Biomechanical Regulation of Renal Ion Transporters

肾离子转运蛋白的生物力学调节

基本信息

批准号：
8896747
负责人：
Thomas R Kleyman
金额：
$ 33.89万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-05 至 2017-08-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8896747
关键词：
Acidosis Acids Address Affect Aldosterone Alkalies Anions Apical Bicarbonates Biological Assay Biomechanics Buffers Caenorhabditis elegans Calcium-Activated Potassium Channel Calcium/calmodulin-dependent protein kinase Calmodulin Carrier Proteins Cations Cell physiology Cells Cytophotometry Cytoskeleton Dependence Dependency Distal Drosophila genus Duct (organ) structure Ductal Epithelium Epithelial Cells Excision Exhibits Extracellular Protein Family Fluorescent Dyes Fluorometry Funding Glycocalyx Hydrostatic Pressure Individual Intercalated Cell Intercalated Duct Investigation Ion Channel Ions Kidney Kinetics Mammals Measures Mechanics Mediating Mediator of activation protein Membrane Membrane Protein Traffic Nephrons Oryctolagus cuniculus Pathway interactions Probability Proteins Proteoglycan Proteolysis Proton Pump Proton-Translocating ATPases Protons Purinoceptor Regulation Research Personnel Rest Role Signal Pathway Signal Transduction Stimulus Stretching Structure Sum Transport Process Tubular formation Variant Vesicle Work Xenopus oocyte absorption base cell type digital epithelial Na+ channel fluid flow inhibitor/antagonist large-conductance calcium-activated potassium channels luminal membrane member programs response sensor shear stress trafficking

项目摘要

DESCRIPTION (provided by applicant): Variability in renal tubular flow rates subject tubular epithelial cells to changes in shear stress and hydrostatic pressure that ultimately affects cellular function. The distal nephron, and specifically the cortical collecting duct (CCD), is comprised of 2 major cell types: Na-absorbing principal cells (70%) and acid-base transporting intercalated cells (30%). Principal cells possess apical epithelial Na channels (ENaCs), which have a key role in transepithelial Na absorption. Acid-base transport by intercalated cells is mediated by apical anion exchangers and proton pumps localized to beta-and alpha-intercalated cells, respectively. Rabbit CCDs respond to an increase in flow with an increase in Na absorption as well as a reduction in bicarbonate secretion. This application will address mechanisms underlying flow-dependence of ENaC activation, and thus extend studies begun in the current funding period, and initiate an investigation directed at exploring mechanisms underlying flow-regulation of proton and bicarbonate transport. Proposed studies will utilize CCDs, cultured epithelial cells and Xenopus oocytes to determine mechanisms by which flow increases ENaC open probability. Studies in rabbit CCDs will address mechanisms by which flow reduces net bicarbonate secretion. These proposed studies should provide new information regarding the regulation of Na and acid/base transport in the CCD.

描述（由申请人提供）：肾小管流速的变异性受试者上皮细胞对剪切应力和静水压力的变化，最终影响细胞功能。远端肾脏，特别是皮质收集导管（CCD），由2种主要细胞类型组成：NA吸收的主要细胞（70％）和酸碱转运的插入式细胞（30％）。主要细胞具有顶上上皮NA通道（ENAC），在跨跨性别Na吸收中具有关键作用。互化细胞通过互换细胞的酸碱转运是由顶端阴离子交换剂和质子泵分别局部定位于β和α嵌入细胞的质子。兔CCD会随着Na吸收的增加以及碳酸氢盐分泌的减少而响应流量的增加。该应用将解决ENAC激活的流动依赖性的机制，从而扩展了当前资助期开始的研究，并启动了针对探索质子和碳酸氢盐运输的流动流量基础机制的研究。拟议的研究将利用CCD，培养的上皮细胞和爪蟾卵母细胞来确定流动增加ENAC开放概率的机制。兔CCD的研究将解决流动减少碳酸氢盐分泌的机制。这些提出的研究应提供有关CCD中NA和酸/碱基转运的新信息。