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.

该应用的目的是表征表观遗传和非观测功能 SIRT1在牙齿氟中毒过程中的自适应反应中。氟化物是一种有效的龋齿预防性，但是慢性过度暴露会导致牙齿氟中毒。超过30％美国的儿童患有牙齿氟中毒。我们的最终目标是制定新颖的策略这可以防止或减少氟中毒，同时保持预防性公共水的好处氟化以防止龋齿。最近我们报道了氟化物激活SIRT1和自噬作为保护细胞免受细胞应激的自适应反应。众所周知，sirt1脱乙酰酸盐组蛋白抑制基因表达（表观遗传脱乙酰化）。 SIRT1也脱乙酰酸A 在调节中起作用的非内酮蛋白数（非遗传脱乙酰基化）自噬，线粒体代谢，细胞存活和生物寿命。但是，确切的 SIRT1及其下游靶标在牙齿氟中毒中的功能尚不清楚。我们的目标建议是确定SIRT1在氟化物引起的压力反应中的功能并找到可以在药理上调节牙齿的适当靶标氟中毒。我们的中心假设是SIRT1可以通过构图自噬发挥保护作用并调节牙齿氟中毒中的表观遗传学。为了检验我们的假设，我们提出了三个特定的目标。 AIM 1。识别用氟化物处理的成成布细胞中的SIRT1非固定靶标体外。 AIM 2。鉴定在用氟化物处理的成熟细胞衍生细胞中的SIRT1组蛋白靶标体外。目标3。确定SIRT1是否超过表达或有条件的敲除效果搪瓷体内发育和牙齿氟中毒。为了实现这些目标，我们将使用SIRT1 过表达和基因敲除成酰胺细胞样细胞LS8（LS8 SIRT1/over和LS8SIRT1/KO细胞）由CRISPR/CAS9技术在体外建立。我们将使用SIRT1的角色使用 SIRT1在体内表达小鼠（SIRT1Super）和有条件的敲除小鼠（SIRT1CKO）。一旦揭示了牙釉质病理生理学中的表观遗传学和非现象SIRT1功能，就可以可能有可能制定新颖的策略来将SIRT1功能操纵为防止牙齿氟中毒。

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