The Role of Iron in Ameloblast Differentiation and Enamel Fluorosis

描述（由申请人提供）：此F30应用程序是为我在口腔和颅面科学加州大学旧金山分校计划的DDS-博士培训的完成提供支持。我已经完成了我的大部分临床牙科培训，并将主要集中在我的博士研究，重点是氟在改变成釉细胞铁运输的作用。氟化物改变牙釉质的生物矿化，这在很大程度上被认为是通过氟化物的基质介导作用发生的。然而，在啮齿动物切牙中，铁色素在氟化成熟成釉细胞中的保留表明氟改变成釉细胞中铁转运的细胞机制。铁对细胞功能很重要，但过量的铁会导致不稳定铁库的增加，会导致自由基形成，从而产生氧化应激。因此，铁的细胞调节对细胞生长和存活至关重要。初步研究发现，沿着成熟成釉细胞铁潴留的增加，铁结合蛋白铁蛋白也随之增加。铁蛋白以晶体形式结合铁以保护细胞免受铁相关的氧化应激，并且可以被核因子κ B（NFκB）上调。本提案的总体目标是研究氟化物增强成釉细胞铁潴留的细胞机制，以及这种机制在调节成熟阶段成釉细胞氧化应激中的作用。这一目标将通过以下两个具体目标来实现。目的1）研究氟对成釉细胞铁吸收和铁储存的影响; 2）研究氟对成釉细胞氧化还原状态的影响。了解氟化物对铁稳态的潜在生物学效应将产生有关氟斑牙背后机制的重要信息，这可能导致确定新的治疗方法，以减少氟斑牙的发病率。

DESCRIPTION (provided by applicant): This F30 application is to provide support for the completion of my DDS-PhD training in the UCSF Program in Oral and Craniofacial Sciences. I have completed most of my clinical dental training and will focus primarily on my PhD research, which focuses on the role fluoride in altering iron transport in ameloblasts. Fluoride alters enamel biomineralization, and this is largely considered to occur through matrix mediated effects of fluoride. However, in the rodent incisor, retention of iron pigment in fluorosed maturation ameloblasts suggests a cellular mechanism by which fluoride alters iron transport in ameloblasts. Iron is important for cell function, but an excess of iron, which results in an increase in the labile iron pool, can cause free radical formation, with resultant oxidative stress Therefore, cellular regulation of iron is critical for cell growth and survival. In preliminary stuies, we found that along with increased iron retention in maturation ameloblasts, the iron binding protein, ferritin, is is also increased. Ferritin binds iron to in a crystalline form to protect th cell from iron related oxidative stress, and can be upregulated by nuclear factor kappa B (NFκB). The overall goal of this proposal is to investigate the cellular mechanisms by which fluoride enhances iron retention in ameloblasts, and the role of this mechanism in modulating oxidative stress in maturation stage ameloblasts. This goal will be addressed by the following two specific aims. Aim 1) to determine how fluoride alters iron uptake and storage in maturation stage ameloblasts; Aim 2) to determine how fluoride modulates the redox state of maturation stage ameloblasts. Understanding the underlying biological effects of fluoride on iron homeostasis will yield important information about the mechanisms behind dental fluorosis, which could lead to the identification of novel therapeutic practices to reduce the incidence of dental fluorosis.