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.

钾通道在人类电解质和血压稳态中起关键作用。我们最近描述了一种新型的人类综合征，结合了早期发作，感觉性耳聋，共济失调，智力低下和电解质失衡（芝麻），并将KCNJ10鉴定为病变基因。 KCNJ10编码在大脑，内耳和肾脏中表达的KIR4.1内向整流器K+通道。在该项目的第一部分中，我计划通过评估导致突变对通道表达，运输和功能的疾病的影响来研究芝麻综合征的病理生理学。然后，将使用增加复杂性的模型（Xenopus卵母细胞，肾细胞系，已建立的敲除小鼠模型），然后将用于检查Kir4.1在肾脏电解质稳态中的作用。我们假设Kir4.1对于远端肾单位中Na+-K+-ATPase的K+的基底外侧回收是必要的，从而提出了上游调节剂的问题。肾素血管紧张素醛固酮系统和WNK（无赖氨酸= K）激酶调节肾脏盐的吸收和钾分泌是这种途径的极好候选者。在本提案的第二部分中，我将研究肾上腺两孔背景钾通道在原发性醛固酮基质中的作用，这是人类高血压的一种形式。