Investigation of New Molecules in Tooth and Root Developmental Anomalies - Project Summary/Abstract Short Root Anomaly (SRA) is a dental anomaly with major adverse clinical outcomes in orthodontics. SRA is a developmental disorder that affects tooth root formation resulting in short roots and unfavorable root to crown ratios. In addition, these patients have an increased risk of root resorption, a serious complication in individuals undergoing orthodontic treatment. The causal gene(s) for SRA remain largely unknown. The long-term goal of this study is to develop a body of knowledge about the critical genes guiding tooth root development that may be used to enhance diagnosis and developf novel therapies for SRA. The overall objective of this proposal is to study the human genotype-phenotype correlation in SRA patients and evaluate the role of SRA associated genes during tooth root formation. Our preliminary studies have identified a mutation in the Histone Cluster 1 H1 Family Member C (H1C) gene associated with SRA. Our central hypothesis is that the H1.2 protein (encoded by the H1C gene) is expressed at key stages of root development; is regulated by NFIC, the root master gene; and that altering its expression in vitro will dysregulate other signaling molecules involved in root formation and elongation. We further hypothesize that H1C mutation relates to a localized SRA phenotype and that mutations in additional genes will contribute to the clinical dental variations of SRA. We will achieve our objective following two specific aims. First, we will carry out in vitro studies of how H1C, the identified SRA associated gene, relates to regulatory pathways critical for tooth root formation and elongation. Second, we will correlate the dental phenotype of SRA patients with known genotype and identify new genes associated with familial SRA. Discovery of novel genes involved in the pathogenesis of SRA will broaden our knowledge about the regulatory pathways of root formation. Our data will permit creation of novel animal models that in the future can serve to develop targeted clinical therapeutics to rescue the root length of the permanent dentition. It will also be of direct benefit for the counseling, diagnosis, and clinical treatment of orthodontic patients, especially those with a high risk for root resorption. These biomarkers may be used to shed light on how SRA predisposes patients to root resorptions. Finally, these studies will facilitate the “bench-to-bedside” transition, from laboratory experiments through clinical trials to point- of-care patient applications implemented through Precision Dentistry.
