Substantial advances in genetics, developmental biology, bioengineering and materials science have made it possible to realistically contemplate the regeneration of mammalian cells, tissues and even organs. The integration of knowledge and principles from these disparate fields is the proper purview of what is now known as systems biology: the study of complex biological processes in order to understand how individual components combine on a global scale to generate particular biological structures, functions and behaviors. The application of such a systems biology approach to the problem of tooth regeneration will make it possible to pursue a rational rather than an empiric strategy to meet this challenge. Indeed, owing to knowledge of the genetic and developmental pathways involved in odontogenesis, the potential availability of relevant cell types and tissue engineering approaches, and its clinical accessibility, the tooth represents an ideal organ for such an approach. ? ? Under this NIDCR-sponsored P20 Planning Grant, we intend to assemble an exceptionally able, interdisciplinary scientific team whose focused task is to develop a coherent strategy for tooth regeneration. Conceptually, we envision two broad inter-related strategies. The first is to use knowledge of early tooth developmental genetics to effect what can be called """"""""in situ repair"""""""": delivery of key molecules or programmed cells directly to the jaw. The second strategy is to harness a repertoire of multi-disciplinary expertise to build as much of a tooth structure as possible in vitro, followed by engraftment of the incipient tooth into the jaw. Both approaches require a detailed, systems-level understanding of the genetic, developmental, engineering, biophysical, biomechanical and clinical parameters involved. The merits of each approach, the formulation and evaluation of new and unconsidered approaches and the articulation of an optimal Concept Development Plan (CDP) will comprise the major tasks of this P20 Planning group. ? ? To facilitate the P20 planning process, we will undertake three Specific Aims. First, we will hold a regular weekly forum and we will organize a retreat to promote vigorous discussion among the P20 planning and other scientists. Second, based upon these discussions, we will undertake 1 or 2 carefully selected pilot and feasibility projects that are pertinent to tooth regeneration. Lastly, we will prepare the above mentioned CDP. Collectively, this P20 Planning Process should engage an extended scientific community around a single worthy challenge: tooth regeneration. The biomedical implications of such an effort, if eventually successful, would be unprecedented and would have broad ramifications for organ regeneration and repair. ? ? ?