Epigenetic and non-epigenetic role of SIRT1 in fluoride-induced cell stress.
SIRT1 在氟化物诱导的细胞应激中的表观遗传和非表观遗传作用。
基本信息
- 批准号:10823889
- 负责人:
- 金额:$ 36.45万
- 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:2023-06-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAcquired Dental FluorosisAmeloblastsApoptosisAttenuatedAutophagocytosisBiologicalCRISPR/Cas technologyCell LineCell SurvivalCellsCellular StressChIP-seqChildChronicCytoprotectionDNA SequenceDeacetylationDental EnamelDental cariesDevelopmentDiseaseEpigenetic ProcessExposure toFluoridesFunctional disorderFutureGene ExpressionGene Expression AlterationGenesGenetic TranscriptionGoalsHistone AcetylationHistone DeacetylaseHistone DeacetylationHistonesHomologous GeneIn VitroInduction of ApoptosisIngestionKnock-outKnockout MiceLongevityMAPK8 geneMating TypesMediatingMetabolicModificationMolecularMusOral healthOxidative StressPathway interactionsPharmacological TreatmentPhenotypePlayPopulationPorosityPredispositionPrevalenceReactive Oxygen SpeciesRegulationReportingRoleSIRT1 geneSignal TransductionTP53 geneTestingTooth structureToxic effectWater fluoridationagedbiological adaptation to stressconditional knockoutendoplasmic reticulum stressepigenetic regulationfluorosisgene repressionin vivoinnovationmalformationmitochondrial metabolismnon-histone proteinnovelnovel strategiesnovel therapeutic interventionoverexpressionoxidative damagepharmacologicpreventprophylacticprotective pathwayresponse
项目摘要
The goal of this application is to characterize epigenetic and non-epigenetic functions of
SIRT1 in adaptive responses during dental fluorosis. Fluoride is an effective caries
prophylactic, however chronic over-exposure can result in dental fluorosis. More than 30% of
children in the U.S. suffer from dental fluorosis. Our ultimate goal is to develop novel strategies
that prevent or reduce dental fluorosis while keeping the benefit of prophylactic public water
fluoridation to prevent caries. Recently we reported that fluoride activates SIRT1 and autophagy
as an adaptive response to protect cells from cell stress. It is known that SIRT1 deacetylates
histones to repress gene expression (epigenetic deacetylation). SIRT1 also deacetylates a
number of non-histone proteins (non-epigenetic deacetylation) functioning in the regulation of
autophagy, mitochondria metabolism, cell survival and organismal lifespan. However, the exact
functions of SIRT1 and its downstream targets in dental fluorosis are unknown. Our goal in this
proposal is to identify how SIRT1 functions in fluoride-induced stress responses and to find
appropriate targets that could be modulated pharmacologically for the treatment of dental
fluorosis. Our central hypothesis is that SIRT1 can play protective roles by intiating autophagy
and regulating epigenetics in dental fluorosis. To test our hypothesis we propose three specific
AIMs. AIM 1. Identify SIRT1 non-histone targets in ameloblast-derived cells treated with fluoride
in vitro. AIM 2. Identify SIRT1 histone targets in ameloblast-derived cells treated with fluoride in
vitro. AIM 3. Determine if SIRT1 over expression or conditional knockout effects enamel
development and dental fluorosis in vivo. To attain these AIMs, we will use SIRT1
overexpressor and knockout ameloblast-like cells LS8 (LS8 Sirt1/over and LS8Sirt1/KO cells)
established by the CRISPR/Cas9 technology in vitro. We will analyze the role of SIRT1 using
SIRT1 over expressing mice (SIRT1super) and conditional knockout mice (SIRT1cKO) in vivo.
Once epigenetic and non-epigenetic SIRT1 function in enamel pathophysiology is revealed, it
may be possible to develop novel strategies to pharmacologically manipulate SIRT1 function to
prevent dental fluorosis.
本应用的目的是表征的表观遗传和非表观遗传功能
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Perfluorooctanoic acid-induced cell death via the dual roles of ROS-MAPK/ERK signaling in ameloblast-lineage cells.
- DOI:10.1016/j.ecoenv.2023.115089
- 发表时间:2023-07-15
- 期刊:
- 影响因子:6.8
- 作者:Fujiwara, Natsumi;Yamashita, Shohei;Okamoto, Motoki;Cooley, Marion A.;Ozaki, Kazumi;Everett, Eric T.;Suzuki, Maiko
- 通讯作者:Suzuki, Maiko
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Maiko Suzuki其他文献
Maiko Suzuki的其他文献
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{{ truncateString('Maiko Suzuki', 18)}}的其他基金
Health Effects of the Fluorinated Pollutants; PFAS on Enamel Development
氟化污染物对健康的影响;
- 批准号:
10697298 - 财政年份:2023
- 资助金额:
$ 36.45万 - 项目类别:
Health Effects of the Fluorinated Pollutants; PFAS on Enamel Development
氟化污染物对健康的影响;
- 批准号:
10827647 - 财政年份:2023
- 资助金额:
$ 36.45万 - 项目类别:
Health Effects of the Fluorinated Pollutants; PFAS on Enamel Development
氟化污染物对健康的影响;
- 批准号:
10371715 - 财政年份:2022
- 资助金额:
$ 36.45万 - 项目类别:
Epigenetic and non-epigenetic role of SIRT1 in fluoride-induced cell stress
SIRT1 在氟化物诱导的细胞应激中的表观遗传和非表观遗传作用
- 批准号:
9706819 - 财政年份:2019
- 资助金额:
$ 36.45万 - 项目类别:
Epigenetic and non-epigenetic role of SIRT1 in fluoride-induced cell stress
SIRT1 在氟化物诱导的细胞应激中的表观遗传和非表观遗传作用
- 批准号:
10165691 - 财政年份:2019
- 资助金额:
$ 36.45万 - 项目类别:
Epigenetic and non-epigenetic role of SIRT1 in fluoride-induced cell stress
SIRT1 在氟化物诱导的细胞应激中的表观遗传和非表观遗传作用
- 批准号:
10408040 - 财政年份:2019
- 资助金额:
$ 36.45万 - 项目类别: