A comprehensive map of polycystin channel regulation and its implications in polycystic kidney disease

多囊蛋白通道调节的综合图谱及其对多囊肾病的影响

• 批准号: 10483183
• 负责人: Erhu Cao
• 金额: $ 66.87万
• 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: 2021-09-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10483183
• 关键词: Acute; Address; Affect; Apical; Autosomal Dominant Polycystic Kidney; Binding; Binding Sites; Biochemical; Biological; Biology; Calcium; Cations; Cell membrane; Cells; Chemicals; Cilia; Collaborations; Complex; Coupling; Cryoelectron Microscopy; Cyst; Data; Detection; Development; Disease; Electrophysiology (science); Endoplasmic Reticulum; Endosomes; Environment; Exhibits; Extracellular Domain; Feedback; Fertilization; Goals; Human; Individual; Investigation; Ion Channel; Ions; Kidney; Kidney Diseases; Knowledge; Learning; Ligand Binding; Ligands; Light; Lipids; Liver; Manuscripts; Maps; Measures; Membrane; Memory; Methods; Modality; Molecular; Monitor; Mutagenesis; Mutation; Optics; Organ; Organelles; Pancreas; Pathogenesis; Physiological; Physiology; Polycystic Kidney Diseases; Positioning Attribute; Process; Property; Proprotein Convertase 1; Proprotein Convertase 2; Protein translocation; Regulation; Role; Signal Transduction; Site; Stimulus; Structure; TRP channel; Ursidae Family; Work; imaging approach; novel; particle; response; sensor; treatment strategy; voltage

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. Precise spatial and temporal regulation of ionic flux is the fundamental principle by which ion channels control such a diverse array of signaling modalities. Spatial regulation is achieved by targeting channels to subcellular compartments ensheathed in membranes such as the endoplasmic reticulum (ER) or endosomes, whereas temporal regulation by specific signals controlling opening and closing of channels. 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 Polycytsic 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 remain poorly understood. The central goal of this project is to understand the fundamental mechanisms at the molecular and cellular level by which polycystin channels are activated in primary cilia. There are three specific aims. The first aim defines the molecular motifs in PC1 and PC2 underlying the temporal regulation of the ciliary polycystin channel complex. The second aims defines the local regulation of polycystins by ciliary calcium levels. The third aim determine the physiological role of ciliary lipids in restricting polycystin activity to primary cilia. This proposal includes preliminary observations of two applicants with complementary expertise on polycystin channel function. Completion of this project will be a critical step towards understanding the fundamental principles of polycystin channel signaling within primary cilia. Our long‐term goal is to understand how dysregulation of polycystin channels causes ADPKD.

项目摘要 离子通道控制着受精、增殖、发育、学习和记忆等多种过程。 离子通道是多跨膜蛋白，每秒转运约106至107个离子穿过 膜。离子通量的精确空间和时间调节是离子通过其在空间和时间上流动的基本原理。 信道控制这样的多种多样的信令模态。空间调控通过瞄准渠道实现 到包被在膜如内质网（ER）或核内体中的亚细胞区室， 而通过特定信号控制通道的打开和关闭的时间调节。初级纤毛 是顶端质膜的触角状突起，富含特定的离子亚群， 称为多囊蛋白。多囊蛋白突变导致常染色体显性遗传性多细胞肾病 （ADPKD），其表现为肾脏和其他器官（如肝脏和胰腺）中的囊肿形成。的 多囊蛋白通道在空间和时间上受到调节的分子机制， 纤毛信号级联仍然知之甚少。本项目的中心目标是了解 在分子和细胞水平上的基本机制，多囊蛋白通道被激活， 初级纤毛有三个具体目标。第一个目标是定义PC1和PC2中的分子基序， 睫状体多囊蛋白通道复合物的时间调节。第二个目标是确定地方法规 通过纤毛钙水平检测多囊藻毒素。第三个目的是确定睫状体脂质的生理作用， 多囊藻毒素对初级纤毛的活性。该提案包括两个申请人的初步意见， 多囊蛋白通道功能的补充专业知识。该项目的完成将是朝着以下目标迈出的关键一步 了解初级纤毛内多囊蛋白通道信号传导的基本原理。我们的长期目标 是了解多囊蛋白通道的失调如何导致ADPKD。