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

基本信息

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
项目类别：
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

项目摘要

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/摘要该候选人于 2017 年 4 月获得了他的第一笔 R01 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 R01 资助完成后作为独立科学家的资助 R01 项目总结如下。由于多余的牙齿形成，多余的牙齿会导致多种牙科并发症。现有的牙列，揭示多生牙形成的分子机制不仅有助于制定针对这种疾病的治疗策略，同时也提供对牙齿再生的见解。在理解形态发生素、生长因子和细胞因子的调节作用方面取得了重大进展转录因子在多生牙形成中的作用，但人们对细胞外的作用知之甚少候选人最近的研究表明，这种病理过程中的蛋白聚糖等成分。牙上皮 Fam20B 失活，这是一种新发现的糖胺聚糖必需的木糖激酶 (GAG) 组装导致小鼠产生多余门牙。他们的初步研究表明，小鼠体内存在 GAG 缺陷。牙上皮导致 WNT 信号的异位激活，并且异位 Sox2 表达是位于同一区域，通常在 E14.5 后应从该位点消失。显示某些 FAM20B 催化的蛋白聚糖上的 GAG 抑制 WNT 信号传导，但促进 Wise- 介导的对 WNT 的离线抑制，向突变胚胎施用 WNT 抑制剂可以挽救该突变体。在某些情况下，这些数据使候选人形成了他的中心假设：某些情况。 FAM20B 催化的蛋白多糖通过负介导干细胞更新来调节牙齿更新他提出了三个具体目标来测试这一点。假设：(1) 确定 FAM20B 催化的蛋白多糖是否通过负作用介导牙齿更新 WNT 信号传导的调节，以及 GAG 介导的 Wise 对 WNT 的抑制是否是多余的基础 (2) 确定 FAM20B 催化的蛋白多糖是否通过调节牙齿更新。介导牙上皮中的干细胞更新，以及（3）鉴定负责的蛋白多糖这项研究的完成将增进对多生牙形成的理解。多生牙形成的分子机制，有助于为牙齿奠定基础由于 FAM20B 和蛋白聚糖主要存在于许多组织中，因此有关知识这项研究的结果可能有助于了解其他组织中蛋白聚糖介导的信号传导。