The Role of FAM20B-Catalyzed Proteoglycans in Tooth Development

项目总结/文摘

Project summary/Abstract The candidate received his first R01 grant in April 2017. At this critical point of his career, he needs at least 75% of protected time on research to develop into the type of scientist he wants to become and secure NIH funding as an independent scientist after this R01 grant is completed. The R01 project is summarized below. Supernumerary teeth can cause a broad range of dental complications. As extra teeth are formed on existing dentition, unraveling the molecular mechanism of supernumerary tooth formation will not only help develop the therapeutic strategy for this disease but also provide insights into tooth regeneration. Despite the significant progress in understanding the regulatory role of morphogens, growth factors, and transcriptional factors in supernumerary tooth formation, little is known about the role of extracellular components such as proteoglycans in this pathological process. The candidate’s recent studies show that inactivation of dental epithelial Fam20B, a newly discovered xylose kinase essential for glycosaminoglycan (GAG) assembly, leads to supernumerary incisors in mice. Their pilot study reveals that GAG deficiency in the dental epithelium leads to ectopic activation of WNT signaling, and that an ectopic Sox2 expression is located in the same area, which normally should disappear from this site after E14.5. Their in vitro study shows that GAGs on certain FAM20B-catalyzed proteoglycans suppress WNT signaling but facilitate Wise- mediated inhibition on WNT. Conversely, administering WNT inhibitor to the mutant embryos rescued the tooth phenotype in some cases. These data led the candidate to form his central hypothesis that certain FAM20B-catalyzed proteoglycans regulate tooth renewal by mediating the stem cell renewal via negative regulation on WNT signaling in the dental epithelium. He proposes three specific aims to test this hypothesis: (1) To determine if FAM20B-catalyzed proteoglycans mediate tooth renewal via negative regulation on WNT signaling, and if GAG-mediated Wise inhibition on WNT underlies the supernumerary tooth formation. (2) To determine whether FAM20B-catalyzed proteoglycans regulate tooth renewal by mediating stem cell renewal in the dental epithelium, and (3) To identify the proteoglycans responsible for the supernumerary tooth formation. The completion of this study will advance the understanding about the molecular mechanism underlying supernumerary tooth formation and help in laying the groundwork for tooth regeneration. As FAM20B and proteoglycans are extensively present in many tissues, the knowledge gained from this study may shed light on the proteoglycan-mediated signaling in other tissues.