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: 10677662
• 负责人: Erhu Cao
• 金额: $ 66.55万
• 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/10677662
• 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; Dedications; 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; 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; Proliferating; Property; Proprotein Convertase 1; Proprotein Convertase 2; Protein translocation; Regulation; Role; Shapes; Signal Transduction; Site; Stimulus; Structure; TRP channel; Visualization; Work; autosome; imaging approach; novel; particle; response; sensor; structural determinants; 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.

项目总结 离子通道控制着受精、增殖、发育、学习和记忆等不同的过程。 离子通道是一种多跨膜蛋白，每秒可传输约106至107个离子。 膜。离子通量的精确时空调节是离子选择的基本原理 信道控制着如此多样化的信令模式阵列。空间调控通过定向渠道来实现 到包裹在内质网(ER)或内小体等膜中的亚细胞室， 而通过控制通道的打开和关闭的特定信号进行时间调节。初级纤毛 是顶端质膜上的天线状突起，富含特定的离子子集 称为多囊蛋白的通道。多囊蛋白基因突变导致常染色体显性遗传性多细胞肾病 (ADPKD)，表现为肾脏和其他器官(如肝脏和胰腺)的囊性形成。这个 多囊蛋白通道在空间和时间上受到调节从而对 纤毛信号级联仍然知之甚少。本项目的中心目标是了解 多囊蛋白通道被激活的分子和细胞水平的基本机制 初级纤毛。有三个具体目标。第一个目的是定义PC1和PC2中的分子基序 睫状多囊蛋白通道复合体的时间调节。第二个目标是界定地方性法规 通过纤毛钙水平检测多囊藻毒素的含量。第三个目的是确定睫状脂在限制中的生理作用 多囊藻毒素对初生纤毛的活性。这项提案包括两名申请者的初步观察结果 在多囊蛋白通道功能方面的互补专业知识。该项目的完成将是迈向 了解初级纤毛内多囊藻毒素通道信号的基本原理。我们的长期目标 了解多囊蛋白通道的失调是如何导致ADPKD的。