Genetic & Functional Analyses of Hypertension Susceptibility Genes

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、中风和肾功能衰竭的重要风险因素。 疾病非遗传因素，如肥胖、高脂肪/高钠饮食、压力和缺乏运动 尽管HTN筛查和治疗方案有显著改善，但HTN的患病率仍在稳步上升。这种现象被称为高血压悖论，强调了了解HTN潜在遗传因素的重要性，以便开发个性化护理来预防和治疗HTN。最近的全基因组关联研究（GWAS）已经发现了在确定血压（BP）和HTN易感性中起作用的变异，但这些信号的生物学基础通常不清楚。该提案旨在通过多学科方法揭示此类GWAS信号的功能意义。我们先前的GWAS研究表明，丝氨酸-苏氨酸激酶STK 39的变体与BP相关，并强调了对正常盐排泄和BP控制至关重要的激酶和共转运蛋白网络的不完全理解。小鼠模型表明，该网络的成员，如没有赖氨酸激酶（WNK）和STK 39编码的Ste 20相关的脯氨酸-丙氨酸-丰富的激酶（SPAK），可能有未知的亚型，是肾段特异性和这些亚型的分布和相互作用是至关重要的适当的肾功能。因此，我们将通过RNA测序产生皮质和髓质富集的人和小鼠肾转录组，这适用于检测新的亚型和罕见的转录本。我们将验证和表征这些激酶和共转运蛋白的转录本和蛋白质亚型，以更好地了解它们如何共同调节肾钠处理。我们的目标是确定和表征这种特定的激酶和协同转运蛋白网络的亚型，这些亚型在功能上是 与众不同在这样做的过程中，我们还将提供高质量的人类和小鼠肾单位片段特异性转录组的研究人员在肾脏基因表达的其他方面感兴趣。在一个平行但互补的目标，我们还将研究新的GWAS信号尚未通过结合我们在转录调控和生物信息学的专业知识来挖掘人类基因组中不断扩大的调控元件注释的特点。最初，我们将专注于复制HTN和BP相关变体，但我们的长期目标是建立一个生物信息学管道，旨在将来自大型遗传研究（如GWAS）的信号转换为人类基因组中的功能元件，以便可以检查任何表型或疾病的潜在生物学。为了实现这些目标，我们汇集了高血压遗传学、转录调控、生物信息学、分子生物学、生物化学和肾脏生理学方面的专家。

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.