This new Mentored Clinical Scientist Award (K08) application requests support for a five-year period of formal research training towards a Ph.D. degree. The candidate is a recent dental graduate with a firm commitment to developing his academic career as a clinician scientist. On completing his Ph.D., the candidate will pursue certificate training in Orthodontics. The career development plan proposes a phased and integrated series of didactic instruction and supervised research training. The overall objectives are to develop the applicant's expertise to conduct independent and creative research in an area of oral biomedical sciences that is relevant to the specialty of Orthodontics. The doctoral research will focus on tooth eruption, a multifactorial process of key signaling interactions between osteoblasts, osteoclasts, and the dental follicle. Despite recent advances in identifying some of the molecules involved in tooth eruption there is little known about the precise nature of the eruptive process. The recent discovery that mutations in Cbfa1, a transcription factor, cause a genetic disorder in humans called cleidocranial dysplasia (CCD) has opened up a new dimension of research in skeletal biology. In addition to skeletal defects, CCD patients have multiple supernumerary teeth and permanent teeth that fail to erupt. Studies in our laboratory have shown high levels of Cbfa1 mRNA expression in dental follicle cells through all phases of tooth eruption. Interestingly, mice that are heterozygous for the null allele, Cbfa(+/-) mice, reveal a skeletal phenotype that closely resembles human CCD. When compared to Cbfa(+/+) littermates, molars in Cbfa1 (+1-) mice are fully formed but fail to erupt. The proposed studies will use Cbfa1 (+/-) mice as an excellent model to study the failure of eruption in human CCD. The central hypothesis to be tested proposes that Cbfa1 plays a key role in dental follicle-mediated signaling of osteoclasts during tooth eruption.
Aim 1 will evaluate the temporo-spatial patterns of Cbfa1 mRNA and protein expression in dental follicle cells during all phases of first mandibular molar eruption using molecular and immunochemical methods.
Aim 2 studies will characterize the tooth eruption defect in Cbfa(+/-) mice using histomorphometric and molecular methods. The effect of the partial absence of Cbfa1 on potential downstream target molecules in dental follicle, in particular those involved in osteoclast signaling, will be studied.
Aim 3 proposes to evaluate potential defects in osteoclast differentiation and function in Cbfa1(+/-) mice. The effects of the partial absence of Cbfa1 on osteoclast numbers and gene expression will be studied. These data will provide new insights into the role of Cbfa1 in signaling events that are specifically mediated by the dental follicle during tooth eruption and will increase our understanding of the pathogenesis of human CCD and other conditions of eruption failure. The proposed research is consistent with the candidate's present level of research experience. Knowledge gained on the basic mechanisms of tooth eruption will prepare the applicant for future involvement in clinical research that will be directed towards the development of therapeutics to aid in the prevention and treatment of anomalies of tooth eruption in humans.
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