Molecular mechanisms of oral deficiencies in Down syndrome
唐氏综合症口腔缺陷的分子机制
基本信息
- 批准号:10658410
- 负责人:
- 金额:$ 151.33万
- 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:2023-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAmeloblastsAmylasesAreaBiogenesisCalcineurinCalcineurin inhibitorCalcium SignalingCarbacholCell LineCellsChromosome 21Confocal MicroscopyCrystal FormationDataDefectDentalDental EnamelDevelopmentDown SyndromeElementsEnamel FormationEnzyme-Linked Immunosorbent AssayEnzymesFeedbackFluids and SecretionsFoundationsGene DosageGeneral PopulationGenerationsGenesGlandGlycolysisGoalsGrowthHealthHeterozygoteHistologyHuman ChromosomesImageIndividualInfectionKnockout MiceKnowledgeLabelLongevityMaturation-Stage AmeloblastMeasuresMechanicsMediatingMembrane PotentialsMitochondriaMitochondrial MatrixModelingMolecularMorphologyMusNADHOralOral cavityOral healthOsmosisOxygen ConsumptionPPP3CA geneParotid GlandPathologyPatientsPhasePilocarpinePredispositionProcessProductionPropertyProtein SecretionProtein phosphataseProteinsPublishingQuality of lifeQuantitative Reverse Transcriptase PCRReporterReportingResearchResearch PersonnelRoleSalivaSalivary GlandsSecondary toSecretory VesiclesSignal TransductionSortingSpeechTaste PerceptionTestingThinnessTimeTooth structureTrisomyUnited States National Institutes of HealthVesicleXerostomiaantimicrobialcalcificationdeciduous toothdosageexperimental studyinduced pluripotent stem cellmechanical propertiesmineralizationmitochondrial dysfunctionmitochondrial membranemouse modelnanoindentationoverexpressionpermanent toothpreventresponsesaliva secretionskeletalsolutetraffickingtranscriptome sequencingtranscriptomic profilinguptakewater channel
项目摘要
Project Summary/Abstract: Individuals with Down syndrome (DS) contend with a diversity of oral
anomalies including poor saliva production and enamel defects that manifest as hypoplasia (thinner
enamel) and hypomineralization. The molecular mechanisms responsible for these alterations are not
known. DS enamel defects are developmental and not simply secondary to hyposalivation. Saliva is
essential to overall oral health, keeping the oral cavity moist and providing important support for speech
and taste. It also contains solutes and enzymes that help prevent bacterial attack. Tooth enamel and
saliva together provide a barrier against bacterial attack and can have a significant impact on health and
quality of life. Regulator of calcineurin 1 (RCAN1) is a gene on human chromosome 21 (Hsa21), trisomy
of which causes DS. RCAN1 is a feed-back inhibitor of calcineurin (Cn) a Ca2+-activated protein
phosphatase that is central to a diversity of intracellular signaling cascades. Loss of Cn function has been
shown to alter the water channel aquaporin, and in salivary glands, disrupts vesicle trafficking essential
for saliva protein secretion. The goal of this proposal is to understand how salivary gland and enamel
formation are altered in DS on a molecular level and to define the role of RCAN1/Cn in this process. In
strong support, our preliminary data show that Dp16 mice [Dp(16)1Yey] an established mouse model of
DS, have mechanically weak and morphologically abnormal enamel. We show that RCAN1 expression
is upregulated in the mineralization phase and that overexpressing RCAN1 in an ameloblast cell line
significantly alters mitochondrial function and increases ROS generation. Our co-investigator has
demonstrated that changes in RCAN1 gene dosage are sufficient to alter mitochondrial dynamics and
function in induced pluripotent stem cells (iPSCs) derived from individuals with DS. There are two central
testable hypotheses in the proposed studies: 1) RCAN1 disrupts enamel crystal formation in DS by
altering mitochondrial function in ameloblasts and 2) RCAN1 suppression of Cn signaling in DS
disrupts Ca2+ signaling in salivary glands leading to hyposalivation. 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 and will use mice expressing fluorescently labelled secretory and maturation
stage. To address the role of RCAN1 trisomy in salivary glands (SG), we will use the Dp16 mice and will
cross them with GFP mice highlighting secretory vesicles in SG to analyze calcium signaling, salivation
as well as protein and solute content in saliva. The proposed studies are significant because they will
both advance our understanding of the mechanisms through which perturbation of normal mitochondrial
function, such as occurs in DS, can impact dental health ameloblast mitochondria and will elucidate the
mechanisms contributing to hyposalivation in DS.
项目摘要/摘要:唐氏综合症(DS)患者面临着多种口头表达方式的挑战
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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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
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:
10586833 - 财政年份:2023
- 资助金额:
$ 151.33万 - 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:
$ 151.33万 - 项目类别:
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