The Role of Iron in Ameloblast Differentiation and Enamel Fluorosis

申请者描述(由申请人提供)：这份F30申请书旨在为我完成加州大学旧金山分校口腔和颅面科学专业的DDS-博士培训提供支持。我已经完成了大部分临床牙科培训，将主要专注于我的博士研究，重点是氟在改变成釉细胞铁运输中的作用。氟改变了釉质的生物矿化，这在很大程度上被认为是通过基质介导的氟的作用发生的。然而，在啮齿动物门牙中，铁色素在氟化成熟的成釉细胞中的滞留表明了一种细胞机制，即氟改变了成釉细胞中的铁运输。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，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生存至关重要。在初步研究中，我们发现随着成熟成釉细胞中铁滞留的增加，铁结合蛋白铁蛋白也增加。铁蛋白以晶体形式与铁结合，保护TH细胞免受铁相关的氧化应激，并可被核因子kappaB(NF？B)上调。这项建议的总体目标是研究氟增强成釉细胞中铁保留的细胞机制，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)研究氟对成熟期成釉细胞铁摄取和储存的影响；2)研究氟对成熟期成釉细胞氧化还原状态的调节作用。了解氟对铁稳态的潜在生物学效应将产生关于氟斑牙发病机制的重要信息，这可能导致识别新的治疗方法来降低氟斑牙的发病率。

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 (NF?B). 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.