Genetik und Physiologie von Kalium-Kanälen in der renalen Elektrolyt- und Blutdruckregulation

肾电解质和血压调节中钾通道的遗传学和生理学

• 批准号: 164257617
• 负责人: Professorin Dr. Ute Scholl
• 金额: --
• 依托单位: Department of Genetics
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/164257617?language=en
• 关键词: Genetik; und; Physiologie; von; Kalium

Potassium channels play a key role in human electrolyte and blood pressure homeostasis. We have recently described a novel human syndrome, combining early onset Seizures, Sensorineural deafness, Ataxia, Mental retardation and Electrolyte imbalance (SeSAME), and identified KCNJ10 as the causative gene. KCNJ10 encodes the Kir4.1 inward rectifier K+ channel expressed in brain, inner ear and kidney. In the first part of this project, I plan to study the pathophysiology of SeSAME syndrome on a molecular level by assessing the impact of disease causing mutations on channel expression, trafficking and function. Models of increasing complexity (Xenopus oocytes, a renal cell line, an established knockout mouse model) will then be used to examine the role of Kir4.1 in renal electrolyte homeostasis. We hypothesize that Kir4.1 is necessary for basolateral recycling of K+ for the Na+- K+-ATPase in the distal nephron, raising the question of upstream regulators; the renin angiotensin aldosterone system and the WNK (with no lysine = K) kinases regulating renal salt reabsorption and potassium secretion are excellent candidates for such a pathway. In the second part of this proposal, I will study the role of adrenal two-pore background potassium channels in primary aldosteronism, a form of human hypertension.

钾通道在人体电解质和血压动态平衡中起着关键作用。我们最近描述了一种新的人类综合征，包括早发性癫痫发作、感音神经性耳聋、共济失调、智力低下和电解质失衡(SESAME)，并确定KCNJ10为致病基因。KCNJ10编码在脑、内耳和肾脏表达的Kir4.1内向整流钾通道。在这个项目的第一部分，我计划通过评估致病突变对通道表达、运输和功能的影响，在分子水平上研究芝麻综合征的病理生理学。然后将使用日益复杂的模型(非洲爪哇卵母细胞、肾脏细胞系、已建立的基因敲除小鼠模型)来研究Kir4.1在肾脏电解质动态平衡中的作用。我们假设Kir4.1对于远端肾单位Na+-K+-ATPase的K+基侧循环是必需的，这提出了上游调节的问题；肾素-血管紧张素-醛固酮系统和WNK(无赖氨酸=K)激酶调节肾盐重吸收和钾分泌是这一途径的极佳候选者。在这项提案的第二部分，我将研究肾上腺双孔背景钾通道在原发性醛固酮增多症中的作用，这是人类高血压的一种形式。