Spatiotemporal mechanical inhomogeneities in the embryonic oral epithelium and mesenchyme lead to tooth invagination

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Project Summary-Abstract Adult tooth loss is an undesirable consequence of dental disease or injury that affects a majority of Americans. Thus, it has become the aim and challenge of bioengineers and regenerative medicine scientists to understand the fundamental principles by which native tissue structures grow and form, and apply this knowledge to recreate oral structures.1 A better understanding of how embryonic teeth develop, especially at early stages of tooth formation (placode organization and initiation of epithelial invagination), is paramount. The primary goal of this proposal is to understand the mechanisms behind the development of embryonic mouse incisor tooth germs. While the process by which biochemical signaling initiates placode formation and position is well described,2 much less is known about how spatiotemporal patterns of physical cues, such as cell-generated forces and tissue elastic properties, influence tooth germ invagination. Hypothesis: Spatially-defined differences in cell tension and tissue stiffness (on the order of tens of microns) drive the epithelial invagination process. The main innovation of this project will be the cutting edge mechanical measurement techniques that I will develop and apply to functionally understand mechanical contributions to tooth germ formation. I will first determine the functional role of epithelial force generation in driving epithelial invagination. Second, I will determine the mesenchyme mechanical contribution on epithelial invagination. And third, I will create an in vitro model of the mouse mandible at the incisor region to examine the interplay between mechanical and soluble chemical cues on epithelial invagination. Accomplishing these aims will allow me to ascertain the mechanics of the developing tooth germ, how mechanical properties of the germ affect and are affected by signaling pathways, and how this interplay contributes to the invagination process. Altogether, these experiments will lay the groundwork to develop regenerative medicine and tissue engineering strategies to grow a functional tooth. This fellowship training plan and the environment in which the research training will take place will foster my growth as a young scientist, and career path as an independent investigator. I intend to develop my skills in fundamental and molecular biology. Coming from the chemical and physical sciences, this fellowship experience will allow me to immerse myself in a new environment with people whose skillset is very different than my own. I will forge a new, multidisciplinary research direction and expand my unique research toolbox. I believe this opportunity will best allow me to study the interface between biology and solid mechanics. This combination of institute, sponsors, and project will enhance my training as an independent researcher and field leader in cross- sector investigations.