Extracellular Matrix and Phosphate/Pyrophosphate Metabolism in Cementum Formation

牙骨质形成中的细胞外基质和磷酸盐/焦磷酸盐代谢

• 批准号: 9303193
• 负责人: Brian Lee Foster
• 金额: $ 24.9万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-21 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303193
• 关键词: Address; Adult; Affect; Area; Automobile Driving; Award; Back; Biological; Biology; Cell Separation; Cells; Cementoblast; Cementogenesis; Cementum Formation; Complex; Crystallization; Data; Dental; Dental Cementum; Dentition; Development; Development Plans; Diphosphates; Disabled Persons; Disease; Environment; Epithelium; Extracellular Matrix; Extracellular Matrix Proteins; Faculty; Foundations; Future; Gene Expression; Goals; Growth; Histology; Immunohistochemistry; In Situ Hybridization; In Vitro; Knockout Mice; Knowledge; Lead; Link; LoxP-flanked allele; Maps; Mentorship; Messenger RNA; Metabolism; Methods; Minerals; Molecular; Mus; Natural regeneration; Odontogenesis; Pathway interactions; Periodontal Diseases; Periodontium; Phenotype; Plant Roots; Positioning Attribute; Process; Proteins; Regulation; Regulator Genes; Reporting; Research; Research Project Grants; Role; Serologic tests; Signal Transduction; Stress; Structure; Testing; Tissues; Tooth regeneration; Tooth root structure; Tooth structure; Training; Transgenic Mice; Translating; Work; base; bone; bone sialoprotein; career; career development; design; functional restoration; improved; in vivo; inhibitor/antagonist; inorganic phosphate; insight; inter-alpha-inhibitor; laboratory experience; microCT; mineralization; novel; novel strategies; osteopontin; overexpression; prevent; programs; public health relevance; regenerative; sensor; skeletal; skeletal tissue; skills; sodium phosphate; symporter; transcriptome sequencing

DESCRIPTION (provided by applicant): Dental cementum covering the tooth root is critical for tooth attachment, long-term stability, and function of the dentition, yet regulation of root development and cementum formation remains poorly understood, hampering efforts towards periodontal regeneration. This application is a Pathway to Independence Award proposal that aims to advance fundamental knowledge on cementum biology by addressing gaps in our current understanding of cementum formation, focusing on areas of: extracellular matrix (ECM) proteins and local phosphate/pyrophosphate regulation implicated to be central to the process of cementogenesis. We propose that a coordination of local matrix proteins and phosphate regulating factors is crucial for proper development and mineralization of cementum. This hypothesis will be tested by three specific aims: 1) To define the role of ECM protein bone sialoprotein (BSP) in cementum formation, using null and conditionally null mice and in vitro approaches; 2) To determine the function of ECM protein osteopontin (OPN) in cementum development, by evaluating OPN-pyrophosphate interactions in tooth development; 3) To establish the role of sodium- phosphate co-transporter PiT1 (SLC20A1) during cementoblast differentiation and function, by mapping its expression during periodontal development, and analyzing the phenotype in PiT1 conditional null mice, including effects on cementum regulatory factors. The applicant is a postdoctoral research fellow highly qualified to lead this research program based on his training studying cementoblasts in vitro and cementum formation in vivo, reporting on phosphate/pyrophosphate metabolism in tooth formation, driving the paradigm- shifting findings regarding pyrophosphate control of cementum formation, and discovering the necessity of ECM protein BSP for cementum mineralization. The applicant's long-term career goal is to lead a productive research program that provides significant insights into the molecular mechanisms driving tooth root formation and mineralization, and translates those insights into novel approaches for regenerating periodontal tissues and restoring function. This project is an ideal starting point for the applicant to transition to his independent research carer because it provides a framework for development of further skills necessary to accomplish the long-term goal. The proposed career development plan incorporates didactic coursework, laboratory training, and a structured mentorship plan to facilitate accomplishment of short-term goals, including development of a skill set for mineralized tissue research, establishing an independent research project, providing a pathway for a faculty position, and affording a future opportunity to build on this proposed work. The applicant's institutional environment provides strong support in areas of postdoctoral development and transition.

描述（由申请人提供）：覆盖牙根的牙骨质对牙齿的附着、长期稳定和牙列功能至关重要，但对牙根发育和牙骨质形成的调控仍然知之甚少，阻碍了牙周再生的努力。该申请是独立之路奖的提案，旨在通过解决我们目前对骨质形成的理解的空白来推进骨质生物学的基础知识，重点关注：细胞外基质（ECM）蛋白和局部磷酸盐/焦磷酸盐调控涉及骨质形成过程的核心。我们认为，局部基质蛋白和磷酸盐调节因子的协调对牙骨质的正常发育和矿化至关重要。这一假设将通过以下三个具体目标进行验证：1)利用空白小鼠和条件空白小鼠以及体外方法确定ECM蛋白骨涎蛋白（BSP）在骨质形成中的作用；2)通过评估骨桥蛋白（OPN）在牙齿发育中的相互作用，确定ECM蛋白骨桥蛋白（OPN）在牙骨质发育中的功能；3)通过定位磷酸钠共转运体PiT1 （SLC20A1）在牙周发育过程中的表达，并分析PiT1条件缺失小鼠的表型，包括对牙骨质调节因子的影响，确定其在成牙骨质分化和功能中的作用。申请人是一名博士后研究员，他在体外研究成骨质细胞和体内骨质形成，报道了牙齿形成中的磷酸盐/焦磷酸盐代谢，推动了焦磷酸盐控制骨质形成的范式转变，发现了ECM蛋白BSP对骨质矿化的必要性，非常适合领导本研究项目。申请人的长期职业目标是领导一个富有成效的研究项目，为驱动牙根形成和矿化的分子机制提供重要的见解，并将这些见解转化为牙周组织再生和恢复功能的新方法。这个项目是申请人过渡到他的独立研究事业的理想起点，因为它为实现长期目标所需的进一步技能的发展提供了一个框架。拟议的职业发展计划包括教学课程、实验室培训和结构化的指导计划，以促进短期目标的实现，包括开发矿化组织研究的技能，建立独立的研究项目，为教师职位提供途径，并提供未来的机会，以这项拟议的工作为基础。申请人的制度环境在博士后发展和转型领域提供了强有力的支持。

项目成果

Global proteome profiling of dental cementum under experimentally-induced apposition.

实验诱导并置下牙骨质的整体蛋白质组分析。

• DOI: 10.1016/j.jprot.2016.03.036
• 发表时间: 2016
• 期刊: Journal of proteomics
• 影响因子: 3.3
• 作者: Salmon,CristianeR;Giorgetti,AnaPaulaO;PaesLeme,AdrianaFranco;Domingues,RomêniaR;Sallum,EnilsonAntonio;Alves,MarceloC;Kolli,TamaraN;Foster,BrianL;NocitiJr,FranciscoH
• 通讯作者: NocitiJr,FranciscoH

On the discovery of cementum.

关于牙骨的发现。

• DOI: 10.1111/jre.12444
• 发表时间: 2017-08
• 期刊: Journal of periodontal research
• 影响因子: 3.5
• 作者: Foster BL

Standardized assessment of bone micromorphometry around teeth following orthodontic tooth movement : A µCT split-mouth study in mice.

• DOI: 10.1007/s00056-021-00336-9
• 发表时间: 2022-11
• 期刊: JOURNAL OF OROFACIAL ORTHOPEDICS-FORTSCHRITTE DER KIEFERORTHOPADIE
• 影响因子: 1.7
• 作者: Trelenberg-Stoll, Viktoria;Wolf, Michael;Busch, Caroline;Drescher, Dieter;Becker, Kathrin
• 通讯作者: Becker, Kathrin