Extracellular Matrix and Phosphate/Pyrophosphate Metabolism in Cementum Formation

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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.