Genetic Mechanisms of Hypertension - from Mutation to Cellular Function

高血压或血压升高影响着全世界超过10亿人。作为中风、心脏病发作、心力衰竭和肾衰竭等疾病的发病率和死亡率的主要风险因素，它每年导致900多万人死亡。然而，许多患者没有得到诊断或没有得到适当的治疗。该提案的总体目标是扩大我们对高血压的遗传学和病理生理学的了解，重点关注所谓的肾素-血管紧张素-醛固酮系统对血压的激素调节。在第一个项目中，我们的目标是在原发性醛固酮增多症家族中识别新的疾病基因。原发性醛固酮增多症是继发性高血压最常见的形式，通常由产生醛固酮的肾上腺腺瘤或双侧肾上腺增生引起。我们先前已经鉴定了导致醛固酮腺瘤和/或家族性醛固酮增多症的离子通道基因突变（KCNJ 5，CACNA 1D，CACNA 1H），但许多家族并不携带任何已知疾病基因的突变。在第二个项目中，我们的目标是描述肾素瘤的基因组结构，这种罕见的肾脏肿瘤产生肾素并导致高血压。我们将确定肿瘤特异性（体细胞）点突变和较大的缺失或重复，可能解释这些肿瘤中增加的肾素产生和增殖。潜在的机制可能对更常见的肾素过量形式的患者有影响，如肾动脉狭窄。最后，我们计划研究钾通道KCNJ 5的相互作用和调节，目的是确定其在人类肾上腺生理学中的作用。为了实现这些目标，我们将使用尖端的基因组学和蛋白质组学技术。为了发现疾病基因，我们将对原发性醛固酮增多症患者以及肾素瘤和相应的正常样本的所有蛋白质编码基因（外显子组）进行测序。我们将在杜塞尔多夫的高性能计算集群上实施最新的下一代测序分析管道。对于相互作用的蛋白质的鉴定，将使用先进的质谱工具，我们相信，这种方法，将临床上重要的问题，分子遗传学和生理学，将导致新的基因，蛋白质和高血压诊断，药物发现和个性化医疗的途径的鉴定。

Hypertension, or elevated blood pressure, affects more than one billion people worldwide. As a major risk factor for morbidity and mortality from diseases such as stroke, heart attacks, heart failure and kidney failure, it contributes to more than nine million deaths each year. Yet, many patients are not diagnosed or do not receive appropriate treatment. The overarching goal of this proposal is to expand our knowledge of the genetics and pathophysiology of hypertension, with a focus on the hormonal regulation of blood pressure by the so-called renin-angiotensin-aldosterone system. In the first project, we aim to identify new disease genes in families with primary hyperaldosteronism. Primary aldosteronism is the most common form of secondary hypertension and is typically caused by aldosterone-producing adrenal adenomas or bilateral adrenal hyperplasia. We have previously identified mutations in ion channel genes that cause aldosterone-producing adenomas and/or familial hyperaldosteronism (KCNJ5, CACNA1D, CACNA1H), but many families do not carry mutations in any of the known disease genes.In a second project, we aim to characterize the genomic landscape of reninomas, rare kidney tumors that produce renin and cause hypertension. We will identify tumor-specific (somatic) point mutations and larger deletions or duplications that may explain the increased renin production and proliferation in these tumors. The underlying mechanisms could have implications for patients with more common forms of renin excess, such as renal-artery stenosis. Lastly, we propose to study the interactions and regulation of the potassium channel KCNJ5, with the goal to define its role in human adrenal gland physiology.To achieve these goals, we will use cutting-edge genomic and proteomic technologies. For disease gene discovery, we will sequence all protein-coding genes (the exome) of patients with primary aldosteronism as well as reninomas and corresponding normal samples. We will implement an up-to-date next-generation sequencing analysis pipeline on the high-performance computing cluster in Düsseldorf. For the identification of interacting proteins, advanced mass spectrometry tools will be used.We believe that this approach, linking clinically important questions to molecular genetics and physiology, will result in the identification of new genes, proteins and pathways for hypertension diagnosis, drug discovery and personalized medicine.