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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

基本信息

批准号：
10317557
负责人：
Peter A Friedman
金额：
$ 46.54万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10317557
关键词：
Affect Attenuated Back Binding Biotin Brain C-terminal Cells Chronic Kidney Failure Code Complex Cyclic AMP Data Disease Dissociation Elements Epithelial Cells Equilibrium Exhibits FGFR1 gene G-Protein-Coupled Receptors GTP Binding GTP-Binding Proteins Goals Heart Hippocampus (Brain)Hormones Human Human Cell Line Kidney Kidney Diseases Learning Ligands Ligase Link MAP Kinase Gene MAPK Signaling Pathway Pathway Mediating Metabolism Modeling Molecular Mus Mutation Osteopenia Outcome PDZ protein PTH gene Patients Phosphorylation Phosphotransferases Prevalence Proteins Proteomics Proximal Kidney Tubules Regulation Rodent Role Scaffolding Protein Secondary Hyperparathyroidism Serum Signal Pathway Signal Transduction Site Small Interfering RNA Structure Synaptic plasticity Tertiary Protein Structure Testing Tissues Ventricular Remodeling base clinically relevant genome wide association study hormone regulation inorganic phosphate insight knock-down novel response scaffold uptake

项目摘要

PROJECT SUMMARY: PTH and FGF23 initiate signaling pathways in renal proximal tubule cells that converge on the [NPT2A:NHERF1] complex to inhibit phosphate uptake. Mice lacking the PDZ protein NHERF1 and humans harboring NHERF1 mutations are hypophosphatemic. Important gaps exist in understanding the elements involved in these actions due to unidentified factors. Numerous GWAS studies of patients with chronic kidney disease implicate RGS14, which harbors a PDZ-recognition motif. We propose that RGS14 is a novel regulator of hormone-sensitive phosphate transport, and provide preliminary data to support this idea. RGS14 is scaffold that integrates G protein, MAPK, and Ca++/CaM signaling pathways. Its actions are best understood in rodent brain, where RGS14 suppresses synaptic plasticity and hippocampal-based learning. Nothing is known about RGS14 effects on hormone action or in kidney. Our preliminary findings show that RGS14 suppresses both PTH- and FGF23-regulated phosphate transport. RGS14 persistently attenuates PTH-regulated phosphate transport in primary human proximal tubule cells. RGS14 knock-down by siRNA reverses this action to reveal full PTH activity. RGS14 add-back to cells lacking the protein blocks PTH actions. Human RGS14 contains a C- terminal PDZ ligand (-DSAL) that directly binds NHERF1. Mutations in the PDZ-ligand disrupt RGS14 binding to NHERF1 and interfere with RGS14 regulation of hormone actions. These findings identify RGS14 as an entirely new element regulating hormone action on a vital homeostatic activity, and raise the hypothesis that RGS14 is a novel regulator of hormone-sensitive [NPT2A:NHERF1]-mediated phosphate transport in renal proximal tubule cells. Three Aims will test this premise. AIM 1 will define how RGS14 regulates assembly, disassembly of [NPT2A:NHERF1], its internalization and hormone-sensitive phosphate uptake. AIM 2 will define the locus of RGS14 effects on PTH and FGF23 signaling and the impact of hormone-directed NHERF1 phosphorylation on RGS14 regulation of the [NPT2A:NHERF1] complex. AIM 3: will define how PTH- and FGF23-directed signaling affect RGS14 interactions with NHERF1 and the [NHERF1:NPT2A] complex. These studies will identify novel roles and molecular mechanisms by which RGS14 regulates NPT2A function and hormone-sensitive phosphate transport in kidney as related to kidney disease.

项目总结：PTH和FGF23在肾近端小管细胞中启动信号通路