BP相关的变体，但是我们的长期目标是建立旨在将信号从大型遗传研究（例如GWAS）转换为人类基因组功能元素的生物信息学管道，以便可以检查任何表型或疾病的基础生物学。为了实现这些目标，我们将研究人员汇集在一起​​，这些研究人员是高血压遗传学，转录调节，生物信息学，分子生物学，生物化学和肾脏生理学专家的研究者。