The Role of FAM20B-Catalyzed Proteoglycans in Tooth Development

FAM20B 催化蛋白多糖在牙齿发育中的作用

• 批准号: 10471850
• 负责人: XIAOFANG WANG
• 金额: $ 14.92万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10471850
• 关键词: Ablation; Address; Area; Biological Process; Cell surface; Cells; Data; Dental; Dentition; Development; Disease; Dose; Embryo; Enamel Organ; Epithelial; Equilibrium; Etiology; Extracellular Matrix; Family; Funding; Genes; Glycosaminoglycans; Grant; Growth Factor; Human; In Vitro; Incisor; Knowledge; Light; Location; Mediating; Molecular; Mus; Organ Culture Techniques; Pathologic Processes; Pattern; Phenotype; Phosphotransferases; Pilot Projects; Play; Proteins; Proteoglycan; Regulation; Research; Research Personnel; Rodent; Role; Science; Scientist; Secure; Side; Signal Transduction; Signaling Molecule; Site; Supernumerary Tooth; Testing; Therapeutic; Time; Tissues; Tooth regeneration; Tooth structure; United States National Institutes of Health; WNT Signaling Pathway; Wages; Xylose; adenoviral-mediated; career; design; epithelial stem cell; experimental study; extracellular; inhibitor; insight; knock-down; member; morphogens; mutant; novel; overexpression; programs; stem cell division; stem cells; transcription factor

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.

项目概要/摘要 候选人于2017年4月获得了他的第一个R 01资助。在他职业生涯的这个关键时刻，他至少需要 75%的受保护时间用于研究，以发展成为他想成为的科学家类型，并确保NIH 作为一个独立的科学家资助后，这R 01赠款完成。R 01项目总结如下。 多生牙会引起一系列的牙科并发症。当额外的牙齿在 现有的牙列，解开多生牙形成的分子机制，不仅有助于 为这种疾病制定治疗策略，同时也为牙齿再生提供见解。尽管 在了解形态发生素、生长因子和 转录因子在多生牙形成中的作用，对细胞外转录因子的作用知之甚少。 蛋白多糖等成分参与了这一病理过程。候选人最近的研究表明， 牙上皮Fam 20 B失活研究 (GAG)组装，导致小鼠多出门牙。他们的初步研究表明， 牙上皮导致WNT信号的异位激活，并且异位Sox 2表达是 位于同一区域，通常应在E14.5之后从该站点消失。他们的体外研究 显示某些FAM 20 B催化的蛋白聚糖上的GAG抑制WNT信号传导，但促进WISE- 介导对WNT的抑制。相反，给突变胚胎施用WNT抑制剂， 在某些情况下的牙齿表型。这些数据使候选人形成了他的中心假设， FAM 20 B催化的蛋白多糖通过负性介导干细胞更新调节牙齿更新 调节牙上皮中WNT信号。他提出了三个具体目标来检验这一点 假设：（1）确定FAM 20 B催化的蛋白聚糖是否通过负性介导牙齿更新 调节WNT信号，如果GAG介导的WNT抑制是多余的 牙齿形成(2)为了确定FAM 20 B催化的蛋白聚糖是否通过以下方式调节牙齿更新： 介导牙上皮干细胞更新，和（3）确定蛋白多糖负责 多生牙的形成这项研究的完成将促进对 多生牙形成的分子机制并帮助为牙齿奠定基础 再生由于FAM 20 B和蛋白聚糖广泛存在于许多组织中，因此， 从这项研究中获得的信息可能有助于了解其他组织中蛋白聚糖介导的信号传导。