Amelogenesis and Ion Transport
釉质生成和离子运输
基本信息
- 批准号:10193340
- 负责人:
- 金额:$ 35.27万
- 依托单位:
- 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:2021-03-15 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AmeloblastsAmelogenesisAnionsApicalArchitectureBicarbonatesBindingCarrier ProteinsCell PolarityCell physiologyCellsChloride IonChloridesClinicComplexCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorCytoskeletonDataDefectDental EnamelDiseaseDistalDysmorphologyEnamel FormationEnamel OrganEpithelial CellsEventExtracellular MatrixF-ActinFamily memberFamily suidaeGene ExpressionGene Expression RegulationGene FamilyHydroxyapatitesIn VitroInheritedInorganic Phosphate TransporterIon ChannelIon TransportIonsKnockout MiceLateralLeadLinkLongevityMaturation-Stage AmeloblastMechanicsMembraneMessenger RNAMicroRNAsMineralsModelingMorphologyMovementMusMutant Strains MiceNaturePathologyPathway interactionsProcessProteinsProtonsRegulationReportingRoleSiteSodiumTimeTissuesapical membranebasebiomineralizationcalcium bicarbonatecell typecellular microvillusextracellularezrinin vivoinorganic phosphatemembermineralizationmutantpreventsodium-hydrogen exchanger regulatory factortranscriptome
项目摘要
PROJECT SUMMARY / ABSTRACT
During enamel formation (amelogenesis) the regulation of extracellular pH (pHe) is critical as shown by
multiple mutant mice lines. Bicarbonate (HCO3-) export to the enamel matrix involves anion exchanger 2 (AE2)
and members of the SLC26A gene family. AE2 is localized to the lateral membrane of maturation ameloblasts,
while SLC26A1, 3, 4, 6 and 7 all localize to the apical/distal membrane of these same cells. In maturation
ameloblasts SLC26A proteins colocalize with the cystic fibrosis transmembrane conductance regulator
(CFTR) and function together to allow for the export of HCO3- and the bidirectional movements of chloride ions
(Cl-) as part of the pHe regulatory process. In other polarized epithelial cell types of a secretory nature,
SLC26A proteins and CFTR form a network with cytoskeletal filamentous actin (F-actin) at the apical pole
dictating, to a large part, cell polarity and microvilli projections. NHERF1/SLC9A3R1 and Ezrin proteins are
also involved with this network interaction. The pH-sensitive sodium dependent phosphate transporter
(SLC34A2/NaPi2b), an inorganic phosphate (Pi) import channel also localizes to the apical pole of maturation
ameloblasts, which may suggest a direct link between pHe regulation and Pi transport activities during enamel
mineralization events. Data suggests that miRNAs, targeting the mRNAs of specific ion transport proteins,
also influence ion transport and pHe regulation. Our prior whole transcriptome analysis of maturation and
secretory enamel organ cells identify a potential role for miR-298 and miR-346 in the regulation of NHERF1,
Slc26a1, Slc26a7 and Cftr. In this application we hypothesize that a “SLC26A/CFTR/NHERF1/NaPi2b
network, directing ion movements directly related to HCO3- and Pi transport and pH regulation, while at the
same time dictating apical membrane architecture, is critical for enamel maturation, and disruptions to this
network result in enamel pathologies that will severely impact on enamel longevity.” We propose the following
specific aims: 1) immunolocalization of NHERF1, EZRIN, CFTR and NaPi2b in maturation ameloblasts; 2)
disrupt SLC26A/CFTR/NHERF1/NaPi2b network in enamel organ cells in vivo using miR-346 and miR-298
delivered directly at the site of mineralization; and; 3) investigate the nature of the NHERF1 and NaPi2b
interactions in enamel organ cells in vitro and in vivo. In this study we anticipate that disrupting the
SLC26A/CFTR network and NaPi2b activity, by directly targeting NHERF1 function, will result in a significant
enamel dysmorphology. Findings from this study will have a significant impact on our understanding of the
biomineralization process as it relates to enamel formation in all mammalian species. This study may also
lead to strategies for handling inherited enamel defects in the clinic; and, in the long run help to prevent and
alleviate the suffering of those afflicted with cystic fibrosis and other diseases.
项目摘要/摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Michael Lansdell Paine其他文献
Michael Lansdell Paine的其他文献
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{{ truncateString('Michael Lansdell Paine', 18)}}的其他基金
Doctoral and Post-doctoral Training in Craniofacial Biology
颅面生物学博士和博士后培训
- 批准号:
9518803 - 财政年份:2011
- 资助金额:
$ 35.27万 - 项目类别:
DOCTORAL AND POST-DOCTORAL TRAINING IN CRANIOFACIAL BIOLOGY
颅面生物学博士和博士后培训
- 批准号:
8884400 - 财政年份:2011
- 资助金额:
$ 35.27万 - 项目类别:
DOCTORAL AND POST-DOCTORAL TRAINING IN CRANIOFACIAL BIOLOGY
颅面生物学博士和博士后培训
- 批准号:
8880175 - 财政年份:2011
- 资助金额:
$ 35.27万 - 项目类别:
DOCTORAL AND POST-DOCTORAL TRAINING IN CRANIOFACIAL BIOLOGY
颅面生物学博士和博士后培训
- 批准号:
8269856 - 财政年份:2011
- 资助金额:
$ 35.27万 - 项目类别:
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