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Regulation of Renal Phosphate Transport by Lipids

脂质对肾磷酸盐转运的调节

基本信息

批准号：
8490357
负责人：
MOSHE LEVI
金额：
$ 37.87万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8490357
关键词：
Acquired Immunodeficiency Syndrome Actins Affect Aging Alcoholism Apical Binding Proteins Biochemical Bone Diseases Cardiovascular Diseases Cardiovascular Physiology Cell physiology Cells Ceramide glucosyltransferase Cholesterol Chronic Chronic Kidney Failure Clathrin Clinical Coupling Detergents Diabetes Mellitus Diet Dietary Factors Dietary Potassium Diffusion Disease Down-Regulation ERM protein Endocytosis Epithelial Cells Excretory function Family Fluorescence Microscopy Functional disorder Galactosidase Gene Mutation Glycosphingolipids Health Heart Diseases Hormonal Hormones Hour Hypophosphatemia Image Immunoelectron Microscopy Ions Kidney Kidney Calculi Kinetics Knockout Mice Lateral Life Lipid A Lipids Malignant Neoplasms Mediating Membrane Membrane Lipids Membrane Microdomains Metabolic Microscopy Modeling Mus Nephrolithiasis Organ Parathyroid gland Pathogenesis Pathway interactions Pharmaceutical Preparations Phospholipids Phosphoproteins Physiologic calcification Physiological Play Potassium Deficiency Production Protein Dynamics Proteins Proximal Kidney Tubules Rattus Recycling Regulation Regulatory Element Resolution Rickets Role Signal Transduction Sodium Sphingomyelins Sterols Syndrome Techniques Tertiary Protein Structure Testing Therapeutic Time Transplantation Tubular formation Up-Regulation Variant Vascular calcification Work absorption acquired immunodeficiency apical membrane basolateral membrane brush border membrane calcification extracellular ezrin fibroblast growth factor 23 globotriaosylceramide in vivo inhibitor/antagonist inorganic phosphate lipid transport nucleotide metabolism overexpression public health relevance response sodium-hydrogen exchanger regulatory factor spatiotemporal urinary

项目摘要

DESCRIPTION (provided by applicant): The regulation of the overall renal tubular Pi transport by dietary, hormonal, or metabolic factors occurs via the proximal tubular apical brush border membrane (BBM) sodium gradient-dependent Pi (NaPi) cotransport proteins. Apical entry of Pi is mediated by coordinated actions of NaPi-2a, NaPi-2c, and PiT-2. Chronic alterations in dietary Pi, PTH, FGF23, Klotho, and other metabolic and dietary factors change the abundance of these transporters in BBM. There are however several important differences between these NaPi cotransporters the most important being that a) the time scale kinetics of the regulation of the NaPi transporters by dietary Pi and PTH are quite different, and b) there is also increasing evidence for the differential regulation of the NaPi transporters. This proposal will test the HYPOTHESES that NaPi-2a, NaPi-2c and PiT-2 are localized in distinct brush border membrane microdomains or nanodomains, resulting in: 1) differential regulation of lateral diffusion and clustering of the NaPi transporters in the brush border membrane; 2) differential interactions with PDZ and ERM domain containing proteins, including NHERF-1, PDZK-1, and ezrin; 3) differential rates of recruitment to endocytic pathways and/or differential mechanisms of endocytosis and internalization from the brush border membrane. AIM 1 will determine if NaPi-2a, NaPi-2c and PiT-2 are localized in distinct BBM microdomains or nanodomains resulting in differential regulation of lateral diffusion and clustering of the NaPi transporters in the BBM in response to alterations in PTH, Pi, membrane lipid composition and actin dynamics. AIM 2 will determine if NaPi-2a, NaPi-2c and PiT-2 have differential interactions with PDZ -ERM domain proteins, including NHERF-1, PDZK-1, and ezrin, which result in the differential internalization rate of the NaPi transporters in response to alterations in PTH, Pi and lipids. AIM 3 will determine if NaPi-2a, NaPi-2c and PiT-2 have differential rates of recruitment to endocytic pathways and/or differential mechanisms of endocytosis and internalization from the brush border membrane in response to PTH, Pi and lipids.

描述（由申请人提供）：饮食、激素或代谢因素对肾小管Pi转运的调节是通过近端小管顶端刷状边界膜（BBM）钠梯度依赖性Pi （NaPi）共转运蛋白发生的。Pi的顶端进入是由NaPi-2a、NaPi-2c和piti -2协同作用介导的。饮食中Pi、PTH、FGF23、Klotho以及其他代谢和饮食因素的慢性改变改变了BBM中这些转运蛋白的丰度。然而，这些NaPi共转运蛋白之间存在一些重要的差异，其中最重要的是a)膳食Pi和PTH对NaPi转运蛋白调节的时间尺度动力学有很大不同，b)也有越来越多的证据表明NaPi转运蛋白的差异调节。本研究将验证NaPi-2a、NaPi-2c和PiT-2定位于不同的刷状缘膜微域或纳米域的假设，从而导致：1)NaPi转运体在刷状缘膜中横向扩散和聚集的差异调节；2)与含有PDZ和ERM结构域的蛋白（包括NHERF-1、PDZK-1和ezrin）的差异相互作用；3)胞吞途径的不同招募率和/或胞吞和内化的不同机制。AIM 1将确定NaPi-2a、NaPi-2c和PiT-2是否定位于不同的BBM微域或纳米域，从而导致NaPi转运体在BBM中横向扩散和聚集的差异调节，以响应PTH、Pi、膜脂组成和肌动蛋白动力学的改变。AIM 2将确定NaPi-2a、NaPi-2c和PiT-2是否与PDZ -ERM结构域蛋白（包括NHERF-1、PDZK-1和ezrin）有不同的相互作用，从而导致NaPi转运体在PTH、Pi和脂质改变时的不同内化率。AIM 3将确定NaPi-2a、NaPi-2c和PiT-2在PTH、Pi和脂质作用下是否具有不同的内吞途径募集率和/或刷状边界膜内吞和内化的不同机制。