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.
Enamel fluorosis in rodents is marked by retention of iron in the maturation ameloblasts. The studies proposed in this application will investigate the mechanisms by which fluoride may affect iron transport in ameloblasts, while laying a foundation for my career goals to be an independently funded dentist scientist.