Regulation of Metal Ion Homeostasis by Channel Kinases

通道激酶对金属离子稳态的调节

• 批准号: 7248888
• 负责人: ALEXEY G. RYAZANOV
• 金额: $ 185.3万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7248888
• 关键词: Regulation; Metal; Ion; Homeostasis; Channel

DESCRIPTION (provided by applicant): The goal of this program is to uncover the mechanism of the regulation of metal ion homeostasis, particularly magnesium homeostasis in vertebrates through the investigation of the structure and function of channel kinases. Channel kinases, also know as "chanzymes" (channels plus enzymes) are recently discovered bifunctional molecules that consist of an ion channel fused to a protein kinase. Recent evidence suggests that channel kinases TRPM6 and TRPM7 play a key role in the regulation of metal ion homeostasis in vertebrates. Specifically, channel kinases have several major functions: 1) As magnesium channels they represent key regulators of magnesium homeostasis and may provide the major magnesium uptake mechanism in mammalian cells; 2) As trace metal ion channels, channel kinases may provide a major ion channel mechanism for cellular entry of trace metal ions such as manganese and zinc. In Project 1 (Andrea Fleig, PI), we will perform biophysical, molecular, and functional analysis of the TRPM7 and TRPM6 ion channels. We will investigate molecular determinants of channel permeation that provide selectivity for divalent metal ions. In Project 2 (Alexey Ryazanov, 4PI), we will investigate the physiological function and mechanism of activation of TRPM7 and TRPM6 kinases. We will determine sequence motifs recognized by these kinases and identify their physiological substrates. In Project 3 (Andrew Scharenberg, PI) we will investigate the role of TRPM7 in the regulation of magnesium homeostasis. We will identify signaling pathways through which TRPM7 mediates magnesium-dependent regulation of cell and organism growth. In Project 4 (John Stokes, PI), we will analyze the role of TRPM6 and TRPM7 in the regulation of magnesium homeostasis using knockout mouse models. We will determine how magnesium balance affects kidney function in mice deficient in TRPM6 or TRPM7. We will also develop mice with conditional and organ-specific knockouts of TRPM6 and TRPM7. These projects will be supported by an Administrative Core (Core A), and an Animal and Analytical Core (Core B). This work has a high degree of medical relevance considering that channel kinases are likely to play a role in such conditions as ischemia and stroke, and since mutations in channel kinases are causing diseases associated with metal ion imbalance.

描述（由申请人提供）：该程序的目的是通过研究通道激酶的结构和功能来揭示金属离子稳态调节的机制，尤其是脊椎动物中镁稳态的机制。通道激酶，也称为“ chanzymes”（通道加酶）最近被发现的双功能分子，由与蛋白激酶融合的离子通道组成。最近的证据表明，通道激酶TRPM6和TRPM7在脊椎动物中金属离子稳态的调节中起关键作用。具体而言，通道激酶具有多个主要功能：1）作为镁通道，它们代表了镁稳态的关键调节剂，并可能提供哺乳动物细胞中主要的镁摄取机理； 2）作为痕量金属离子通道，通道激酶可以为痕量金属离子（如锰和锌）的细胞进入提供主要的离子通道机制。在项目1（Andrea Fleig，PI）中，我们将对TRPM7和TRPM6离子通道进行生物物理，分子和功能分析。我们将研究通道渗透的分子决定因素，以提供二价金属离子的选择性。在项目2（Alexey Ryazanov，4PI）中，我们将研究TRPM7和TRPM6激酶激活的生理功能和机制。我们将确定这些激酶识别的序列基序，并确定它们的生理底物。在项目3（PI的Andrew Scharenberg）中，我们将研究TRPM7在镁稳态调节中的作用。我们将确定TRPM7介导细胞和生物生长的镁依赖性调节的信号通路。在项目4（John Stokes，PI）中，我们将使用基因敲除小鼠模型分析TRPM6和TRPM7在镁稳态调节中的作用。我们将确定镁平衡如何影响缺乏TRPM6或TRPM7的小鼠的肾功能。我们还将开发带有条件和器官特异性敲除TRPM6和TRPM7的小鼠。这些项目将由行政核心（核心A）以及动物和分析核心（核心B）支持。考虑到通道激酶可能在缺血和中风等疾病中起作用，并且由于通道激酶的突变引起与金属离子不平衡相关的疾病，因此这项工作具有高度的医学相关性。