Molecular Signaling in Dentinogenesis and Dental Caries Risk

ABSTRACT Dental Caries is one of the most common chronic diseases worldwide, and one of the most understudied conditions in patients with rare diseases, critically undervalued in healthcare. The high prevalence of dental caries emphasizes the imperative need for studies focused on understanding host susceptibility, to deliver more

efficient prevention strategies tailored to each individual. Over the last decade, human genetic studies have made significant progress in identifying genetic risk factors associated with dental caries susceptibility, occurrence, and progression. Nevertheless, there is no follow-up on genome-wide association studies (GWAS)

that identified dental caries risk genes, including those coding for transcription factors as dental caries risk loci. Recently, the candidate’s research has demonstrated that deficiency of the mineralization-regulating transcription factor Trps1 in odontoblasts —the cells that form dentin—compromises the quality of dental tissues

and increases susceptibility to dental caries. However, further studies are required to elucidate the role of Trps1 in dentinogenesis and its effect on enamel, to explain the higher predisposition of these tissues to acid-induced demineralization. This project builds upon the clinical findings of the increased susceptibility of dental caries in

patients with heterozygous mutations in the TRPS1 gene coding for the TRPS1 transcription factor (OMIM 190350). The specific aims of this proposal are to (i) determine the mechanism whereby Trps1 regulates communication between developing odontoblasts/ameloblasts and the formation of mantle dentin, as well as to

(ii) identify genes and cellular processes dysregulated in the tooth due to Trps1 deficiency in odontoblasts. The experimental design employs Trps1 conditional knockout mice and uses advanced methodology to assess mineralized dental tissues and global changes of gene expression in dentin and enamel-forming cells.

Specifically, we will (i) determine the effect of Trps1 on the micro- and nanomorphology of dentin and enamel including dentino-enamel junction, (ii) assess the role of Trps1 in formation of mantle dentin (essential to support the overlying enamel layer), (iii) assess whether Trps1 regulates the Wnt signaling pathway implicated in

molecular communication between developing odontoblasts/ameloblasts and (iv) determine consequences of odontoblast- specific Trps1 deficiency on global changes of gene expression in ameloblasts and odontoblasts. This proposal constitutes a proof-of-concept of the importance of transcription factors in susceptibility to dental

caries. A fundamental understanding of the transcriptional regulation of the formation and mineralization of dental tissues, as well as the crosstalk between odontoblasts/ameloblasts, will result in opportunities to develop better options for prevention of dental caries and for the identification of high-risk groups with developmental defects

of dental tissues. The results of these studies will improve our knowledge of the basic processes involved in the formation of the dentin-enamel interface and will also lead to personalized healthcare and the identification of targets required for the development of new advanced materials and/or procedures for mineralized tissue repair.