Functional Polarity of PTH Receptor Signaling: Cellular and Molecular Mechanisms
PTH 受体信号传导的功能极性:细胞和分子机制
基本信息
- 批准号:9978053
- 负责人:
- 金额:$ 58.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-20 至 2021-06-30
- 项目状态:已结题
- 来源:
- 关键词:25-hydroxyvitamin DAdaptor Signaling ProteinAddressAffinityAgonistApicalBilateralBindingBiochemicalBiologicalBiomedical ResearchBloodCREB1 geneCYP27B1 geneCell physiologyCell surfaceCellsChronic Kidney FailureClinicalConflict (Psychology)Cyclic AMPDataDevelopmentDiseaseDown-RegulationEndocrinologyEndosomesEpithelial CellsEquilibriumEventFluorescenceFluorescence MicroscopyFluorescence Resonance Energy TransferGTP-Binding ProteinsGenerationsGenetic TranscriptionGoalsHealthHomeostasisHormone Receptor TestHumanHypophosphatemiaIonsKidneyKnockout MiceLigandsLinkLocationMDCK cellMeasuresMediatingMedicalMetabolismMicroscopyMineralsMixed Function OxygenasesModelingMolecularMusOutcomePDZ proteinParathyroid Hormone ReceptorPatientsPeptidesPhosphorylationPhysiologicalPilot ProjectsProductionPropertyProtein Hormone ReceptorProteinsProximal Kidney TubulesReceptor ActivationReceptor SignalingRenal tubule structureResearchRoleScaffolding ProteinSecondary HyperparathyroidismSerumSignal TransductionSignaling ProteinSpecificityStructureSurfaceTechniquesTestingTherapeuticTransactivationUrineVitamin Danalogapical membranebasebasolateral membranebiophysical toolsexperimental studyin vivoinnovationinorganic phosphatekidney cellmouse modelnovelparathyroid hormone-related proteinpolarized cellprogramsreceptorreceptor bindingreceptor expressionreceptor functionscaffoldsodium-hydrogen exchanger regulatory factorstemuptake
项目摘要
Project Summary
The goal of this project is to determine the mechanisms underlying the molecular and cellular endocrinology
of parathyroid hormone receptor (PTHR) signaling as it relates to phosphate and vitamin D balance. PTHR
is uniquely expressed on both apical and basolateral membranes of the polarized cells that form renal
proximal tubules. The biological consequences of bilateral PTHR expression or its origin are unknown. The
premise of the proposal is that characterizing asymmetric PTHR actions will fill a major gap in our
understanding of PTHR signaling and function and reconcile conflicting views of PTH action. Pilot studies
show that PTHR signals from both basolateral and apical membranes but only basolateral PTHR activation
induces transcription of the 1α-vitamin D hydroxylase (CYP27B1). Apical PTHR signaling primarily inhibits
phosphate transport. The molecular and cellular mechanisms regulating PTHR actions are incompletely
defined. The PTHR interacts at apical membranes with the PDZ scaffolding protein NHERF1, which tethers
the receptor and regulates G-protein signaling and function. Absence of NHERF1 or its downregulation
causes relocation of PTHR to basolateral membranes with an increased 1,25[OH]2D in mice and humans.
Preliminary data show that Scribble, a basolateral PDZ protein, exerts a reciprocal effect, where
downregulation causes accumulation of PTHR at apical membranes. We hypothesize that the polarized
PTHR arrangement arises from the segregated location of NHERF1 and Scribble. We advance a research
program to uncover new aspects of PTHR signaling in polarized kidney cells and test the central hypothesis
that polarized PTHR expression is driven by the asymmetric location of the PDZ adaptor proteins, Scribble
and NHERF, which in turn underlies the signaling bias of apical and basolateral PTHR actions on vitamin D
and phosphate homeostasis. We propose three closely linked aims to evaluate this idea. The first two aims
of address the hypothesis that basolateral PTHR activation preferentially stimulates the 1α-vitamin D
hydroxylase, whereas apical PTHR signaling primarily blocks Pi transport. Aim 1 will determine the role of
Scribble and NHERF in the generation of PTHR polarity and its asymmetric signaling in human kidney
proximal tubule epithelial cells. Aim 2 uses live-cell FRET microscopy and other state-of-the art
fluorescence techniques to characterize basolateral and apical membrane signaling properties of PTHR and
the effect of NHERF1 and Scribble on biased G protein signaling. Aim 3 will delineate the in vivo actions of
polarized proximal tubule PTHR by testing the role of Scribble on PTHR-dependent vitamin D and
phosphate metabolism using a novel, conditional proximal tubule Scribble knockout mouse model that we
generated. The outcomes will frame innovative therapeutic approaches targeting disorders of mineral
metabolism.
项目摘要
这个项目的目标是确定分子和细胞内分泌学的基础机制。
甲状旁腺激素受体(PTHR)信号转导与磷酸盐和维生素D平衡有关。PTHR
在形成肾脏的极化细胞的顶膜和基侧膜上都有独特的表达
近端小管。双侧PTHR表达的生物学后果或其来源尚不清楚。这个
该提案的前提是,表征不对称的PTHR行动将填补我们在
了解PTHR信号和功能,并调和对PTH作用的相互矛盾的观点。试点研究
显示PTHR信号来自基底侧膜和根尖膜,但仅来自基底外侧PTHR激活
诱导1-α-维生素D羟基酶(CYP27B1)转录。心尖PTHR信号主要抑制
磷酸盐运输。调节PTHR作用的分子和细胞机制还不完全。
已定义。PTHR在顶膜与PDZ支架蛋白NHERF1相互作用,NHERF1系住
受体和调节G-蛋白信号和功能。NHERF1的缺失或其下调监管
导致PTHR在小鼠和人的基底侧膜上重新定位,1,25[OH]2D增加。
初步数据显示,底侧PDZ蛋白Scribble发挥了相互作用,其中
下调会导致PTHR在顶膜积聚。我们假设极化的
PTHR排列源于NHERF1和Scribble的分离位置。我们推进了一项研究
在极化肾细胞中发现PTHR信号的新方面并检验中心假说的计划
这种极化的PTHR表达是由PDZ接头蛋白的不对称位置Scribble驱动的
和NHERF,这反过来又是顶端和基底外侧PTHR作用于维生素D的信号偏向的基础
和磷酸盐动态平衡。我们提出了三个密切相关的目标来评估这一想法。前两个目标
解决了基底外侧甲状旁腺素受体激活优先刺激1α-维生素D的假说
羟基酶,而顶端PTHR信号主要阻断PI转运。目标1将决定
Scribble和NHERF在人肾PTHR极性及其不对称信号产生中的作用
近端小管上皮细胞。AIM 2使用活细胞FRET显微镜和其他最先进的
荧光技术表征PTHR和PTHR的基侧和根尖膜信号特性
NHERF1和Scribble对偏向G蛋白信号转导的影响。目标3将描述在体内的作用
通过检测Scribble对PTHR依赖的维生素D和维生素D的作用来极化近端小管PTHR
使用一种新的、条件性近端小管Scribble基因敲除小鼠模型的磷酸盐代谢
已生成。这些结果将为针对矿物质紊乱的创新治疗方法奠定基础。
新陈代谢。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Scribble scrambles parathyroid hormone receptor interactions to regulate phosphate and vitamin D homeostasis.
- DOI:10.1073/pnas.2220851120
- 发表时间:2023-06-06
- 期刊:
- 影响因子:11.1
- 作者:Stewart, Bryce Z.;Mamonova, Tatyana;Sneddon, W. Bruce;Javorsky, Airah;Yang, Yanmei;Wang, Bin;Nolin, Thomas D.;Humbert, Patrick O.;Friedman, Peter A.;Kvansakul, Marc
- 通讯作者:Kvansakul, Marc
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Peter A Friedman其他文献
Peter A Friedman的其他文献
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{{ truncateString('Peter A Friedman', 18)}}的其他基金
RGS14 Regulation of Hormone-sensitive NPT2A-mediated Phosphate Transport
RGS14 激素敏感 NPT2A 介导的磷酸盐转运的调节
- 批准号:
10618970 - 财政年份:2021
- 资助金额:
$ 58.76万 - 项目类别:
RGS14 Regulation of Hormone-sensitive NPT2A-mediated Phosphate Transport
RGS14 激素敏感 NPT2A 介导的磷酸盐转运的调节
- 批准号:
10317557 - 财政年份:2021
- 资助金额:
$ 58.76万 - 项目类别:
RGS14 Regulation of Hormone-sensitive NPT2A-mediated Phosphate Transport
RGS14 激素敏感 NPT2A 介导的磷酸盐转运的调节
- 批准号:
10450178 - 财政年份:2021
- 资助金额:
$ 58.76万 - 项目类别:
Functional Polarity of PTH Receptor Signaling: Cellular and Molecular Mechanisms
PTH 受体信号传导的功能极性:细胞和分子机制
- 批准号:
9380356 - 财政年份:2017
- 资助金额:
$ 58.76万 - 项目类别:
BINDING CAPACITY OF THE PDZ2 DOMAIN OF NHERF1
NHERF1 的 PDZ2 结构域的结合能力
- 批准号:
8364320 - 财政年份:2011
- 资助金额:
$ 58.76万 - 项目类别:
COMPLEX FORMATION AND BINDING AFFINITY OF NHERF1 TO C-TERMINAL PEPTIDES
NHERF1 与 C 端肽的复合物形成和结合亲和力
- 批准号:
8364344 - 财政年份:2011
- 资助金额:
$ 58.76万 - 项目类别:
EBP50 REGULATION OF PTH RECEPTOR IN BONE AND KIDNEY
EBP50 对骨和肾中 PTH 受体的调节
- 批准号:
7903700 - 财政年份:2009
- 资助金额:
$ 58.76万 - 项目类别:
NOVEL REGULATORY MECHANISMS CONTROLLING BONE REPAIR AND OSTEOPOROSIS
控制骨修复和骨质疏松的新型调节机制
- 批准号:
7252994 - 财政年份:2007
- 资助金额:
$ 58.76万 - 项目类别:
NOVEL REGULATORY MECHANISMS CONTROLLING BONE REPAIR AND OSTEOPOROSIS
控制骨修复和骨质疏松的新型调节机制
- 批准号:
7447840 - 财政年份:2007
- 资助金额:
$ 58.76万 - 项目类别:
EBP50 REGULATION OF PTH RECEPTOR IN BONE AND KIDNEY
EBP50 对骨和肾中 PTH 受体的调节
- 批准号:
7049700 - 财政年份:2006
- 资助金额:
$ 58.76万 - 项目类别:














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