Ion Channel Function and Regulation of the Polycystin-1/2 Complex in Kidney Physiology and Polycystic Kidney Disease

多囊蛋白-1/2复合物在肾脏生理学和多囊肾病中的离子通道功能和调节

• 批准号: 10029791
• 负责人: Feng Qian
• 金额: $ 58.35万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10029791
• 关键词: Affect; Amino Acids; Architecture; Autosomal Dominant Polycystic Kidney; Binding; Biochemical; Biological Assay; Biological Process; C-terminal; Calcium; Cations; Coiled-Coil Domain; Complex; Coupling; Cryoelectron Microscopy; Cyst; Cystic kidney; Development; Disease; EF Hand Motifs; Electrophysiology (science); Ensure; G-Protein-Coupled Receptors; Goals; Homo; Human; Ion Channel; Ion Channel Protein; Ions; Kidney; Kidney Diseases; Knock-in Mouse; Laboratories; Life; Link; Liquid substance; Live Birth; Maps; Measures; Mediating; Methods; Molecular; Morphogenesis; Morphology; Mutant Strains Mice; Mutate; Mutation; N-terminal; Nephrons; PKD1 gene; PKD2 gene; PKD2 protein; Pathogenesis; Pathogenicity; Pathway interactions; Permeability; Physiology; Play; Polycystic Kidney Diseases; Potassium; Preventive; Process; Property; Proteins; Proteolysis; Publishing; Regulation; Renal function; Role; Signal Pathway; Signal Transduction; Site; Sodium; Structure; System; TRP channel; Tail; Testing; Therapeutic; Uncertainty; Xenopus oocyte; extracellular; gain of function; in vivo; insight; loss of function; mouse model; mutant; nephrogenesis; new therapeutic target; novel; polycystic kidney disease 1 protein; preservation; prevent; protein complex; receptor; stoichiometry; success; targeted treatment; therapeutic target; therapy development

Project Summary/Abstract The long-term goals of our laboratories are to understand the biological functions of polycystin proteins (PC1 and PC2) encoded by autosomal dominant polycystic kidney disease (ADPKD) genes PKD1 and PKD2, and to determine the pathogenic pathways when they are mutated. By so doing, we seek to establish a firm mechanistic understanding of the ADPKD pathogenesis, which can be used to guide the rational development of therapies. A great obstacle to the development of effective ADPKD therapies has been the lack of a precise understanding of polycystins’ key biological function and how its malfunction initiates and drives the disease process. We have most recently discovered that the complex formed by PC1 and PC2 (PC1/PC2), with both of proteins lining the channel pore, functions as a calcium-permeable ion channel, in contrast to the homomeric PC2 channel which primarily conducts sodium and potassium. This finding indicates that the polycystin complex gains unique ion channel properties from the assembly of PC1 and the resulting PC1/PC2 channel plays a key role in kidney physiology and ADPKD. In this multi-PI application, we will use our newly developed gain-of-function (GOF) PC1/PC2 channel mutant to determine how the PC1/PC2 ion channel function is regulated at a molecular level by extracellular and intracellular domains and how Ca2+ plays a role in this regulation. We will develop a new ADPKD mouse model that is defective in PC1/PC2 ion channel function and use it to determine that the channel function is essential for proper kidney development and inactivation of this function is the real culprit for ADPKD. To determine whether enhancing the PC1/PC2 ion channel function can be used as a therapeutic strategy, we will develop another new mouse model with the GOF of PC1/PC2 channel function and use it to determine that it can rescue the disease in a PKD1 mutant mouse that mimics human ADPKD. We anticipate that the proposed studies will provide new insights into the fundamental molecular mechanism of function and regulation of the PC1/PC2 channel and define its channel function as the key determinant of ADPKD. Overall, the project will likely lead to a better understanding of normal kidney development, reveal the primary culprit for developing ADPKD when PC1 or PC2 are mutated, and help form the basis for targeting the PC1/PC2 channel for preventative and therapeutic purposes.

Project Summary/Abstract The long-term goals of our laboratories are to understand the biological functions of polycystin proteins (PC1 and PC2) encoded by autosomal dominant polycystic kidney disease (ADPKD) genes PKD1 and PKD2, and to determine the pathogenic pathways when they are mutated. By so doing, we seek to establish a firm mechanistic understanding of the ADPKD pathogenesis, which can be used to guide the rational development of therapies. A great obstacle to the development of effective ADPKD therapies has been the lack of a precise understanding of polycystins’ key biological function and how its malfunction initiates and drives the disease process. We have most recently discovered that the complex formed by PC1 and PC2 (PC1/PC2), with both of proteins lining the channel pore, functions as a calcium-permeable ion channel, in contrast to the homomeric PC2 channel which primarily conducts sodium and potassium. This finding indicates that the polycystin complex gains unique ion channel properties from the assembly of PC1 and the resulting PC1/PC2 channel plays a key role in kidney physiology and ADPKD. In this multi-PI application, we will use our newly developed gain-of-function (GOF) PC1/PC2 channel mutant to determine how the PC1/PC2 ion channel function is regulated at a molecular level by extracellular and intracellular domains and how Ca2+ plays a role in this regulation. We will develop a new ADPKD mouse model that is defective in PC1/PC2 ion channel function and use it to determine that the channel function is essential for proper kidney development and inactivation of this function is the real culprit for ADPKD. To determine whether enhancing the PC1/PC2 ion channel function can be used as a therapeutic strategy, we will develop another new mouse model with the GOF of PC1/PC2 channel function and use it to determine that it can rescue the disease in a PKD1 mutant mouse that mimics human ADPKD. We anticipate that the proposed studies will provide new insights into the fundamental molecular mechanism of function and regulation of the PC1/PC2 channel and define its channel function as the key determinant of ADPKD. Overall, the project will likely lead to a better understanding of normal kidney development, reveal the primary culprit for developing ADPKD when PC1 or PC2 are mutated, and help form the basis for targeting the PC1/PC2 channel for preventative and therapeutic purposes.