The Role of Iron in Ameloblast Differentiation and Enamel Fluorosis

描述（由申请人提供）：这份F30申请是为了支持我在UCSF口腔和颅面科学项目中完成DDS-PhD培训。我已经完成了大部分临床牙科培训，并将主要专注于我的博士研究，重点是氟化物在改变成釉细胞铁转运中的作用。氟化物改变牙釉质生物矿化，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，在啮齿动物的门牙中，氟化成熟成釉细胞中铁色素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池的增加，从而导致自由基的形成，从而导致氧化应激。因此，细胞对铁的调节对细胞的生长和存活至关重要。在初步研究中，我们发现随着成熟成釉细胞中铁潴留的增加，铁结合蛋白铁蛋白也增加。铁蛋白以晶体形式结合铁，保护细胞免受铁相关的氧化应激，并可通过核因子κB （NFκB）上调。本研究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，以及该机制在成釉细胞成熟阶段调节氧化应激中的作用。这一目标将通过以下两个具体目标来实现。目的1)确定氟化物如何改变成熟阶段成釉细胞对铁的吸收和储存；目的2)确定氟化物如何调节成熟阶段成釉细胞的氧化还原状态。了解氟化物对铁稳态的潜在生物学效应将为氟牙症的机制提供重要信息，这可能导致确定新的治疗方法，以减少氟牙症的发病率。

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.