Polycystin activators as novel therapeutic approach for ADPKD

多囊蛋白激活剂作为 ADPKD 的新型治疗方法

• 批准号: 10456345
• 负责人: Markus G Delling
• 金额: $ 8.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456345
• 关键词: Affect; Agonist; Apical; Autosomal Dominant Polycystic Kidney; Biological Assay; Biological Products; Biology; Cell Line; Cell membrane; Cells; Cellular Assay; Cilia; Collaborations; Communities; Complex; Cyst; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cystic kidney; Development; Disease; Electrophysiology (science); Environment; Fertilization; Functional disorder; Goals; Healthcare Systems; Human; Image; Impairment; Ion Channel; Ions; Kidney; Kidney Transplantation; Lead; Learning; Length; Life; Lipids; Liver; Manuscripts; Membrane; Memory; Methods; Missense Mutation; Molecular; Monitor; Mutate; Mutation; Nonsense Mutation; Optics; Organ; PKD2 protein; Pancreas; Pathogenicity; Patients; Physiological; Physiology; Positioning Attribute; Process; Protein translocation; Regulation; Research; Science; Signal Transduction; Specificity; System; Therapeutic; United States National Institutes of Health; base; high throughput screening; human disease; kidney epithelial cell; loss of function; loss of function mutation; novel; novel therapeutic intervention; novel therapeutics; patch clamp; polycystic kidney disease 1 protein; potency testing; precision medicine; small molecule; tool

PROJECT SUMMARY Ion channels control such diverse processes as fertilization, proliferation, development, learning and memory. Ion channels are multispan transmembrane proteins that transport ~106 to 107 ions per second across membranes. The primary cilium is an antenna-shaped protrusion from the apical plasma membrane and are enriched in a specific subset of ion channels called polycystins. Mutations in polycystins cause Autosomal Dominant Polycystic Kidney Disease (ADPKD), which manifests in cyst formation in kidney and other organs, such as liver and pancreas. The molecular mechanisms by which polycystin channels are spatially and temporally regulated and thus contribute to ciliary signaling cascades still remains poorly understood. The central goal of this project is to develop small molecule activators of the polycystin channel as novel tools to study the fundamental mechanisms of polycystin signaling at the molecular and cellular level. Such tools are currently unavailable to the research community and are likely to function as novel therapeutics for ADPKD. Recently ion channel agonists have been developed as novel therapeutics to restore dysfunctional ion channel activity in humans. Examples include activators of cystic fibrosis transmembrane conductance regulator (CFTR) ion channels as therapeutics for the treatment of cystic fibrosis. This proposal contains two specific aims: the first aim proposes imaging-based high throughput screens to identify agonists of polycystin channels using novel cellular assays that we have recently developed to interrogate polycystin ion channel activity. In the second aim will test the potency of such agonists to restore activity of polycystin channels with missense mutations in PC1 or PC2. Such missense mutations can likely be revitalized by specific agonists and account for ~35% of all pathogenic ADPKD mutations.

项目概要 离子通道控制着受精、增殖、发育、学习和记忆等多种过程。 离子通道是多跨跨膜蛋白，每秒传输约 106 至 107 个离子 膜。初级纤毛是从顶端质膜伸出的天线状突起， 富含称为多囊蛋白的离子通道的特定子集。多囊蛋白突变导致常染色体 显性多囊肾病（ADPKD），表现为肾脏和其他器官囊肿形成， 例如肝脏和胰腺。多囊蛋白通道空间和分布的分子机制 暂时调节并因此对纤毛信号级联起作用仍然知之甚少。这 该项目的中心目标是开发多囊蛋白通道的小分子激活剂作为新工具 在分子和细胞水平上研究多囊蛋白信号传导的基本机制。此类工具有 目前研究界无法使用，并且可能作为 ADPKD 的新疗法。 最近，离子通道激动剂已被开发为恢复功能失调的离子通道的新型疗法 在人类中的活动。例子包括囊性纤维化跨膜电导调节剂的激活剂 （CFTR）离子通道作为治疗囊性纤维化的疗法。该提案包含两个具体内容 目标：第一个目标提出基于成像的高通量筛选来识别多囊蛋白通道的激动剂 使用我们最近开发的新型细胞测定法来检测多囊蛋白离子通道活性。在 第二个目标将测试此类激动剂恢复错义多囊蛋白通道活性的效力 PC1 或 PC2 突变。这种错义突变可能会通过特定的激动剂和解释而恢复活力 约 35% 的致病性 ADPKD 突变。