Recent advances in developmental biology, computational and genome science, and tissue engineeringhave made it possible to contemplate the regeneration of mammalian organs. The integration of knowledgefrom these disparate fields now enables the study of how individual components combine on a global scaleto generate particular biological structures and functions. The application of such a systems-basedapproach to the problem of tooth engineering will make it possible to pursue rational rather than empiricstrategies to fabricate a properly differentiated, enamel bearing tooth in vitro. Owing to current knowledge ofthe genetic pathways involved in odontogenesis and its clinical accessibility, the tooth represents an idealtarget organ for the SysCODE Consortium. Like many mammalian organs, the tooth forms via a commondevelopmental mechanism that involves the sequential, ordered exchange of signals between interactingepithelial and mesenchymal cell populations. We hypothesize that this complex, dynamic regulatorynetwork can be resolved at the genetic and ultimately molecular level by the integration of different scientificdisciplines and that this information can be used in the form of a molecular blueprint to design and build atooth. To accomplish this goal, we propose three Specific Aims.
In Aim 1, we will generate a dynamic timeseries of spatially resolved gene expression lists for the interacting epithelial and the mesenchymal cellpopulations that regulate early tooth morphogenesis. These analyses will be expanded to include selectmouse mutants, limited proteomic data for abundant ECM proteins (w/ Project 5), and micromechanicaldesign principles (w/ Project 6).
In Aim 2, in conjunction with the SysCODE Computational Team, we willsynthesize this information into a gene regulatory network (GRN), and with other data, into a molecularblueprint for early tooth development. This will involve the identification and ordering of canonical signalingpathways between dental epithelium and mesenchyme and analysis of transcriptional regulatory networksusing new genomic and computational tools. Lastly, in Aim 3, we will employ tissue engineering platformsdeveloped in Projects 7 and 9 in conjunction with the molecular blueprint and engineering design principlesto direct tooth development in vitro. In sum, this Project has the potential to provide a paradigm for howinterdisciplinary research can address a high impact problem whose solution can transform medicine.
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