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:唐氏综合征(DS)患者面临多种口腔疾病,
异常,包括唾液分泌不足和牙釉质缺陷,表现为发育不全(较薄
釉质)和低矿化。导致这些改变的分子机制不是
知道的DS釉质缺陷是发育性的,而不仅仅是继发于唾液不足。唾液是
对整体口腔健康至关重要,保持口腔湿润,为说话提供重要支持
和味道。它还含有有助于防止细菌攻击的溶质和酶。牙釉质和
唾液一起提供了抵抗细菌攻击屏障,
生活质量钙调神经磷酸酶1(RCAN 1)是人类21号染色体(Hsa 21)上的一个基因,三体
导致DS。RCAN 1是钙调神经磷酸酶(Cn)的反馈抑制剂,Cn是一种钙激活蛋白
磷酸酶是细胞内信号级联的多样性的中心。Cn功能丧失
显示改变水通道水通道蛋白,并在唾液腺中,破坏囊泡运输的必要条件,
分泌唾液蛋白质。这项研究的目的是了解唾液腺和牙釉质
在分子水平上改变DS中的RCAN 1/Cn形成,并定义RCAN 1/Cn在该过程中的作用。在
我们的初步数据显示Dp 16小鼠[Dp(16)1 Yey]是一种建立的
DS,具有机械薄弱和形态异常的釉质。我们发现RCAN 1表达
在矿化阶段上调,在成釉细胞系中过表达RCAN 1
显著改变线粒体功能并增加ROS生成。我们的合作调查员
证明RCAN 1基因剂量的变化足以改变线粒体动力学,
在来自DS个体的诱导多能干细胞(iPSC)中发挥作用。有两个中央
在所提出的研究中可检验的假设:1)RCAN 1通过以下方式破坏DS中的釉质晶体形成:
改变成釉细胞中的线粒体功能和2)RCAN 1抑制DS中的Cn信号传导
破坏唾液腺中的Ca 2+信号传导,导致唾液分泌不足。我们将使用DS鼠标模型
(Dp16小鼠,Rcan 1-KO小鼠,Dp 16 x Rcan 1-KO小鼠),以解决线粒体在
这些小鼠的成釉细胞,并将使用表达荧光标记的分泌和成熟
阶段为了阐明RCAN 1三体在唾液腺(SG)中的作用,我们将使用Dp 16小鼠,并将
将它们与GFP小鼠杂交,突出SG中的分泌囊泡,以分析钙信号传导、唾液分泌
以及唾液中的蛋白质和溶质含量。拟议的研究是重要的,因为它们将
这两项研究都促进了我们对正常线粒体微扰机制的理解,
功能,如发生在DS,可以影响牙齿健康成釉细胞线粒体,并将阐明
导致DS中唾液分泌不足的机制。
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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