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

项目摘要-摘要 成人牙齿脱落是影响大多数美国人的牙病或牙伤的不良后果。 因此，理解这一点成为生物工程师和再生医学科学家的目标和挑战。 自然组织结构生长和形成的基本原理，并应用这些知识来重建 口腔结构1.更好地了解胚胎牙齿是如何发育的，特别是在牙齿的早期阶段 形成(胎盘组织和上皮内陷的启动)是最重要的。这样做的主要目标是 这项研究的目的是了解小鼠门牙胚胎发育的机制。 虽然生化信号启动胎盘形成和定位的过程被很好地描述，2 关于物理线索的时空模式，如细胞产生的力和组织，我们知道的更少 弹性性能，影响牙胚内陷。 假设：细胞张力和组织硬度在空间上的差异(几十微米量级) 推动上皮内陷过程。这个项目的主要创新将是尖端的机械 我将开发和应用的测量技术，以从功能上理解机械贡献 牙胚的形成。我将首先确定上皮力产生在驱动上皮细胞中的功能作用 内陷。其次，我将确定间质在上皮内陷中的机械作用。和 第三，我将在切牙区建立一个小鼠下颌骨的体外模型，以检验两者之间的相互作用 上皮内陷的机械和可溶化学线索。实现这些目标将使我能够 确定发育中的牙胚的机械性能，牙胚的机械性能如何影响和 受信号通路的影响，以及这种相互作用如何促进内陷过程。总而言之，这些 实验将为开发再生医学和组织工程生长策略奠定基础 一颗功能正常的牙齿。 这项奖学金培训计划和进行研究培训的环境将培养我的 作为一名年轻科学家的成长，以及作为一名独立调查员的职业道路。我打算把我的技能提高到 基础生物学和分子生物学。来自化学和物理科学，这一团契经历 会让我沉浸在一个新的环境中，与那些技能与我自己截然不同的人在一起。 我将打造一个新的、多学科的研究方向，并扩大我独特的研究工具箱。我相信这一点 机会将最好地让我研究生物学和固体力学之间的接口。这一组合 研究所、赞助商和项目将加强我作为交叉领域独立研究员和领域领导者的培训。 部门调查。

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.