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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要离子通道控制诸如受精，增殖，发展，学习和记忆等多样化过程。离子通道是多跨跨膜蛋白，每秒运输约106至107个离子膜。原发性纤毛是从根尖质膜的天线形突出，是富集在称为polycystins的离子通道的特定子集中。多囊突变引起常染色体主要的多囊性肾脏疾病（ADPKD），在肾脏和其他器官中表现出囊肿形成例如肝脏和胰腺。多囊这通道在空间上和在时间上受到的调节，因此有助于睫状信号级联反应仍然知之甚少。这该项目的核心目标是开发多囊这通道的小分子激活剂作为新工具研究分子和细胞水平的多囊信号传导的基本机制。这样的工具是目前，研究社区无法获得，并且很可能充当ADPKD的新型治疗方法。最近，离子通道激动剂已开发为恢复功能失调的离子通道的新型治疗剂人类的活动。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治疗剂。该建议包含两个特定的目的：第一个目的提出了基于成像的高吞吐量屏幕，以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询问多囊离子通道活性。在第二个目标将测试此类激动剂的效力，以恢复错过的多囊通道的活动 PC1或PC2中的突变。这种错义突变可能会被特定的激动剂和帐户振兴对于所有病原ADPKD突变的约35％。