Redox and Ca2+ signaling regulation of enamel mineralization
牙釉质矿化的氧化还原和 Ca2 信号传导调节
基本信息
- 批准号:10586833
- 负责人:
- 金额:$ 48.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-10 至 2028-02-28
- 项目状态:未结题
- 来源:
- 关键词:Acquired Dental FluorosisAddressAdultAffectAmeloblastsAmelogenesisAnabolismApatitesBiogenesisBiological AssayBrainCalciumCell LineCell physiologyCellsChromosome 21ComplexConfocal MicroscopyCrystal FormationDataDefectDental EnamelDental cariesDevelopmentDiseaseDown SyndromeElectron TransportEnamel FormationExposure toFluoridesFoundationsFunctional disorderFundingGenerationsGenesGenetic DiseasesGenus HippocampusGlycolysisGoalsGrowthHeterozygoteHistologyHomeostasisHuman ChromosomesImageImpairmentIn VitroIncisorIndividualIntakeKnockout MiceLabelMaturation-Stage AmeloblastMeasuresMechanicsMembrane PotentialsMetabolicMineralsMitochondriaMitochondrial DNAMitochondrial MatrixModelingMorphologyMusMuscleNADHNutrientOral healthOrganellesOxidation-ReductionOxygen ConsumptionPancreasPatientsPlayProcessProductionPropertyProtein BiosynthesisProteinsReactive Oxygen SpeciesRecommendationRegulationReporterReportingRiskRodentRoleSafetySignal TransductionSortingStructureTestingTissuesTooth structureTrisomybonecalcificationdosagedrinking waterfluorosishigh riskhuman diseaseimprovedin vivoinduced pluripotent stem cellmineralizationmitochondrial dysfunctionmitochondrial membranemitochondrial metabolismmouse modeloverexpressionresponsesegregationsingle cell analysissingle-cell RNA sequencingskeletaltranscriptometranscriptome sequencingtranscriptomic profilinguptake
项目摘要
Project Summary: Proper mineralization of dental enamel protects against bacterial attack that causes
tooth decay (caries). The ameloblasts cells are responsible for producing and secreting an abundance of
proteins (laying a foundation for enamel growth) as well as engaging in active mineral transport (calcifying
the enamel). These functions are stage dependent with amelogenesis being divided into the secretory
(protein synthesis) and maturation stage (mineralization). However, the mechanisms providing metabolic
support for these processes and how mitochondrial dysfunction might alter them is poorly understood.
Mitochondria are organelles within the cells that convert nutrients into energy via the production of ATP,
and deficiency in mitochondrial function results in human diseases. Mitochondria play an important role
in enamel as evidenced by defects in mitochondrial DNA causing abnormal enamel development.
Therefore, the goal in this competing renewal proposal is to investigate the interplay between
mitochondrial function and enamel formation during environmental insults and determine whether this is
altered in patients with genetic disorders that effect mitochondrial function. We will specifically address
this in the context of Down syndrome (DS), or Trisomy 21, and during dental fluorosis, a process in which
exposure to excess of fluoride during development weakens tooth enamel. DS patients present with
enamel defects including hypocalcification and hypoplasia, both caused by developmental defects in
enamel formation. Mitochondrial dysfunction is widely reported in DS. The overarching hypothesis of
this proposal is that altered mitochondrial function in DS ameloblasts alters enamel crystal
formation and impacts sensitivity to fluorosis. In strong support, our preliminary data show that Dp-
16 mice (an established mouse model of DS) have mechanically weak and morphologically abnormal
enamel. Moreover, overexpression of RCAN1 (a gene associated with DS pathophysiology that is
expressed in ameloblasts) in enamel cell lines, significantly impaired mitochondrial function. We have
also reported that fluoride exposure of enamel cells significantly affected the biosynthesis of the proteins
of the electron transport chain (ETC) responsible for maintaining ATP production, but not in other cells
tested, suggesting unique sensitivity of enamel cells to fluoride, possibly associated with higher ROS
levels. In the proposed studies we will use DS mouse models (Dp16 mice, Rcan1-KO mice, Dp16 x
Rcan1-KO mice) to address the role of mitochondria in the ameloblasts of these mice. We will also use
recently developed reporter mice expressing fluorescently labelled secretory and maturation stage
ameloblasts to induce fluoride and investigate mitochondrial defects using single cell RNASeq and bulk
RNAseq to compare ameloblasts with other tissues. To address if ameloblasts of DS models are more
sensitive to fluoride, we will treat the cells with fluoride and analyze mitochondrial function.
项目总结:牙釉质的适当矿化可以防止细菌的攻击
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Calcium Transport in Specialized Dental Epithelia and Its Modulation by Fluoride.
- DOI:10.3389/fendo.2021.730913
- 发表时间:2021
- 期刊:
- 影响因子:5.2
- 作者:Costiniti V;Bomfim GH;Mitaishvili E;Son GY;Li Y;Lacruz RS
- 通讯作者:Lacruz RS
Overexpression of RCAN1, a Gene on Human Chromosome 21, Alters Cell Redox and Mitochondrial Function in Enamel Cells.
- DOI:10.3390/cells11223576
- 发表时间:2022-11-11
- 期刊:
- 影响因子:6
- 作者:
- 通讯作者:
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Rodrigo S. Lacruz其他文献
Casup2+/sup-activated chloride channel ANO1: A new regulator of osteoclast function
- DOI:
10.1016/j.ceca.2022.102633 - 发表时间:
2022-09-01 - 期刊:
- 影响因子:4.000
- 作者:
Nicola C. Partridge;Rodrigo S. Lacruz - 通讯作者:
Rodrigo S. Lacruz
The evolutionary history of the human face
人类面部的进化史
- DOI:
10.1038/s41559-019-0865-7 - 发表时间:
2019-04-15 - 期刊:
- 影响因子:14.500
- 作者:
Rodrigo S. Lacruz;Chris B. Stringer;William H. Kimbel;Bernard Wood;Katerina Harvati;Paul O’Higgins;Timothy G. Bromage;Juan-Luis Arsuaga - 通讯作者:
Juan-Luis Arsuaga
Rodrigo S. Lacruz的其他文献
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{{ truncateString('Rodrigo S. Lacruz', 18)}}的其他基金
Molecular mechanisms of oral deficiencies in Down syndrome
唐氏综合症口腔缺陷的分子机制
- 批准号:
10658410 - 财政年份:2023
- 资助金额:
$ 48.4万 - 项目类别:
Redox and Ca2+ signaling regulation of enamel mineralization
牙釉质矿化的氧化还原和 Ca2 信号传导调节
- 批准号:
10162310 - 财政年份:2018
- 资助金额:
$ 48.4万 - 项目类别:
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