Enamel is a principal component of the dentition, and defects in this hard tissue are associated with a wide variety of diseases. These include a multitude of relatively rare conditions, such as amelogenesis imperfecta, as well as some that affect a large percentage of the population, such as molar incisor hypomineralisation and caries. They have in common a tremendous impact on the quality of life and cost >$100b/year in the US alone. Even though significant progress has been made in our understanding of the genetic, physiologic and developmental mechanisms that drive the secretion and maturation of enamel, many crucial questions remain unanswered, including the nature of the cellular processes, protein-protein and protein-mineral interactions involved, as well as how the underlying biology determines the biophysical and structural properties of the mineralized tissue. A current hurdle to progress is the need for heightened integration of developmental and cell biological processes with mechanical and physical measurements. In this application, we propose to produce a toolkit of novel genetic mouse reagents combined with a systems-level, multi-scale amelogenesis atlas. We will use both the mouse incisor, an ever-growing tooth that houses large populations of cells at every stage of amelogenesis throughout life, and the mouse molar, which is more similar to human teeth. In Phase I (2 years), we will develop a suite of next-generation mouse reagents and lay the groundwork for the enamel atlas. We focus on genes of interest from the pre-ameloblast, secretory and maturation stages. Professor Joester will be responsible for the following: Aim 1.4: Biophysical atlas of wild type mouse incisor and molar. We will establish best practices for analysis of the structure, elemental composition, and mechanical properties at overlapping length scales from atomic-scale to whole-tooth dimensions, using state of the-art imaging mass spectrometry, electron- and X-ray imaging, and vibrational spectro-microscopy. Thereby, we will create a comprehensive picture of the biophysical properties of enamel. In Phase II (3 years), we will validate the reagents and create the enamel atlas by performing extensive, multi-scale, multi-modality characterization of the effects of disruption of gene function in a spatiotemporally specific manner. Professor Joester will be responsible for the following: Aim 2.2: Proteomic analysis of teeth from mutant mice produced in Phase I. We will compare spatially resolved proteomes of teeth from mutant mice with healthy littermates and the reference model from Aim 1.4. Aim 2.3: Biophysical analysis of teeth from mutant mice produced in Phase I in comparison with those of their healthy littermates, and the reference model from Aim 1.5. By mapping gene expression, specifying local proteomes, and creating metrics for enamel structure, composition, and properties, and by quantitatively assessing the perturbations at each of these levels in mutant mice, we will create a platform that will enable our community of enamel researchers to delineate mechanisms of disease and novel pathways in order to move toward intervention.
|Effective start/end date||8/1/19 → 7/31/24|
- University of California, San Francisco (11549sc // 5UG3DE028872-02)
- National Institute of Dental and Craniofacial Research (11549sc // 5UG3DE028872-02)
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