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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：
Maiko Suzuki
金额：
$ 36.45万
依托单位：
NOVA SOUTHEASTERN UNIVERSITY
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：
https://reporter.nih.gov/project-details/10823889
关键词：
Ablation Acquired Dental Fluorosis Ameloblasts Apoptosis Attenuated Autophagocytosis Biological CRISPR/Cas technology Cell Line Cell Survival Cells Cellular Stress ChIP-seq Child Chronic Cytoprotection DNA Sequence Deacetylation Dental Enamel Dental caries Development Disease Epigenetic Process Exposure to Fluorides Functional disorder Future Gene Expression Gene Expression Alteration Genes Genetic Transcription Goals Histone Acetylation Histone Deacetylase Histone Deacetylation Histones Homologous Gene In Vitro Induction of Apoptosis Ingestion Knock-out Knockout Mice Longevity MAPK8 gene Mating Types Mediating Metabolic Modification Molecular Mus Oral health Oxidative Stress Pathway interactions Pharmacological Treatment Phenotype Play Population Porosity Predisposition Prevalence Reactive Oxygen Species Regulation Reporting Role SIRT1 gene Signal Transduction TP53 gene Testing Tooth structure Toxic effect Water fluoridation aged biological adaptation to stress conditional knockout endoplasmic reticulum stress epigenetic regulation fluorosis gene repression in vivo innovation malformation mitochondrial metabolism non-histone protein novel novel strategies novel therapeutic intervention overexpression oxidative damage pharmacologic prevent prophylactic protective pathway response

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。 SIRT1在氟斑牙适应性反应中的作用氟化物是一种有效的龋病预防性的，但是长期过量暴露会导致氟斑牙。超过30%的美国的儿童患有氟斑牙。我们的最终目标是开发新的战略预防或减少氟斑牙，同时保持预防性公共水的好处用氟化来预防龋齿。最近我们报道了氟化物激活SIRT1和自噬作为一种适应性反应，以保护细胞免受细胞压力。已知SIRT1脱乙酰基组蛋白抑制基因表达(表观遗传脱乙酰化)。SIRT1还可以脱乙酰化一个非组蛋白蛋白(非表观遗传脱乙酰化)在调节细胞周期中的作用自噬，线粒体新陈代谢，细胞存活和生物寿命。然而，准确的 SIRT1及其下游靶点在氟斑牙发病中的作用尚不清楚。我们在这方面的目标建议确定SIRT1在氟化物诱导的应激反应中如何发挥作用，并找到可通过药物调节的适当靶点用于牙科治疗氟中毒。我们的中心假设是SIRT1可以通过启动自噬来发挥保护作用以及调控氟斑牙的表观遗传学。为了检验我们的假设，我们提出了三个具体的目标。目的1.在氟处理的成釉细胞中鉴定SIRT1非组蛋白靶点在试管中。目的2.在氟处理的成釉细胞中鉴定SIRT1组蛋白靶点体外培养。目的3.确定SIRT1过度表达或条件性基因敲除是否影响牙釉质体内发育和氟斑牙。为了实现这些目标，我们将使用SIRT1 过表达和敲除的成釉细胞样细胞LS8(LS8 Sirt1/Over和LS8Sirt1/KO细胞) 由CRISPR/CAS9技术体外建立。我们将使用以下工具分析SIRT1的角色 SIRT1高表达小鼠(SIRT1Super)和条件性基因敲除小鼠(SIRT1cKO)。一旦表观遗传和非表观遗传SIRT1在釉质病理生理学中的作用被揭示，它有可能开发新的策略来药理学地操纵SIRT1功能以预防氟斑牙。

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：
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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