Extracellular Matrix and Phosphate/Pyrophosphate Metabolism in Cementum Formation

描述（由申请人提供）：覆盖牙根的牙骨质对于牙齿附着、长期稳定性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。该应用程序是一个独立奖提案的途径，旨在通过解决我们目前对牙骨质形成的理解中的差距来推进牙骨质生物学的基础知识，重点关注以下领域：细胞外基质（ECM）蛋白质和局部磷酸盐/焦磷酸盐调节，这些蛋白质和磷酸盐/焦磷酸盐调节对牙骨质形成过程至关重要。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。本研究将通过三个具体的目的来验证这一假设：1）使用无效和条件无效小鼠和体外方法来确定ECM蛋白骨唾液蛋白（BSP）在牙骨质形成中的作用; 2）通过评估ECM蛋白骨桥蛋白（OPN）与焦磷酸盐在牙齿发育中的相互作用来确定OPN在牙骨质发育中的功能; 3）通过定位磷酸钠协同转运蛋白PiT 1（SLC 20 A1）在牙周组织发育过程中的表达，分析PiT 1基因敲除小鼠的表型，包括对牙骨质调节因子的影响，探讨其在成牙骨质细胞分化和功能中的作用。申请人是一名博士后研究员，非常有资格领导这项研究计划，他的培训研究了体外成牙骨质细胞和体内牙骨质形成，报告了牙齿形成中的磷酸盐/焦磷酸盐代谢，推动了关于焦磷酸盐控制牙骨质形成的范式转变发现，并发现了ECM蛋白BSP对牙骨质矿化的必要性。申请人的长期职业目标是领导一个富有成效的研究计划，为驱动牙根形成和矿化的分子机制提供重要见解，并将这些见解转化为再生牙周组织和恢复功能的新方法。该项目是申请人过渡到他的独立研究照顾者的理想起点，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导师计划，以促进短期目标的实现，包括矿化组织研究技能的发展，建立一个独立的研究项目，为教师职位提供途径，并提供未来的机会，以建立这项拟议的工作。申请人的机构环境在博士后发展和过渡领域提供了强有力的支持。

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.