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

基本信息

  • 批准号:
    10197924
  • 负责人:
  • 金额:
    $ 55.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
项目摘要/摘要 我们实验室的长期目标是了解多囊蛋白(PC1)的生物学功能 和PC2)由常染色体显性遗传性多囊肾病基因PKD1和PKD2编码,并 当致病途径发生突变时,确定致病途径。通过这样做,我们寻求建立一种坚定的机械主义 了解ADPKD的发病机制,可用于指导合理开发治疗方法。 开发有效的ADPKD疗法的一大障碍是缺乏准确的理解 了解多囊藻毒素的关键生物学功能及其故障如何启动和驱动疾病过程。我们有 最近发现由PC1和PC2(PC1/PC2)形成的复合体,两种蛋白质都排列在 通道孔,起到钙离子通道的作用,而不是同质的PC2通道 主要传导钠和钾。这一发现表明,多囊藻毒素复合体获得了独特的离子 PC1和由此产生的PC1/PC2通道的组装所产生的通道特性在肾脏中起着关键作用 生理学和ADPKD。在这个多PI应用中,我们将使用新开发的函数增益(GOF) PC1/PC2通道突变体,以确定PC1/PC2离子通道功能如何在分子水平上调节 通过胞外和胞内结构域以及钙离子如何在这一调节中发挥作用。我们将开发一种新的 建立ADPKD小鼠PC1/PC2离子通道功能缺陷模型,并用其确定该通道 功能对肾脏的正常发育至关重要,而这一功能的失活才是ADPKD的真正罪魁祸首。 为了确定增强PC1/PC2离子通道功能是否可以作为一种治疗策略,我们 将开发另一个具有PC1/PC2通道功能的GOF的新鼠标型号,并用它来确定 它可以在一只模仿人类ADPKD的PKD1突变小鼠身上拯救这种疾病。我们预计,拟议的 这些研究将为深入研究细胞周期蛋白的功能和调控的基本分子机制提供新的思路。 PC1/PC2通道,并将其通道功能定义为ADPKD的关键决定因素。总的来说,该项目将 可能有助于更好地了解正常的肾脏发育,揭示肾脏发育的主要罪魁祸首 当PC1或PC2突变时,ADPKD,并有助于形成针对PC1/PC2通道的基础 预防和治疗目的。

项目成果

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Feng Qian其他文献

Feng Qian的其他文献

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{{ truncateString('Feng Qian', 18)}}的其他基金

Antibody Validation Vector Core
抗体验证载体核心
  • 批准号:
    10693926
  • 财政年份:
    2020
  • 资助金额:
    $ 55.9万
  • 项目类别:
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:
    10405087
  • 财政年份:
    2020
  • 资助金额:
    $ 55.9万
  • 项目类别:
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:
    10665001
  • 财政年份:
    2020
  • 资助金额:
    $ 55.9万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 55.9万
  • 项目类别:
Antibody Validation Vector Core
抗体验证载体核心
  • 批准号:
    10231257
  • 财政年份:
    2020
  • 资助金额:
    $ 55.9万
  • 项目类别:
Antibody Validation Vector Core
抗体验证载体核心
  • 批准号:
    10058978
  • 财政年份:
    2020
  • 资助金额:
    $ 55.9万
  • 项目类别:
Antibody Validation Vector Core
抗体验证载体核心
  • 批准号:
    10456640
  • 财政年份:
    2020
  • 资助金额:
    $ 55.9万
  • 项目类别:
The Molecular Mechanisms of Polycystin-1 Proteolytic Cleavage in Kidney Health and Polycystic Kidney Disease
多囊蛋白-1 蛋白水解切割在肾脏健康和多囊肾病中的分子机制
  • 批准号:
    9383569
  • 财政年份:
    2017
  • 资助金额:
    $ 55.9万
  • 项目类别:
The Molecular Mechanisms of Polycystin-1 Proteolytic Cleavage in Kidney Health and Polycystic Kidney Disease
多囊蛋白-1 蛋白水解切割在肾脏健康和多囊肾病中的分子机制
  • 批准号:
    9348875
  • 财政年份:
    2016
  • 资助金额:
    $ 55.9万
  • 项目类别:
The Proteolytic Cleavage of Polycystin-1: How and Why
Polycystin-1 的蛋白水解裂解:如何以及为何
  • 批准号:
    7989311
  • 财政年份:
    2009
  • 资助金额:
    $ 55.9万
  • 项目类别:

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