Structure-based identification of optimized mutant Kir3.4 inhibitors for renoprotection (C07 (A03 + A04))

基于结构的肾脏保护优化突变型 Kir3.4 抑制剂的鉴定 (C07 (A03 A04))

• 批准号: 516847250
• 金额: --
• 依托单位: Institut für Medizinische Physik und Biophysik (IMPB)
• 依托单位国家: 德国
• 项目类别: Collaborative Research Centres
• 财政年份: 2023
• 资助国家: 德国
• 起止时间: 2022-12-31 至 无数据
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/516847250?language=en
• 关键词: Structure; based; identification; optimized; mutant

Somatic and germline mutations in the K+ channel gene KCNJ5 (Kir3.4) cause aldosterone-producing adenomas and familial hyperaldosteronism, respectively. Using cryo-electron microscopy, we aim to elucidate the structures of WT and mutant Kir3.4. Based on structural information, we will refine specific inhibitors of mutant Kir3.4 or identify new inhibitors with optimized properties. We will test their inhibitory potential in vitro and in vivo, using a previously established pig model with KCNJ5 mutation. This will allow us to understand molecular mechanisms of Kir3.4 channel dysfunction and optimize inhibitors for the diagnosis (based on a drop in aldosterone upon short-term administration) and long-term therapy (leading to tumor shrinkage) of patients with KCNJ5 mutations.

K+通道基因KCNJ5（KIR3.4）中的体细胞和种系突变分别引起产生醛固酮的腺瘤和家族性高醛溶剂。使用冷冻电子显微镜，我们旨在阐明WT和突变体Kir3.4的结构。基于结构信息，我们将完善突变kir3.4的特定抑制剂，或鉴定具有优化特性的新抑制剂。我们将使用具有KCNJ5突变的先前建立的猪模型在体外和体内测试其抑制潜力。这将使我们能够了解KIR3.4通道功能障碍的分子机制，并优化诊断抑制剂（基于短期服用时醛固酮的下降）和KCNJ5突变患者的长期治疗（导致肿瘤收缩）。