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

基本信息

批准号：
10586833
负责人：
Rodrigo S. Lacruz
金额：
$ 48.4万
依托单位：
NEW YORK 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：
2023-03-10 至 2028-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586833
关键词：
Acquired Dental Fluorosis Address Adult Affect Ameloblasts Amelogenesis Anabolism Apatites Biogenesis Biological Assay Brain Calcium Cell Line Cell physiology Cells Chromosome 21 Complex Confocal Microscopy Crystal Formation Data Defect Dental Enamel Dental caries Development Disease Down Syndrome Electron Transport Enamel Formation Exposure to Fluorides Foundations Functional disorder Funding Generations Genes Genetic Diseases Genus Hippocampus Glycolysis Goals Growth Heterozygote Histology Homeostasis Human Chromosomes Image Impairment In Vitro Incisor Individual Intake Knockout Mice Label Maturation-Stage Ameloblast Measures Mechanics Membrane Potentials Metabolic Minerals Mitochondria Mitochondrial DNA Mitochondrial Matrix Modeling Morphology Mus Muscle NADH Nutrient Oral health Organelles Oxidation-Reduction Oxygen Consumption Pancreas Patients Play Process Production Property Protein Biosynthesis Proteins Reactive Oxygen Species Recommendation Regulation Reporter Reporting Risk Rodent Role Safety Signal Transduction Sorting Structure Testing Tissues Tooth structure Trisomy bone calcification dosage drinking water fluorosis high risk human disease improved in vivo induced pluripotent stem cell mineralization mitochondrial dysfunction mitochondrial membrane mitochondrial metabolism mouse model overexpression response segregation single cell analysis single-cell RNA sequencing skeletal transcriptome transcriptome sequencing transcriptomic profiling uptake

项目摘要

Project Summary: Proper mineralization of dental enamel protects against bacterial attack that causes tooth decay (caries). The ameloblasts cells are responsible for producing and secreting an abundance of proteins (laying a foundation for enamel growth) as well as engaging in active mineral transport (calcifying the enamel). These functions are stage dependent with amelogenesis being divided into the secretory (protein synthesis) and maturation stage (mineralization). However, the mechanisms providing metabolic support for these processes and how mitochondrial dysfunction might alter them is poorly understood. Mitochondria are organelles within the cells that convert nutrients into energy via the production of ATP, and deficiency in mitochondrial function results in human diseases. Mitochondria play an important role in enamel as evidenced by defects in mitochondrial DNA causing abnormal enamel development. Therefore, the goal in this competing renewal proposal is to investigate the interplay between mitochondrial function and enamel formation during environmental insults and determine whether this is altered in patients with genetic disorders that effect mitochondrial function. We will specifically address this in the context of Down syndrome (DS), or Trisomy 21, and during dental fluorosis, a process in which exposure to excess of fluoride during development weakens tooth enamel. DS patients present with enamel defects including hypocalcification and hypoplasia, both caused by developmental defects in enamel formation. Mitochondrial dysfunction is widely reported in DS. The overarching hypothesis of this proposal is that altered mitochondrial function in DS ameloblasts alters enamel crystal formation and impacts sensitivity to fluorosis. In strong support, our preliminary data show that Dp- 16 mice (an established mouse model of DS) have mechanically weak and morphologically abnormal enamel. Moreover, overexpression of RCAN1 (a gene associated with DS pathophysiology that is expressed in ameloblasts) in enamel cell lines, significantly impaired mitochondrial function. We have also reported that fluoride exposure of enamel cells significantly affected the biosynthesis of the proteins of the electron transport chain (ETC) responsible for maintaining ATP production, but not in other cells tested, suggesting unique sensitivity of enamel cells to fluoride, possibly associated with higher ROS levels. In the proposed studies 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. We will also use recently developed reporter mice expressing fluorescently labelled secretory and maturation stage ameloblasts to induce fluoride and investigate mitochondrial defects using single cell RNASeq and bulk RNAseq to compare ameloblasts with other tissues. To address if ameloblasts of DS models are more sensitive to fluoride, we will treat the cells with fluoride and analyze mitochondrial function.

项目摘要：牙釉质的适当矿化可防止细菌侵袭，从而导致蛀牙（龋齿）。成釉细胞负责产生和分泌大量的蛋白质（为牙釉质生长奠定基础）以及参与活性矿物质运输（钙化牙釉质）。这些功能取决于阶段，釉质发生分为分泌性和分泌性。（蛋白质合成）和成熟阶段（矿化）。然而，提供代谢的机制人们对这些过程的支持以及线粒体功能障碍如何改变它们知之甚少。线粒体是细胞内的细胞器，通过产生 ATP 将营养物质转化为能量，线粒体功能缺陷会导致人类疾病。线粒体发挥重要作用线粒体 DNA 缺陷导致牙釉质发育异常。因此，这个竞争性更新提案的目标是调查之间的相互作用环境损害期间线粒体功能和牙釉质形成，并确定这是否是患有影响线粒体功能的遗传性疾病的患者发生了改变。我们将专门针对这是在唐氏综合症 (DS) 或 21 三体症的背景下，以及在氟牙症期间发生的，在此过程中在发育过程中接触过量的氟化物会削弱牙釉质。 DS 患者出现牙釉质缺陷，包括低钙化和发育不全，两者都是由发育缺陷引起的牙釉质的形成。线粒体功能障碍在 DS 中被广泛报道。总体假设是该提议认为，DS 成釉细胞中线粒体功能的改变会改变牙釉质晶体形成并影响对氟中毒的敏感性。在强有力的支持下，我们的初步数据显示 Dp- 16只小鼠（已建立的DS小鼠模型）机械无力且形态异常搪瓷。此外，RCAN1（一种与 DS 病理生理学相关的基因，在釉质细胞系中的成釉细胞中表达），线粒体功能显着受损。我们有还报道牙釉质细胞接触氟化物显着影响蛋白质的生物合成负责维持 ATP 产生的电子传递链 (ETC)，但在其他细胞中则不然经测试，表明牙釉质细胞对氟化物具有独特的敏感性，可能与较高的 ROS 有关水平。在拟议的研究中，我们将使用 DS 小鼠模型（Dp16 小鼠、Rcan1-KO 小鼠、Dp16 x Rcan1-KO 小鼠）来解决线粒体在这些小鼠成釉细胞中的作用。我们还将使用最近开发的报告小鼠表达荧光标记的分泌和成熟阶段使用单细胞 RNASeq 和bulk 诱导成釉细胞诱导氟化物并研究线粒体缺陷 RNAseq 用于比较成釉细胞与其他组织。解决 DS 模型的成釉细胞是否较多的问题由于对氟化物敏感，我们将用氟化物处理细胞并分析线粒体功能。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mibefradil alters intracellular calcium concentration by activation of phospholipase C and IP3 receptor function.

Mibefradil 通过激活磷脂酶 C 和 IP3 受体功能来改变细胞内钙浓度。

DOI：
发表时间：
2021-04-30
期刊：
影响因子：
4
作者：
Souza Bomfim, Guilherme H;Mitaishvili, Erna;Aguiar, Talita Ferreira;Lacruz, Rodrigo S
通讯作者：
Lacruz, Rodrigo S

Overexpression of RCAN1, a Gene on Human Chromosome 21, Alters Cell Redox and Mitochondrial Function in Enamel Cells.

RCAN1（人类 21 号染色体上的基因）的过度表达会改变牙釉质细胞中的细胞氧化还原和线粒体功能。

DOI：
发表时间：
2022-11-11
期刊：
影响因子：
6
作者：
Li Y;Costiniti V;Souza Bomfim GH;Neginskaya M;Son GY;Rothermel B;Pavlov E;Lacruz RS
通讯作者：
Lacruz RS

Mitochondrial Function in Enamel Development.

牙釉质发育中的线粒体功能。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Costiniti, Veronica;Bomfim, Guilherme H;Li, Yi;Mitaishvili, Erna;Ye, Zhi;Zhang, Jie;Townsend, Danyelle M;Giacomello, Marta;Lacruz, Rodrigo S
通讯作者：
Lacruz, Rodrigo S

Mitochondria modulate ameloblast Ca2+ signaling.

线粒体调节成釉细胞 Ca2 信号传导。

DOI：
发表时间：
2022-02
期刊：
影响因子：
0
作者：
Costiniti, Veronica;Bomfim, Guilherme H S;Neginskaya, Maria;Son, Ga;Mitaishvili, Erna;Giacomello, Marta;Pavlov, Evgeny;Lacruz, Rodrigo S
通讯作者：
Lacruz, Rodrigo S

Altered Ca2+ signaling in enamelopathies.

牙釉质病中 Ca2 信号传导发生改变。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Eckstein, Miriam;Aulestia, Francisco J;Nurbaeva, Meerim K;Lacruz, Rodrigo S
通讯作者：
Lacruz, Rodrigo S

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Rodrigo S. Lacruz其他文献

Regulatory T cells and IFN-γ-producing Th1 cells play a critical role in the pathogenesis of Sjögren’s Syndrome

调节性 T 细胞和产生 IFN-γ 的 Th1 细胞在干燥综合征的发病机制中发挥着关键作用

DOI：
10.1101/2024.01.23.576314
发表时间：
2024-01-24
期刊：
bioRxiv
影响因子：
0
作者：
Yin;Wenyi Li;Maxwell McDermott;Ga;George Maiti;Fang Zhou;A. Tao;Dimitrius Raphael;Andre L Moreira;Boheng Shen;M. Vaeth;Bettina Nadorp;S. Chakravarti;Rodrigo S. Lacruz;Stefan Feske
通讯作者：
Stefan Feske