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

K+通道基因KCNJ5（Kir3.4）的体细胞和生殖细胞突变分别引起醛固酮腺瘤和家族性醛固酮增多症。使用冷冻电子显微镜，我们的目的是阐明WT和突变Kir3.4的结构。基于结构信息，我们将改进突变Kir3.4的特异性抑制剂或鉴定具有优化性质的新抑制剂。我们将使用先前建立的具有KCNJ5突变的猪模型在体外和体内测试它们的抑制潜力。这将使我们能够了解Kir3.4通道功能障碍的分子机制，并优化抑制剂用于KCNJ5突变患者的诊断（基于短期给药后醛固酮的下降）和长期治疗（导致肿瘤缩小）。

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.