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.
本申请的目的是表征表观遗传和非表观遗传功能,
SIRT 1在氟斑牙适应性反应中的作用氟化物是有效的防龋剂
然而,长期过度暴露可导致氟斑牙。的30%以上
美国的儿童患有氟斑牙。我们的最终目标是开发新的策略
预防或减少氟斑牙,同时保持预防性公共用水的好处,
氟化以防止龋齿。最近,我们报道了氟化物激活SIRT 1和自噬,
作为一种适应性反应来保护细胞免受细胞应激。已知SIRT 1脱乙酰基
组蛋白抑制基因表达(表观遗传去乙酰化)。SIRT 1还可以使
非组蛋白蛋白(非表观遗传脱乙酰化)的数量,
自噬、线粒体代谢、细胞存活和生物体寿命。但具体
SIRT 1及其下游靶点在氟斑牙中的功能尚不清楚。我们的目标是
一项提案是确定SIRT 1如何在氟化物诱导的应激反应中发挥作用,
可以被调制的适当的目标,用于治疗牙齿
氟中毒我们的中心假设是SIRT 1可以通过启动自噬来发挥保护作用
和调节氟斑牙的表观遗传学。为了验证我们的假设,我们提出了三个具体的假设。
瞄准器AIM 1.氟化物作用下成釉细胞SIRT 1非组蛋白靶点的鉴定
体外AIM 2.在氟处理的成釉细胞中鉴定SIRT 1组蛋白靶点
体外AIM 3.确定SIRT 1过表达或条件性敲除是否影响釉质
体内发育和氟斑牙。为了实现这些目标,我们将使用SIRT 1
过表达和敲除成釉细胞样细胞LS 8(LS 8 Sirt 1/over和LS 8 Sirt 1/KO细胞)
通过CRISPR/Cas9技术在体外建立。我们将分析SIRT 1的作用,
体内SIRT 1过表达小鼠(SIRT 1 super)和条件性敲除小鼠(SIRT 1cKO)。
一旦揭示了表观遗传和非表观遗传SIRT 1在釉质病理生理学中的功能,
可能会开发新的策略来操纵SIRT 1功能,
预防氟斑牙。
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: