Genetic Mechanisms of Hypertension - from Mutation to Cellular Function

高血压或血压升高影响着全球超过10亿人。作为中风、心脏病、心力衰竭和肾衰竭等疾病发病率和死亡率的一个主要风险因素，它每年造成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。这项提议的首要目标是扩大我们对高血压的遗传学和病理生理学的认识，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高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，通常由醛固酮分泌肾上腺腺瘤或双侧肾上腺增生引起。我们之前已经发现了导致醛固酮产生腺瘤和/或家族性高醛固酮增多症（KCNJ5, CACNA1D, CACNA1H）的离子通道基因突变，但许多家族没有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瘤的基因组景观，肾瘤是一种产生肾素并引起高血压的罕见肾肿瘤。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，这可能解释这些肿瘤中肾素产生和增殖的增加。潜在的机制可能对肾素过量的更常见形式的患者有启示，如肾动脉狭窄。最后，我们建议研究钾通道KCNJ5的相互作用和调控，以确定其在人肾上腺生理中的作用。为了实现这些目标，我们将使用尖端的基因组和蛋白质组学技术。对于疾病基因的发现，我们将对原发性醛固酮增多症患者以及肾腺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d<s:1> sseldorf的高性能计算集群上实现最新的下一代测序分析流水线。为了鉴定相互作用的蛋白质，将使用先进的质谱分析工具。我们相信，这种方法将临床重要问题与分子遗传学和生理学联系起来，将导致新的基因，蛋白质和高血压诊断途径的鉴定，药物发现和个性化医疗。

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.